CA2116574A1 - A pharmaceutical exerting antitumor acitivity - Google Patents
A pharmaceutical exerting antitumor acitivityInfo
- Publication number
- CA2116574A1 CA2116574A1 CA 2116574 CA2116574A CA2116574A1 CA 2116574 A1 CA2116574 A1 CA 2116574A1 CA 2116574 CA2116574 CA 2116574 CA 2116574 A CA2116574 A CA 2116574A CA 2116574 A1 CA2116574 A1 CA 2116574A1
- Authority
- CA
- Canada
- Prior art keywords
- tumors
- pharmaceutical
- tumor
- hormone
- ion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
A PHARMACEUTICAL EXERTING ANTITUMORAL ACTIVITY
Abstract The invention pertains to medicine, in particular, to experimental and clinical oncology and may be used for treatment of the hormone-susceptible malignant tumors in women as well as in cases of the neglected oncological process when these tumors have lost their susceptibility to hormones. The proposed pharmaceutical consists of a mechanical mixture of 2-4 g DL-valine and a low non-therapeutic dose of 0.020-0.025 g methyltestosterone for treatment of hormone-susceptible cancer tumors in women and of a mechanical mixture of 2-4 g DL-valine, 0.005-0.010 g methandrostenolone, and 0.3-0.5 g phthivazid for treatment of cancer tumors which have no hormone-susceptibility. The technical result of the application of the proposed pharmaceutical consisis in that even in neglected cases the tumors decrease in size, sometimes to complete resolution, the pain syndrome is relieved completely, the life of incurable patients is prolonged significantly with satisfactory subjective condition, and sometimes with resolution of the tumors. The use of this pharmaceutical is not accompanied by any signs of toxici-ty, it even enhances the resistance of the organism to tumors which is manifested in normalization of hemopoie-sis, weight gain, considerably enhanced working capacity.
The lack of side effects permits it to be used in outpa-tient wards.
Abstract The invention pertains to medicine, in particular, to experimental and clinical oncology and may be used for treatment of the hormone-susceptible malignant tumors in women as well as in cases of the neglected oncological process when these tumors have lost their susceptibility to hormones. The proposed pharmaceutical consists of a mechanical mixture of 2-4 g DL-valine and a low non-therapeutic dose of 0.020-0.025 g methyltestosterone for treatment of hormone-susceptible cancer tumors in women and of a mechanical mixture of 2-4 g DL-valine, 0.005-0.010 g methandrostenolone, and 0.3-0.5 g phthivazid for treatment of cancer tumors which have no hormone-susceptibility. The technical result of the application of the proposed pharmaceutical consisis in that even in neglected cases the tumors decrease in size, sometimes to complete resolution, the pain syndrome is relieved completely, the life of incurable patients is prolonged significantly with satisfactory subjective condition, and sometimes with resolution of the tumors. The use of this pharmaceutical is not accompanied by any signs of toxici-ty, it even enhances the resistance of the organism to tumors which is manifested in normalization of hemopoie-sis, weight gain, considerably enhanced working capacity.
The lack of side effects permits it to be used in outpa-tient wards.
Description
23 ~EEI '94 14:~2 P.6 3 7 '~
,... . .
A PII~RMACEUl'IC~ EXERq'ING A~!~q~U~ OR AC~IVITY
r'he imrentien portain to medicine, ln particular~
to ~;perirnental end olinical oncology and may be u~ad Inor treat~ent o~ the hormone-~en~iti~e malisnant tumor~ in 5 women as ~Yell as in ca~es o~ the neclected oncolo~ical I~ro~e.~.q t~rh~n the~e tllmor~ :lo~ their sQn.~iti~rit~ to hor_ mo~es .
Pharmaceutical~ are l~no~ Yhich in experimsnt~ in ~rit~o e:~ert cytotoxic e~îect~ on e.nim~l and human mali~-10 r.ant cells pre~ent Q~3 ~usp.en~ion~ o~ indi~idllal cell~ inthe culture mediun~ or ~ a c~ll monolayer to ti~us cul-~_ ture (see ~nventor'~ cexti~icate *or in~rention ~o. 7507~37 of 28.03.19~30 A 61 K 31/195 "A pharmaceutical e~ertir antitumor acti~rity in vitro" by ~J.D~ Kislyako~ and 5 co-author9 ).
~ rhe~e are chemical sub~t~lce~ o~ simple composition ~Lnd Enothod~ o~ prep~ration, synthetic D~-~mizlo acid3 po3sessin~ a broad spectruT:I o~ cytotoxic e~ect~ Qn cer-tain hurnan and an~ :nal mal~nant cell~ ~ D~-alanine, DI.-leu-20 c~ne, ~-phenylalanine, DL-~lycine, D~-methionin~, D~-vry-ptophan, and D~-Yaline.
In contrast to others, the ~yntheti¢ arnixlo aoid ...
~-valine in ..he experiment3 in Yltro exerts tlle ~tron~e~t cytotoV~ic ~î~eot on mammalian cancer cells l,~Jithout an~
~~ 25 d~ age o~ non-rlaligIl~nt cells.
ho~rever, the GL~in a~d Yery ~igni~ica:nt shorlcor~inG o~
the above-~lent~ oned drug~, among them DL-vQline ~ con~ist~
i2~ th-3ir capacity to dama~e only indiYidual rns,li~nant cell~
~nd to e::ert no such e~ect in e~?erl~ents in vi~o when 30 thesQ cell~ for:n dense cancer ~iu~ors in ma~rLrnal~. ~hese drug~ are not a~si.:lilated b~J t~:~or ¢~113 a3 readily a~ b~
Iree ~loatin~ cell~ the cullure ~diu~ oontainin~ ther~
There~ore the abo~resaid d~U~ require ccrtain conduotors ~Jhich could a~is l; cancer cell~ o~ den3e tu!TIors in ms~r.rr.~}s : 35 to e.ssi~.ilate thet ~.
Pharmaceutioals are also Irno~m Yrhich we have selec1;ed -- a~ the prototgpe and which exert ~Ln ~tiblastic e~ect on ~ " ~ ~ g ~
23 FEEI ' 94 14: 34 p, 7
,... . .
A PII~RMACEUl'IC~ EXERq'ING A~!~q~U~ OR AC~IVITY
r'he imrentien portain to medicine, ln particular~
to ~;perirnental end olinical oncology and may be u~ad Inor treat~ent o~ the hormone-~en~iti~e malisnant tumor~ in 5 women as ~Yell as in ca~es o~ the neclected oncolo~ical I~ro~e.~.q t~rh~n the~e tllmor~ :lo~ their sQn.~iti~rit~ to hor_ mo~es .
Pharmaceutical~ are l~no~ Yhich in experimsnt~ in ~rit~o e:~ert cytotoxic e~îect~ on e.nim~l and human mali~-10 r.ant cells pre~ent Q~3 ~usp.en~ion~ o~ indi~idllal cell~ inthe culture mediun~ or ~ a c~ll monolayer to ti~us cul-~_ ture (see ~nventor'~ cexti~icate *or in~rention ~o. 7507~37 of 28.03.19~30 A 61 K 31/195 "A pharmaceutical e~ertir antitumor acti~rity in vitro" by ~J.D~ Kislyako~ and 5 co-author9 ).
~ rhe~e are chemical sub~t~lce~ o~ simple composition ~Lnd Enothod~ o~ prep~ration, synthetic D~-~mizlo acid3 po3sessin~ a broad spectruT:I o~ cytotoxic e~ect~ Qn cer-tain hurnan and an~ :nal mal~nant cell~ ~ D~-alanine, DI.-leu-20 c~ne, ~-phenylalanine, DL-~lycine, D~-methionin~, D~-vry-ptophan, and D~-Yaline.
In contrast to others, the ~yntheti¢ arnixlo aoid ...
~-valine in ..he experiment3 in Yltro exerts tlle ~tron~e~t cytotoV~ic ~î~eot on mammalian cancer cells l,~Jithout an~
~~ 25 d~ age o~ non-rlaligIl~nt cells.
ho~rever, the GL~in a~d Yery ~igni~ica:nt shorlcor~inG o~
the above-~lent~ oned drug~, among them DL-vQline ~ con~ist~
i2~ th-3ir capacity to dama~e only indiYidual rns,li~nant cell~
~nd to e::ert no such e~ect in e~?erl~ents in vi~o when 30 thesQ cell~ for:n dense cancer ~iu~ors in ma~rLrnal~. ~hese drug~ are not a~si.:lilated b~J t~:~or ¢~113 a3 readily a~ b~
Iree ~loatin~ cell~ the cullure ~diu~ oontainin~ ther~
There~ore the abo~resaid d~U~ require ccrtain conduotors ~Jhich could a~is l; cancer cell~ o~ den3e tu!TIors in ms~r.rr.~}s : 35 to e.ssi~.ilate thet ~.
Pharmaceutioals are also Irno~m Yrhich we have selec1;ed -- a~ the prototgpe and which exert ~Ln ~tiblastic e~ect on ~ " ~ ~ g ~
23 FEEI ' 94 14: 34 p, 7
2 ~ ~ ~ J ~ '1 . ~ .
the hormon~-~en~itlve ~Qli~n~nt tumor~ i~ women~ mammary gland cancer a~d o~ry cancer tSee I;~.as~oV~ky, ~;D. in "Ph~rrnaceuticsl~ JîedlZinQt' Publishar~, t"~,, 1985, part I, p~ 5'~-603 and part II, p~ 470-471~. ~h~ are ~yiit~-tically obtain~d 3teroid hormone~, deri~ative~ oi a ~trong androgen, te~to~terone, th~ male ~ex hormone~ ~non~ these pharmaceutical3, the followin~ have ~ound th~ wide~ cli-nical applioation ~or trcatment o~ hormone-~u~coptible mammary ~land c~ncer Qnd o~ary c~ncer ~n wo~en: testo-~terone propionQte, medrote~trone propionate (or 2cC-~e-thyldihydrote~to~terone), prolote~tone ~a ln~tU~e of' 204-~ethyldihydrotesto3teron~ ether3~. Oil ~olu~ion~ o~
the~e dru~s ~re inoculated intrar.~u~culax~ly~ In ~0l1~-te~n treatrnent, ~ometlme~ another derivative to ta3to~ terone, tnethyltesto~teron~, ~s given becau~e it- hQ~ a ~eQker ant~-blastic eD~ect but i~ Qd~antQgeous becau~e o~ it~ oral ~sublin~ual) adt~lni3tration. All the3e hormones~Qre u3ual-ly ~dm~n~tered in ~ery lar~e dc~s ~rom 50 to~:100 m~
daily, and are u~ed mainly in highly advanced ~tages ~ th 20 met~t~se~ of mammary gl~nd ~nd o~ary canc~rn~ ll th~
~bove-~e~tioned d~u~3, bein~ te~to3terone d~rlvati~e~, e~.srt a ~ore or les~ mark~d andro~enlc ef~ec~ on ~he ~e-m~le or~s~, r~ul'cin~, a~ter a long-ter~ tre~t~nent with large dose~, in sever~.~ide-e~ct~, the de~elopr~ent ~' Z5 oi.general to:~lcity le~dln~ to th~ ~ollo~.vin~ côm~licat-ion~s di~turbance.o~ wator-electrolyt~ met~olI~ xo di~orde~ in the ~unotion~ o~ th~ er, ~idna~., he~rt, hypercalc~rqi~ ~ndrome, a3 ~.7C~ noth~r ~Qt'O~ CmP~
lication ~or wornen~ na OL ~irillsm ~oci~ed with Q
h~h libido.
~or tho ~ fication o~ the ~ntitu~or e~fec~ the~
pharm~ceutical~ were or~inally t~ted e~p~ir.lental rat3 with D~.~A-induced ~nary ~l~nd cancer by 3uboutQneou~ or I intramu~cular in~ec~ion~ oi oil ~olution~ o~ the dru~ in ¦ 35 a doae o~ 2-3 mg daily per ~ rat wei~hins 150-200 ~, that bout 15 In~ bod~ woi~ht t~e Be~kro~nt, A.~ 'Anti-tumor e~icao~ o~ hor~one~ in mammar~ gland cencer i9 rat3", Vopro~ oncologii, 1971, ~. XVII, ~o. 9, p~ 95 98).
1. .
.
.. . . . . . . .................. . .. .. . . . . . .
. . . : : ., . ,~- .. . .. ~ .,-, -23 FE~3 ' 94 14: 35 P . E3 2 ~ 7 ~
~o the same group o~ antitumor drugs belollg~ methylte~to_ sterone adminlstered or~lly tho ant~blasti¢ eY~ect o~
YJh~ch i~ 2-3 time~ we~ r than that o~ oil-~oluble t~sto-sterone deri~ati~es; there~ore it~ experimcnt~l the~pou-ti¢ dose i~ about 25-~0 m~/lcg per day.
De~pite their antltumor e~fect on the ho~nono~~u3-ceptible induced ma~n~ry ~lQnd c~noer in rat , all the3e ~ynthetic deriYQtives o~ testo~terone revo~lod in th~
experiTnents a num~er o~ signi~ic~nt shortcomin~J
1~ 1. In the pre~ence o~ sQveral cQncer ~no~ o~ ~he Taa~n~r~ ~land in ono animal, mainly 3mall "arldition~
._ ¢~cer tumorq undentent resolu~ion ~Jhcre~ the '~nuin~
tumor~ which had achie~d Q controllebl3 ~i~e o~ ~bout ~.0 cm3 vlere con3ido~bly more re~ist~nt to the ~r~at-ment~ .
2. Re~1~e~sio~ o:~ tile tu~nor~ in many ca9~ did ~iot procecd to ~h~ erd, and ~nocul~t~on o~ the dl~,3 sa~ulted only ~n th~ i~hibition o~ thc ~rowth, ~ ret;li3~0~, ~ol-lowe~ by new irre~er~ible ~ro~vth o~ the ~ame tumor~.
the hormon~-~en~itlve ~Qli~n~nt tumor~ i~ women~ mammary gland cancer a~d o~ry cancer tSee I;~.as~oV~ky, ~;D. in "Ph~rrnaceuticsl~ JîedlZinQt' Publishar~, t"~,, 1985, part I, p~ 5'~-603 and part II, p~ 470-471~. ~h~ are ~yiit~-tically obtain~d 3teroid hormone~, deri~ative~ oi a ~trong androgen, te~to~terone, th~ male ~ex hormone~ ~non~ these pharmaceutical3, the followin~ have ~ound th~ wide~ cli-nical applioation ~or trcatment o~ hormone-~u~coptible mammary ~land c~ncer Qnd o~ary c~ncer ~n wo~en: testo-~terone propionQte, medrote~trone propionate (or 2cC-~e-thyldihydrote~to~terone), prolote~tone ~a ln~tU~e of' 204-~ethyldihydrotesto3teron~ ether3~. Oil ~olu~ion~ o~
the~e dru~s ~re inoculated intrar.~u~culax~ly~ In ~0l1~-te~n treatrnent, ~ometlme~ another derivative to ta3to~ terone, tnethyltesto~teron~, ~s given becau~e it- hQ~ a ~eQker ant~-blastic eD~ect but i~ Qd~antQgeous becau~e o~ it~ oral ~sublin~ual) adt~lni3tration. All the3e hormones~Qre u3ual-ly ~dm~n~tered in ~ery lar~e dc~s ~rom 50 to~:100 m~
daily, and are u~ed mainly in highly advanced ~tages ~ th 20 met~t~se~ of mammary gl~nd ~nd o~ary canc~rn~ ll th~
~bove-~e~tioned d~u~3, bein~ te~to3terone d~rlvati~e~, e~.srt a ~ore or les~ mark~d andro~enlc ef~ec~ on ~he ~e-m~le or~s~, r~ul'cin~, a~ter a long-ter~ tre~t~nent with large dose~, in sever~.~ide-e~ct~, the de~elopr~ent ~' Z5 oi.general to:~lcity le~dln~ to th~ ~ollo~.vin~ côm~licat-ion~s di~turbance.o~ wator-electrolyt~ met~olI~ xo di~orde~ in the ~unotion~ o~ th~ er, ~idna~., he~rt, hypercalc~rqi~ ~ndrome, a3 ~.7C~ noth~r ~Qt'O~ CmP~
lication ~or wornen~ na OL ~irillsm ~oci~ed with Q
h~h libido.
~or tho ~ fication o~ the ~ntitu~or e~fec~ the~
pharm~ceutical~ were or~inally t~ted e~p~ir.lental rat3 with D~.~A-induced ~nary ~l~nd cancer by 3uboutQneou~ or I intramu~cular in~ec~ion~ oi oil ~olution~ o~ the dru~ in ¦ 35 a doae o~ 2-3 mg daily per ~ rat wei~hins 150-200 ~, that bout 15 In~ bod~ woi~ht t~e Be~kro~nt, A.~ 'Anti-tumor e~icao~ o~ hor~one~ in mammar~ gland cencer i9 rat3", Vopro~ oncologii, 1971, ~. XVII, ~o. 9, p~ 95 98).
1. .
.
.. . . . . . . .................. . .. .. . . . . . .
. . . : : ., . ,~- .. . .. ~ .,-, -23 FE~3 ' 94 14: 35 P . E3 2 ~ 7 ~
~o the same group o~ antitumor drugs belollg~ methylte~to_ sterone adminlstered or~lly tho ant~blasti¢ eY~ect o~
YJh~ch i~ 2-3 time~ we~ r than that o~ oil-~oluble t~sto-sterone deri~ati~es; there~ore it~ experimcnt~l the~pou-ti¢ dose i~ about 25-~0 m~/lcg per day.
De~pite their antltumor e~fect on the ho~nono~~u3-ceptible induced ma~n~ry ~lQnd c~noer in rat , all the3e ~ynthetic deriYQtives o~ testo~terone revo~lod in th~
experiTnents a num~er o~ signi~ic~nt shortcomin~J
1~ 1. In the pre~ence o~ sQveral cQncer ~no~ o~ ~he Taa~n~r~ ~land in ono animal, mainly 3mall "arldition~
._ ¢~cer tumorq undentent resolu~ion ~Jhcre~ the '~nuin~
tumor~ which had achie~d Q controllebl3 ~i~e o~ ~bout ~.0 cm3 vlere con3ido~bly more re~ist~nt to the ~r~at-ment~ .
2. Re~1~e~sio~ o:~ tile tu~nor~ in many ca9~ did ~iot procecd to ~h~ erd, and ~nocul~t~on o~ the dl~,3 sa~ulted only ~n th~ i~hibition o~ thc ~rowth, ~ ret;li3~0~, ~ol-lowe~ by new irre~er~ible ~ro~vth o~ the ~ame tumor~.
3. I~ a ~ynthetic andro~en produced coT~plste re~-re~.on of the t~tlor~ re~p~ o~ th~ tumor ~rowth were lator observ~d on th~ sams site.
4, Rep~ated u~o of th~ ~ynth~tic Qndro~e~ ~vhich had ori~al~y ¢aused regre~-lon for ;tre~tr.lent o~ ~e~rly fro~?r-~næ tumor~ ter r~mi~ion.ox ~31QP~Ln~ tUmO1~ producad no ~nti.t~o~ e~fcct, that i3, su3coptibillt~l to t1l~s dru~
was lo~t aorapletely.
was lo~t aorapletely.
5. ~Yl~h three oll-~olu~le te~o~terone deri~a'i~
te~to~teronc propionate, 2 ~-~e~h~ld-lh~droto~to~terone propionate, and 2d~ -msthyldihydrote~to3~erone, mor~ acti~
~e than me~hylte3~0sterone, the par c~nt o~ ~en2ral reg-~e~sion o~ all tumor~ wa~ ~0%, 70% and ~0~0, re~pectiYel~, per ccnt of comp~et~ regres~ion (disQppear~nce o~ tumor) 10%, 50~0 end~20%1 re~p~c~ivelg, and per c~nt o~ partial ~5 decre~e of tumors 30~ 20~o Qnd 60pg r~spooti~ely,~ for each `~
;~ d~u~ a~ter 30 d~J~ o~ &dr.~ini~tration~ ~or ~n e~ec~i~e~sn- :
tltumor ao~ion the~e ~alue~ ~re low~ tllero w~r~ 60^~, 30~o . ,.
...... _ Z3 FEB ' 94 14: 37 P . 9 2 ~
..... _ ~ ~ .
and 20~' o~ tumora which did not re&r~s ~t ~ 'or ~a¢h prapa~ation, r~specti~ely.
rl~ ~n~ into account all the abo~e-mention~ ortcom-~ 9 0~ th~ pro~ot~pc~ we propo~e a now pharmaceutioal producin~ ~ hi~h cl~nlca~ e~ct.
~ le p~armac~uticQl exhibiting the Qnt~tumor acti~ity consi~ts o~ a mech~nical mixturs o~ 2-4 g o~ D~-valin~ an~
low nonth~r~ uti~ do~a ~0.020_0. 025 ~3) methyta~to~t~t~o~
~or u30 in ca~3c~ o~ horrlon~-~u3c~3ptiblo cancer tumor~ ln lo ~tomsn ~nd o~ a mech~nical m~xture o~ o~ DL-~Qllna, 0,005~0~010, of' m~thandro~tenolo~e, and 0,3-0.5 ~ o~
p~thi~a~id ~or u~e.ln oa~o~ G~ c~ncer tumo~ not ~u~a~p~
tible to horrnone~
Thu~, the in~en~ion i~ ncw bccausc it i~ unlmoY~ ~t ~5 the current level o~ med~cine deYelopmont. i~h~ in~nt~a level o~ the propo~ed ph~rmaceut~cal po~e~ing ntitumor ~cti~it~ doe~ not clearly ~ollo~r ~ror~ the lsvel o~ de~e-lopment o~ current chemot~erapy o~ the hor~on~-~u~ceptibLe malignant ~umors in worlen tt~e prototypo).'~.$he i~ention ma~ p~acticall~ be u~ed on a largs rc~le ~or.succe~ul therap~l in outpatient ~Jarcl~ o~ hormone-su~ceptible malig-nanttumor~ in women, ~ve~ ar adYanced csa~e~, when thi3 ho~one-~u~ceptibillty rnay b~ coTnpl2tely lost ~nd all ~h~
con~entional m~thod~ o~ chemo-hormone-the~apy becol~e ir.
~_ 25 ~L~ecti~o.
~ he ~ucces~ul application o~ ths n ~ harmacautical may be due ~o it~ ~tron,~ anti~la~tlc prop~r-t~es, it~ effec-tive action b~in~ completely ha~nl~, a~ its pro-p~rty to enh~nce the p~tient 13 de~ence forc~ ~nd ~o ~er~
a ~trong anal~etic e~ect.
~ he es3ence o~ the in~ention i3 pro~nted by the en-t~rety o~ the e~entlal ~eatur~ su~icient ~or th~ achie~
~ement o~ thc nece~&ry result.
~ or theoretical sub3tant~at~0n o~ the proport~a~ of tha ~lle~ed pharmaceut~cal and con~l~mQtion o~ the no~elt~
~nd th~ inven~e lev~l o~ the propo3ed invention, th~ new antitu~or dru~ W~3 tcsted experimentall~.
`""' '' ' ;'~ ' , , . , .: . , . , i , . ~
Z3 FEB '94 14:3~ P.10 ~Yhon u~od Yor ~ro~,tlr.~nt a:e hormon~ u~ilcePt1~
induced m~mn~r~ ~lan~ cancer tumor~ in ~om3le rats, the proposod pharmaceut~c~l consists o~ ~ msohanical ~i~.ture o~ 500-550 mg of synthetic ~m~no acld D~-~aline ~ld a low non-ther~poutic do~e of 5-20 m~ methylte~tostero~e Per kilo body wei~;ht of tho aniT~al administered daily by the oral route; in oa~es o~ lon~ ~rowin~ m~mary gland cun-cer tumor~ in rat~ Y~th lo~t hormone-~u~ceptibillty tho new antitu~or drug con~l~t~ o~ ~ mecha~ical mi~ture o~
500-550 ~ DL-valina , 20-25 mg o~ ~abolic hormone Meth~ndrostenolone, and 40-50 m~ phthiv~id per 1 k~ ~o-dy weight per` day.
In all ~er~io~3 of the ~ev~ antitumor dru~ ~pplic~t-ion it i~ ~ecessary to keep a prote~n-rich and ~t-poo~
diet.
~ he e~perim~ntal data obt~ined in the ~tudie~ of the inmo~t meohanisms o~ th~ ~ntibla3tic e~ect on canc~r t~mor~ o~ ~he.ne~ anti~umor dru~ i~ the form o~ mechan~o ; mi~tUrB3 0~ aminO a~id ~L-V~ e ~nd 10YJ no~-therap~uti~
2~ do~e~ of andro~cn~ - m~th~lte~to3tero~a or met~l2ndxo~tsno- ' -lone (an an~boli¢ with very waak ~n.dro~enio propertie~) I ~howed tha medi~tory role of the3e hor~ones ~or D~-valine ! required fox t~e a~imilation thereo~ by c~ncer c~ or-¦ min~ don~e tu~or~ ~n ma~nal~.
~he li~it quanti~ati~e ~alue~ o~ the ~nlxuure co~po~
nonts depe~d on the degree o~ act$vity o~ ~he en~ire ~n~
tumor prepar~t~on. A~ ~hoYm by the expe~ ental ~tudie.s, the optimal do~c of D~-vnline is 550 m~Jk~ 3 decre~e . to 500 m~/k~ has no snEluenc~ on ~t~ e~ect, nc~Sther doa~
Fs ~urther incre~e o~' the do~e, ~or in3tance b~ 2--old, A decreas~ o~ D~-vallna do3e belo~ 500 ~g~kg wors~n~ the ~ntibl~stic ef~eot o~ the mi~ure and with Q.do~ 2-lolA
lower than the optim~l ~275 m~fkg) thS3 regres~ion e~eet dicappear~ ¢ompletely~ ~he non-therapeuti3 do~e o~ ;nath~rl-testo~terone o~ 5 m,~ per kilo body ur~ight i~. combin~tlon i with ~L-valin~ giY3~ the optimal antibl~s~ic e~ct on . ir~uced c~ncer tumor~ of the ~lz~ of 4.0 cm3 to 6.0 _~3 ulhich stlll have Yery h~gh ho~mone-ssu~GeptibSlit~ l','ith :
.`
~` ~ A~ r 23 FE13 '9'1 14:40 P.ll ~ ~ C ~ ~ 7 ~
..... _~
te~to~teronc propionate, 2 ~-~e~h~ld-lh~droto~to~terone propionate, and 2d~ -msthyldihydrote~to3~erone, mor~ acti~
~e than me~hylte3~0sterone, the par c~nt o~ ~en2ral reg-~e~sion o~ all tumor~ wa~ ~0%, 70% and ~0~0, re~pectiYel~, per ccnt of comp~et~ regres~ion (disQppear~nce o~ tumor) 10%, 50~0 end~20%1 re~p~c~ivelg, and per c~nt o~ partial ~5 decre~e of tumors 30~ 20~o Qnd 60pg r~spooti~ely,~ for each `~
;~ d~u~ a~ter 30 d~J~ o~ &dr.~ini~tration~ ~or ~n e~ec~i~e~sn- :
tltumor ao~ion the~e ~alue~ ~re low~ tllero w~r~ 60^~, 30~o . ,.
...... _ Z3 FEB ' 94 14: 37 P . 9 2 ~
..... _ ~ ~ .
and 20~' o~ tumora which did not re&r~s ~t ~ 'or ~a¢h prapa~ation, r~specti~ely.
rl~ ~n~ into account all the abo~e-mention~ ortcom-~ 9 0~ th~ pro~ot~pc~ we propo~e a now pharmaceutioal producin~ ~ hi~h cl~nlca~ e~ct.
~ le p~armac~uticQl exhibiting the Qnt~tumor acti~ity consi~ts o~ a mech~nical mixturs o~ 2-4 g o~ D~-valin~ an~
low nonth~r~ uti~ do~a ~0.020_0. 025 ~3) methyta~to~t~t~o~
~or u30 in ca~3c~ o~ horrlon~-~u3c~3ptiblo cancer tumor~ ln lo ~tomsn ~nd o~ a mech~nical m~xture o~ o~ DL-~Qllna, 0,005~0~010, of' m~thandro~tenolo~e, and 0,3-0.5 ~ o~
p~thi~a~id ~or u~e.ln oa~o~ G~ c~ncer tumo~ not ~u~a~p~
tible to horrnone~
Thu~, the in~en~ion i~ ncw bccausc it i~ unlmoY~ ~t ~5 the current level o~ med~cine deYelopmont. i~h~ in~nt~a level o~ the propo~ed ph~rmaceut~cal po~e~ing ntitumor ~cti~it~ doe~ not clearly ~ollo~r ~ror~ the lsvel o~ de~e-lopment o~ current chemot~erapy o~ the hor~on~-~u~ceptibLe malignant ~umors in worlen tt~e prototypo).'~.$he i~ention ma~ p~acticall~ be u~ed on a largs rc~le ~or.succe~ul therap~l in outpatient ~Jarcl~ o~ hormone-su~ceptible malig-nanttumor~ in women, ~ve~ ar adYanced csa~e~, when thi3 ho~one-~u~ceptibillty rnay b~ coTnpl2tely lost ~nd all ~h~
con~entional m~thod~ o~ chemo-hormone-the~apy becol~e ir.
~_ 25 ~L~ecti~o.
~ he ~ucces~ul application o~ ths n ~ harmacautical may be due ~o it~ ~tron,~ anti~la~tlc prop~r-t~es, it~ effec-tive action b~in~ completely ha~nl~, a~ its pro-p~rty to enh~nce the p~tient 13 de~ence forc~ ~nd ~o ~er~
a ~trong anal~etic e~ect.
~ he es3ence o~ the in~ention i3 pro~nted by the en-t~rety o~ the e~entlal ~eatur~ su~icient ~or th~ achie~
~ement o~ thc nece~&ry result.
~ or theoretical sub3tant~at~0n o~ the proport~a~ of tha ~lle~ed pharmaceut~cal and con~l~mQtion o~ the no~elt~
~nd th~ inven~e lev~l o~ the propo3ed invention, th~ new antitu~or dru~ W~3 tcsted experimentall~.
`""' '' ' ;'~ ' , , . , .: . , . , i , . ~
Z3 FEB '94 14:3~ P.10 ~Yhon u~od Yor ~ro~,tlr.~nt a:e hormon~ u~ilcePt1~
induced m~mn~r~ ~lan~ cancer tumor~ in ~om3le rats, the proposod pharmaceut~c~l consists o~ ~ msohanical ~i~.ture o~ 500-550 mg of synthetic ~m~no acld D~-~aline ~ld a low non-ther~poutic do~e of 5-20 m~ methylte~tostero~e Per kilo body wei~;ht of tho aniT~al administered daily by the oral route; in oa~es o~ lon~ ~rowin~ m~mary gland cun-cer tumor~ in rat~ Y~th lo~t hormone-~u~ceptibillty tho new antitu~or drug con~l~t~ o~ ~ mecha~ical mi~ture o~
500-550 ~ DL-valina , 20-25 mg o~ ~abolic hormone Meth~ndrostenolone, and 40-50 m~ phthiv~id per 1 k~ ~o-dy weight per` day.
In all ~er~io~3 of the ~ev~ antitumor dru~ ~pplic~t-ion it i~ ~ecessary to keep a prote~n-rich and ~t-poo~
diet.
~ he e~perim~ntal data obt~ined in the ~tudie~ of the inmo~t meohanisms o~ th~ ~ntibla3tic e~ect on canc~r t~mor~ o~ ~he.ne~ anti~umor dru~ i~ the form o~ mechan~o ; mi~tUrB3 0~ aminO a~id ~L-V~ e ~nd 10YJ no~-therap~uti~
2~ do~e~ of andro~cn~ - m~th~lte~to3tero~a or met~l2ndxo~tsno- ' -lone (an an~boli¢ with very waak ~n.dro~enio propertie~) I ~howed tha medi~tory role of the3e hor~ones ~or D~-valine ! required fox t~e a~imilation thereo~ by c~ncer c~ or-¦ min~ don~e tu~or~ ~n ma~nal~.
~he li~it quanti~ati~e ~alue~ o~ the ~nlxuure co~po~
nonts depe~d on the degree o~ act$vity o~ ~he en~ire ~n~
tumor prepar~t~on. A~ ~hoYm by the expe~ ental ~tudie.s, the optimal do~c of D~-vnline is 550 m~Jk~ 3 decre~e . to 500 m~/k~ has no snEluenc~ on ~t~ e~ect, nc~Sther doa~
Fs ~urther incre~e o~' the do~e, ~or in3tance b~ 2--old, A decreas~ o~ D~-vallna do3e belo~ 500 ~g~kg wors~n~ the ~ntibl~stic ef~eot o~ the mi~ure and with Q.do~ 2-lolA
lower than the optim~l ~275 m~fkg) thS3 regres~ion e~eet dicappear~ ¢ompletely~ ~he non-therapeuti3 do~e o~ ;nath~rl-testo~terone o~ 5 m,~ per kilo body ur~ight i~. combin~tlon i with ~L-valin~ giY3~ the optimal antibl~s~ic e~ct on . ir~uced c~ncer tumor~ of the ~lz~ of 4.0 cm3 to 6.0 _~3 ulhich stlll have Yery h~gh ho~mone-ssu~GeptibSlit~ l','ith :
.`
~` ~ A~ r 23 FE13 '9'1 14:40 P.ll ~ ~ C ~ ~ 7 ~
..... _~
- 6 -~urther growth o~ the tumors the horl~one-~u~ceptibilit~
docllnes, ~nd ~or tumor ~i~9~ over 6.o cm3 up;~o B~10 cm3 it w~a~ ~ound better to u3e D~-valine in col~blnatio~ Wit}l methylte~to~terone, 10 m~/kilo bod~ r~ei~ht.
~he~e optimal do~e~ o~ meth~lt~tosterone are con-~ider~d to be nontherapeutic becau~e they aloncl without DI-valine, cau~e no re~res~ion or aven lnhibition o~ the gxo~th o~ the hormo~-euscept~,ble mar.lm~r~ nd cuncer tumor~ in ra~ ethylte~to~terone alone cause re~r~-~ion o~ ~ch ~xperiment2l tumor3 only be~inn~n.~; ~ith a dose o~ 25 m~lc~ body wei~ht, and re~re~on ~3 thi~ ca~e ~ho~3 ~11 the abo~e-mentloned ~hortcomlng~ o ~t~ anti-blastic e~ec~ o~ oil-solublo testo~t~rone ~ do~ri~rs,ti~re~ ~
tth~ prototype), Accordins to our data, tho m~chanica 15 mixture o~ ~-Yaline ~th 25 m~fl:~ methyltesto~t~rone has l;h~ ne sho~tcomi.n~ o~:' tih~ ~ntlbla~ l;ic e~ ec~ but le~s marl~ed th~ in the proto1i~yp~. ~ do~e o~ methglte~tostaro-no belo~r 5 ~k~ ¢ombinatlon ~rith D~ rQ1i~e produce3 a 3~ icantlS~ 1O~;Jer ro~re3~ion o~ tlle hormolie~u3cep-20 tible cancer twnors in rat3.
In exper~ment~ uritll sim~lar lon~-tar~ gro~nz tu~or3 1~ or~3 or l~r~er in ~i~e whioh have parti~llg or comple~e-l~r lo~t their andro~an ~u~oeptibll~tiy a ~och~nio~l mixtu-re of DI-v~lina ~Jith ar.other ~ery weak ~ndroon, ~oth~-Z5 drostenolone, in a do~e o~ 20-~ m~ body ~l~ht wa~
~ound to b~ optimal. A 2-fold cl~cre~e o~ tha~do~e tl2~5 mg~kg) in mi~ture ~th D~-val~no lnst~ad o~ ~ære~3ion o~u~ed ln~igni~iaant i~l~b~.tion o~ $row~h of ~h~a c.~ncer twmor~ Qnd an incroa~ ~ad no e~Lect on tho X~.sulta.
Ho~e~er, re~e~ion o~ e;c~erimont~l c~ncer tumor3 in r~t~`tr~at~d ~r th ~ mi:~ture o~ D~-v~line ~rith tne-th~-drostenolone ~lone wa~ e~l;rer.l~ly ~low, ~o t~at in 30 da~J~
o~ the experiment ~11 the t~nor~ re~re~ed only by 30~_ 71~ o~ its original ~ze~ ~nd on the aver~se by only 52C~o (~ble 1), PhthiYa~d, ~ kno.~ dru~ for tub~rculo~is r~ith a ~on~ m~ brano~ropic ef~ect, ~l~s ~oun~ to be capQbl~ to incre~o con3iderabl~ th~ conductivi~y o~ DT~ llne by .. . . ... ......
~3 FE13 '94 14:42 P.12
docllnes, ~nd ~or tumor ~i~9~ over 6.o cm3 up;~o B~10 cm3 it w~a~ ~ound better to u3e D~-valine in col~blnatio~ Wit}l methylte~to~terone, 10 m~/kilo bod~ r~ei~ht.
~he~e optimal do~e~ o~ meth~lt~tosterone are con-~ider~d to be nontherapeutic becau~e they aloncl without DI-valine, cau~e no re~res~ion or aven lnhibition o~ the gxo~th o~ the hormo~-euscept~,ble mar.lm~r~ nd cuncer tumor~ in ra~ ethylte~to~terone alone cause re~r~-~ion o~ ~ch ~xperiment2l tumor3 only be~inn~n.~; ~ith a dose o~ 25 m~lc~ body wei~ht, and re~re~on ~3 thi~ ca~e ~ho~3 ~11 the abo~e-mentloned ~hortcomlng~ o ~t~ anti-blastic e~ec~ o~ oil-solublo testo~t~rone ~ do~ri~rs,ti~re~ ~
tth~ prototype), Accordins to our data, tho m~chanica 15 mixture o~ ~-Yaline ~th 25 m~fl:~ methyltesto~t~rone has l;h~ ne sho~tcomi.n~ o~:' tih~ ~ntlbla~ l;ic e~ ec~ but le~s marl~ed th~ in the proto1i~yp~. ~ do~e o~ methglte~tostaro-no belo~r 5 ~k~ ¢ombinatlon ~rith D~ rQ1i~e produce3 a 3~ icantlS~ 1O~;Jer ro~re3~ion o~ tlle hormolie~u3cep-20 tible cancer twnors in rat3.
In exper~ment~ uritll sim~lar lon~-tar~ gro~nz tu~or3 1~ or~3 or l~r~er in ~i~e whioh have parti~llg or comple~e-l~r lo~t their andro~an ~u~oeptibll~tiy a ~och~nio~l mixtu-re of DI-v~lina ~Jith ar.other ~ery weak ~ndroon, ~oth~-Z5 drostenolone, in a do~e o~ 20-~ m~ body ~l~ht wa~
~ound to b~ optimal. A 2-fold cl~cre~e o~ tha~do~e tl2~5 mg~kg) in mi~ture ~th D~-val~no lnst~ad o~ ~ære~3ion o~u~ed ln~igni~iaant i~l~b~.tion o~ $row~h of ~h~a c.~ncer twmor~ Qnd an incroa~ ~ad no e~Lect on tho X~.sulta.
Ho~e~er, re~e~ion o~ e;c~erimont~l c~ncer tumor3 in r~t~`tr~at~d ~r th ~ mi:~ture o~ D~-v~line ~rith tne-th~-drostenolone ~lone wa~ e~l;rer.l~ly ~low, ~o t~at in 30 da~J~
o~ the experiment ~11 the t~nor~ re~re~ed only by 30~_ 71~ o~ its original ~ze~ ~nd on the aver~se by only 52C~o (~ble 1), PhthiYa~d, ~ kno.~ dru~ for tub~rculo~is r~ith a ~on~ m~ brano~ropic ef~ect, ~l~s ~oun~ to be capQbl~ to incre~o con3iderabl~ th~ conductivi~y o~ DT~ llne by .. . . ... ......
~3 FE13 '94 14:42 P.12
- 7 -~etha~dro~tenolon~ ~nto th~ cells o~ lo~-term ~ro~ng den~e tumor~ ol rat ma~nary ~lQnds. rl'he optim~l do~ o~
phtllivnæld ~a~ ~ound cmplrlcall~ to b~ 45-50 ~k~ bod~
wo~ht. A co~sidera~le ~ncrea~e or dccre~ o~ the do~e eith~r does not af~eo~ th3 tumor growth or may even ~nhan-c~ it.
~'able 1 A phr~aceutical e~ertin~ antotumor~l acti~lty ~ ite random-bred ra~ ~th induoed m~mnary glQnd cancer.
~reatme~t: D~aline (550 m~tkg) ~nd methandro-~~ ~tenolone ~25 m~ ) in com~ari~on with untre~ted t~nor-bo&ri~ ~nim~13 (condi-tional tumor size~ in cm3) 15 ~,~ Initial I n t e r v a 1 9 I~o. dat~ Je~lc 2 ~leek~. 3 weelss 4 ~q~
CON~RO~ GROUP ~untrea~d) 1 4 7,~ 20.2 37.3 died 2 ~9 5.7 7.0 .13.3 20~
20 3 a~ 6,o10,2 16.0 25~1 d~ed b) 5,05vO 5.3 B.2 4 5.16.6 7.l 7.~ ~.0 ; 5 7-312.5 19,0 30.2 42.0 ..
6 a.o9.6 20,0 ~6.0 di~d 25 7 ~,84,5 9.5 14.2 23.0 . 56 ~ 2 7 ~ 3 1 0. 3 t~h 5,.3~.7 11~6 ~n.2 20.7 ~ean and ~ariat-- io~ ran- .
30 ~ 3.~-~.0 4.5-1~.5 5.3-~0 7.~-37.3 a.O-42~0 P: compari~on <~0.05 <0.01 <0.01 <0.01 ~th lniti~
,~
P R O G P. E S S I O IT
. ' ~::
. ~
23 FE~3 '94 14: 43 P. 13 ~_ 2~3 ~3 ~1 ~
Tablc 1 ~cont~nued) : :~
R~t~. Initi~l I n t e r ~ a 1 s .~,, No, tlata 1 r~ek 2 weëk~ 3 weelc~ 4 ll;e~Ls ~ re~
re~-~o~
EXP~I?.~ r~ I, GROUP (DIJ~ ne L~nd metllandro~
~tenolon~ ) 4D6 ~4 3.4 2"1 2~0 56 210.5 11.2 6,9(nec- 6.1 5~ 52 ro-35.5 5.7 ~7 2.8 . ~ 2~3 ~o 4 7,2 3.4 ~.6 2.7 ~ 2,1 71 55.2 ~.0 2.~ 2,5 ~ 2.~ 57 61.7 5.8 5.5 5.8 ~ 5.5 30 7G.6 6.3 5.6 ~.6 4,2 36 6.3 ~,0 .~0 4,3 , 3.3 50 1~ 9 4.5 3.7 3,6 2.8 ~i 2.0 53 mo 1;~ o 6. 5 5. 3 ~ ~ 3- 7 ~ ?,. ~ 52 moan . . . . ~.
ana VQ~
ria~ion 4 ~j 3~0 11,2 2~-649 2.~-6.1, 30-71 P - ~>o,05 <0,05. <0,01 -. ~0.
. 2 0 . PL E ~ P~ E S S I 0 P - corapar~on o~ eaeh ~r~e~: witll th~`~it~l da~a.
oompars.t~e analg~ w~th th~ pr7~otyp~ - oil-~olub-1~ synthe~lc te~-.,ost~rons dcriYati~s~ ~lnisterad ~ n-t0r~ donc on the baæi3 o:f th~ Rxpo~m~ntal d~ta sho-25 ~Jed the ne~r s,ll.e~,Gd ant~tur.~or dru,s,r to b~ Ri~;nilicantl~r erent Irom t}la kno~vn on~
1~ ~rl~ alle~ea antitumor dru~; e~rl~ the anti~la~ tic e~Ieot b~ t}lo close interaction of 2 componenl;~ OI a rnech~-nical ~tu~c: DL-valine arnixlo acid capable o~ roduci~
30 Qn idependellt cytolysi~ e~ect onl~r ~xl indl~r~du~l mar,lma-$aTn c~ cer c~ in Yitro and a~ ~ndro~.3en o~pi3ble o~ per-~orm~n~ in ~ ~T~ nollthor9,peutlc do3e J~113 role o~` t,h~ con-.
~ , . .
~ " " ~
-23 FEB ' 94 14: 44 P . 14 - ^` 21~.6a7 1 ductor o~ 3 ~no ~cid i~to .,h~ cell3 o~ ~ ~ol~d m~nuna-lia~ tn~liænant t~nor.
2. ~he ~ e~ the m~chanic~l mix.turo ~Yith D~-~aline aclino arCl~ contal~n, in co,npaxison wlth tho pro-tot~,rpe ~25-~',0 m/l~), Q lottr (5-10 m~X~) ~o~ltl~er~peutic do~e o~ a 1;e~to~JI,3ron~ deri~rati~e, methyltesto3teron~, e~orting no ant~bla~tic e~fecl; ~Yithout Dl,-v&line,.
3, ~o n~YJ ~nl;itumor dru,~ d~ers oon~iderably ~OT:~
th~ p~otot~rp~ al30 by ~highly ~`ecti~,-e antibla~tic s,c~
10 l;ion:
a) in t:he pxo~ence o~ se~roxal tutnor.s in ~ anin~Ql, tha '~m~in" tumor~ ~ioh ha~e ac}~oved ~ con~roll~ble ~e ~4~0 cm3) under~o resolut~on :~il"St 01' ~ m~Ulta~l~lOUi~ly ~Jil~.h l'ædditional~1 onos;
b) ~o disconti~u~tion of re~re3~10n, or occux e~ce oi' xel:~ia3ion ~ollowed b~ ir~ttexsible tumor ~J,ro~th i.~ o~-8erved upon adminis~rD.tion o~ ~he ne~l prep~tion;
C) llo r~lap~es o~ turnor growth ~ ob~erved ~:~ter oo~plete resolu~io~ ther~ol;
d~ in repe~ted u~o o~ the ne~J preparation, no l0313 o~ sen3it;i.vi.,3~ to ~ t i~ ob~erved;
a) daily ~dmi~istration îor 30 ~ay~ o~ "he propo~od preparat~on producs~ the re~;~es~ion ef:E~ct r~lated ~Lth the de~oe OI tumor hormone-~3u300ptibilit~J and meth~Jltestost~
25 rone dos~ Yith a do~e of 5 ~g/kg per cent o~ general Y~eg- :
~e~sion ~ 89% ~10%.o~ tu~or~ did not re~ol~e - 2 out o~ :
17); cot:lplot~ re~re~sion tdi~pp~aranc~ 0~ tunors) wa~ ob-~arved lrri~ G55~ of tuDIo~ (11 out ~ l7? and p~rtial re~
ra~ioll (b~J 53%~85$ o~ the in~t~ e o~ the t;umoY~) :
30 ~rith 2~%, th~t ~ r tumor~ out o~ 17 tsee ~s.bl~ 2~; rrith ~o~e o* 10 mgJI;g ~oneral re$~e~sion rla3 ob~erved urith 100S~U of tl,;mor9~ thal; is, all the t~ or~ ~93ol~red on tlls ~ r~go by ~30~?7, oo.~r.plet:e r~:Tr~ssion with 20%, a~l in ~0%
o~ the tumor~ r~olution achie~Yed 61% to 955~ o~ tho i~$-35 ti~l size o~ 1;he tumor wihin 30 day~ o~ tn~ e~p~rirnont (~e ~,3~1~ 3). ::~
4. ~.h~ Qlle~3ed a~ltitUmor preparal;ion, in co~tr~3t l;o 23 FE~ ' 94 14: 46 P . 15 2 ~ ;3 7 ~
the prototype and other kno~m oyto3tatic~, alon~S~ld~ r,ri1;}
~he re~ol~in~ e~ect OIl ms.lign~ll; I;w~or i~ al~o capable i;o enh~ce the de~e~ce ~orce3, ~,1. r~ tanca to ~lmor o~ tlle tumor bee,rer, ~ indlcated by:
a) ~ ni~icant incr~a~e in the boày ~r~i~h~ OL tho a~imal Rccompany~ng t~3 re~re~io~ t~ee ~able 4~;
b ~ ha~mopoieei~ ~timul~tion lea~l~g ~c. normali~at-;io~ .ereof ln tlle courF~e o~ twno~ re~re~iorl tsee ~'able 5);
c ) a si~ni~iG~nt increa~e ~2-3-~old) OI t;h~ ~u~
~ral ti~le oi~ the arims,ls in ca~e~ e~ C~1t l~
tumor e~ect achiev~d in 30 d~y~ o~ tll~ e~perl~ent Q~
cor~pared with that oî cont~ol (un,,~e~l;ed) ~nl~ a~t;er t~ ination o~ the e~p~ritnent.
. ~able 2 A phQrm~c~utical e~;ert;lnz antiLurl~.ora~ ac ~i~rity Induced m~ ary ~ nd c~cer ~n r~ndom-b~d ~/hit~ ~erns,le rat~. Cond~tio~l tu~lor ~i~ec3 ~in cm3) in ti3:~tms~t l,~it'n 5 m~sJ~;~; snethylteeto~terone ~r.d 5~
Re,t.I~litlal ~umor ~ze~ ~Liver ~n~,e~v~l.s o~.
~o. da~,a 1 week 2 w~ek,s 3 w~ek~ 4 wo-elc~
CO~ROh GP~OIJP (u~.,rea'~s~) ~.D, .7,5 11.5 ,c ~ 21.,3 '2 4.6 6,~ 7.1.~ 7.1 7.3 3 7.2 ~ 8.4.1~ 14.~ 17.2 7.~2 12.0 1~.2~ 30.5 5~.~
~,1 9.3 22.1 ~ 3Z.4 di~d G 3.9 ~,22 23.~ iecl - 7 3.8 5~3 ~ 15.a 21 . 30 ~ 3 3.S 5,~ 5.9 6.7 9,6 : 0 1, ~ 2 .. 7 4 . 7 9 , 7 9 6 ." ~12, 5 13 . 3 1 S . 1 21 ~'~3 G.3 2~5 35.5 ~led . ~O.Oe' ~QtS~ 10 ~5 I.lorS ~' __ ___ !~
23 FE2 '94 1~: 47 P 16 2 ~ 7 ~
....... ~ _ -- 1 1 ~
~abl~ 2 ~conl;inuod3 . _ Rat.Initial ~umor gi~se~ ter intervs,l~ o~
No. d~ta 1 week 2 wsek~ 3 week~ ~, w~ei~
Arithm~tic 5.2 7.5 12.7 13.7 ~0~8 mean and ~raria~ion ranses (3. 8-7 . 2 ) tl . 8-12~ 5 ) ~2 . 7-23- 4 ) (4 69-; t~ 3-P in compari~on ~0.05 ~01r01 ~0.01 ~0.01 wlth initial 10 datc, (be 1rre~1~9 in ¢ontrol eroup ) P in compariBon 15 o:~ control end experlm~nt~l ~ 0,05 ~0.01 ~0.01 ~;0.01<0.
anlm~l~ (by ~teeks ) E~ JT~L GROUP (treated ~ith the p~apax- :
~tion) R~t~Initi~l ~or ~3iZ9S a~tex intcr.tr~l~ o~ :
~JO. dF''I;Q 1 ~'IL'~3 2 l~r}~3 3 r,rl~ 4 ~Jk~ % re~-~e3~3-0~1 1 4~ 2~0 0,81 O 0 100 2 4~2 2~2 0~7 0-4 100 3 4~1r 1~0 0~0~1r 0 0 100 4 4~0 0~8 0,0~ 0 0 100 5 a) 5.6 ~.~ û o O 100 3~ b) 1.0 0.8 0 0 0 100 ,6 ~,~9 ~,7 3~8 2v8 1.0 80 7 4.~ ~0.4 0.1 0; 0 100 :8 a) 6.4 5.3 ~.8 2.9 3.0 53 : : b) 0~2 0 0 0 0 100 9 : 4~7 3.5 1.1 0~1 o 100 ~' ' ~ ~ .-: ", . . . , : ,- ,.
Z3 FE13 ' 94 14: 49 P . 17 ~a~l~ 2 (oo~t~nuod ) R~. Ini~i~l D.r.o-~ ~Iz~ ~% r~
5, 7 3 . 2 2 ~ 2 1 . 0 0- 10~
11 7.6 G.5 3.9 3.5 2,074 . 5 1~ ~7 3,,2 2,3 1.2~ ~75d5 13 7,8 4.G 5~1 2,0 0 100 14 a) 6.2 7.3 7~5 ~.7 10.7 3 ~, 2, 5 3 5_ .
~o. O:e , .
_ rats~tu mor~ 1 __,_ ,__ "_ ,_ , ,"_ _ __ _ , ... ,, _~, ._.. __ , .,.. _, ~.. , _ ~ithmoti~c ll~7 3 2.1 1~5 : 1~2 82rj~
'Q,at~Ldn ~o~ 2-7 . 8 3 tO-7 . 3 ) tO-7 . ~ ) ~0-~. 7 ~ ~0-l o. 5 ) (o-1 oo ) rQnge~ j, . ... mor3 p in coT~pari~ , I;um.
son t~i"h in~- <0,01 <0.01 ~o.ol <~,01 ~>50S~
t~ al data 2 tum.
(by ~e~ks in . ~with-20 ~:~?cr~r~ental .. out . ~;roup) . ~ s~ sn~
b) se~rer~ ~ur.~or~ ~ n o~o ~nt:.
.:
. .
23 FE13 '94 14:50 P.lE
, 2.~ 3 .. - 13 -T~ble 3 A pharm~ceutlc~l ex~rtin~ a~titumor~l acti~ity Induced ~mm~ry ~lQnd a~ncer in random~bred white mic~
(conditional tumor ~iz~ in cm3) tx~nted Y~th 10 m~/1Cs ~ethylt~sto~t~rone and 550 mg~1cg ~-v~line _ 5 R~t. Initial ~umor si~e~ a~ter intor~al~ o~ _ ~Jo~ data 1 w~k 2 week~ . 3 we~ 4 woelc~
G~NTR0~ G~OUP. ~un~reatsd) 1 4 7.8 20.2 37.3 died 2 3,9 5~7 7.0 13.3 20,2 10 3 a) 6.0 10.2 16.0 25.1 di~d ~) 5-0 5-~ 5.3 ~-2 . :
5.1 6.6 7.1 7.8 8.1 7.3 1~5 19.0 30.2 42.0 6 8.0 9.6 2000 36.0 di~d 15 7 3.~ 4.5 9.5 1~2 23~0 a ~.5 6.2 7.1 8.3 10.3 ~ : .
Ax~thm.
meQ~ ~nd 5.3 8.7 11.6 20.~ 20.7 Yari~tion 20 r~n~e~ ~3.~-B.0)(4.5-12.5~ ~5-3-20? (7.8 37.3)(a.0-~200) a~ com- ~ .05 <0,01 <0,01 c~0.01 pQred ~th ~nitial data _ P ~ 0 ~ R E S S I 0 ~J _ _ ~at. Initial Iu~or ~ize~ a~ter in~erv~l~ o~
~,o. ~a 1 ~Jee~ 2 ~reeks 3 we~k~ 4 ~eeks qO re~-r~_ ~ion _ _ .___ _ ~P~RIL~TTA~ GRoUP (D~-~alln~ ~n~ me'h~l-te~o~tero~e) 30 1 6.8 3~20.7 0.8 O.B 88 2 ~.o 4.3~.0 3~ 6~
3 4,2 3.o2.3 o.~ 0 100 ~ 7,o 8.66.9 3.9 2.0 71 :~
7.3 7.45.0 2,~ 2.5 66 Z~ FE~ 'g4 14: 52 P. 19 & ~i 7 ~able ~ ~continued ) 6 6.7 ~.1 2.4 0.9 o.6 ~5 '1 7~,1 5.0 2,2 1.0 0.9 a7 ~.Z 6.~ 5,0 3.3 2.~ ~6 9 5,~ ~-o 2,3 1.6 0 100 7-5 7.8 5.G 4.1 2,9 61 ., ,,, ~, ,.. .. .~.. .... ~ .
AritlLm. 6. 3 5~ 4 3~ 6 2 . 1 1~ ~ 80 m~n a~d ~rLo.~ion 10 r~ges ~4.2-8.2) (~.o-~.6) (o~7-6~9) - . tO-2.9) (0~ ~-4.1 ) (61 -1 00) P a~ com- .
pared ~th ?0.05 <0.01~<0.01 ~0.01 2 tu~n~, .
inLtial . ~: 1007 1~ d~ta . ~ll " ' O i,~
.~ 50%
1~ ~ G R E ~ ~ I 0-~
5~bl~ ~
A p~l~rmaceutical e~rtin~ titumoral ~ctL~rity Induced m~rn~ry 6land cancer in r~ndom-bred ic.l~2le ~, ~ rat~ . Uei~ht chan~e~ (in ~,) o~ e~p~r.l~1;al ra1;~ ~
~,r~ated ~,~th 5 mg ~eth~3.testosteron~ ~nà 550 m~
25D~-~alinc p~r k~ bo~y ~lei~ht and c~trol a~l~m~
(u~;ro~ted ) during on~ month -.~
~;ti'$R~J~ OUP (A~ imal~ th ~nor re:l,r2s~io~) '.Y3~ we~
~lo~ Pl ~ wa~c 2 3 4 ~a w~el;s ~ck~ w~3k~ 1 mon-1 220 230 2~0 245 250 ~3 2 260 265 270 270 275 +15 3 24 0 225 260 260 265 ~25 4 200 210 215 220 220 ~20 35 5 200 210 220 235 2~0 ~40 . ..... ............. ~ ' F~
23 FE13 ' 94 14: 53 P . 20 - ~5 --~s;bl~ 4 (continued) .
6 160 1~30 18; 190 195 ~15 7 200 210 215 220 230 ~30 ~3 240 2~0 245 250 2G0 ~20 ~ 220 220 230 235 2~0 ~20 2~0 255 260 260 255 ~15 1 1 170 1~0 190 190 200 ~30 Ari~hmet. 213 ~20 230 234 239 ~23 variation(160-260) ~1a~2~t5)5 27()9 (195-275) P a~ r.OT;lpQ-~o,o5 ~,0.
red YJit~l ~ init;~al tby w~eXs~
15CONI~R0~ GROUP (with pro~re~ion) R~t.Ini- ln 1 in 2 in 3 ln 4 ~rteeka ~ i;t los~
~o, tial w~elc wee'.ca wl~ we$~ht~ o~ in 1 Tnonth tD~ ani- with ~al mor mal mal tu-wi~h- wlth- mor out out tumor tu-~ ~ mor~ _ _ 2go220 240 24 0 25020 Z30 -20 -0 2 250230 230 2~0 240 6 23~ -16 -10 3 220215 290 2~5 2002~ 1~0 -40 -20 4 240230 220 235 23050 1~0 -60 ~10 200.190 195 190 1~020 160 _~.o-20 6 2602~0 250 230 24020 220 _~o -20 Arit~;~. 23G22~ Z37 23~ 200 _36 -13 mea~ and ~rari~t-3 ion ~200_~190~ .,5- (190- (160-234~ (0-20) ran~ es ~60) 260) 2 9o) 285) P as ~o~- ~0.05 ~0~05>0.05 <t)45 pared with . init~ al tbY -weck~ ) , _ . _. _.__,.. ... .............................. ~, Z3 FE13 ' 9~ 14: 55 P . 21 2 ~ 7 i~
.. ..... _ ..
qlable 5 A pharmaceutical exertin~ itumoral ac~ivit~
Stimulation o~ he:mopoie~ ccompanying ~unor ~e~
sion in ~emale rat~ witll induc~d manunary gland cancer tr~ted w~th DI-Yaline aIld msthylte~tosterone (~;ho ~on-parametrical method o~ ~atl tical tr~atme~t by the "I" criterion of Wilcockson-;tla~n-Witney. ~he me~n valu~ and vari~t~on r~n~ ar~ presented), AniT~al Hemoglo- Erythrocyte,~ ~ucoc~e 10 ~roup3 bir by in 1 ~m3 in 1 mm Sally~
~' - te~t _ _ _ ... ...... . ...... .. .
--~ 2 3 I
-r~ormql ~7 4534000 5300 (10 anim~,l3)(84-90) ~402000û~4920000) t4000-6600) II
Controls `76 4165000 ,'9650 w~lh tu~or~ ~4~-96) (3100000-4~00000) :(7~00~12000) 20 (untreat~d) .
P in compari~
son OI ,~rou~s ~ .0 ~ 05 > . O . o~ ~0 . 01 ~ I snd II
III . ;~
~5 ~ .pQ~imental ~ 91428 . -.~057 ~rith tur;lor~, (66-g4) (3820000-4710000) .:(6900-13500) treQtod P ir~ compari- ~ ,~ ~
~on o~ $roup~ ~0.05 >0.05 ~0.05 II end III
. _ ,_~_._ .__. ___._", .. _ .. ~_ .. _.__.. " .. ,, . ___.............. ~ .
P i~. compar~-~on o~ ~oups ~o.05 >0~05 ~0.01 I a~d II-~
. . _ ,__ _ . ~,,__. ~
: ITotes ~ increas~, - Y decrease 9 r- - unchallged~
. ~:
23 FEE~ '94 14:56 P.22 ~` 2 ~ 7 ~
.... .~ ._ ~able 5 (continu~d) Animal ~o~ino-Stab So~,m~n- l~lono- ~ympho $roup~ phil~form~ te~i cyte~ cytes 1 5 6 _ 7 ~ _, 9 __ _ Normal 2,9 3. 4 38,7 5.6 5~.2 (10 a~imals) ~o-6~ t2-7~s) (19-56) (2-8) (36-6B?
II
~ontrol,q 2~6 7.2 62 1c7 27.~
l,~th tumo~ (o-5~ 0) (4-11 )(56 6B)(1-r~) ~22-35) -- tUntreated ) ~ __," ,,_ " ,,,,,_,_ p in comp~ri- ~ + t ~on of group~>0,05 ~0,01 ~0.01~0.01 . ~o.ol 15 I and II ~_~ __.~....~ .... - -III
~cp~r~ental 2. 0 3. 6 45 4.7 43 ~Yit}l 'tllt;lOY'g ~ ~0, 5-4. o) (2, 0-5. 0) (31 61 ) t2-~) (31 59) treated 20 P in comps,ri~
~on o~ ærouP~ > 0.05 <.Q.5 <0.05 <,0.05 <0.01 P in compari- ~ ,_ ~ .. ~ ~
son o~ ~roups ~ 0 . 05 ~ 0 . 05 ~ 0 . 05 ~ 0 . 05 > 0 . 05 25 I ~nd III
~ ,............................................ .
I~o~e~: ~ a lncreQi~e, ~ ~ d~or~a~e, ,-~ a unch~l3od, `i.' ' ' ., ' ' ": .' , ,.:. ., . , . '' ~ ' . . ...
- - Z3 FE~ ' 94 14: 58 P . Z3 2~ ..37~
~able 6 A ph~rmacoutical e~csrt~n,~ ~ntitumo~l aoti~rity ~lle e~ect oi~ ~ mixture o~ D~-valin~ ~550 m~/k~), methandro~tenoloIle (25 ~g~lcg) and phthivazid t50 clg/l;~) on l~r3e .~ tumo:r~ (or on several tu~
mor~ ~n one animal) of induo~d ms3n.~ary gl~nd cancer ~n ra~dom-bred white rat~ . tConditional tumor ~ize~
in cm3) . . , ~ . . . _ . ~
I. It~eated Qnim3l~ (e~,~porimenta,l) R~t Mo . Ini - At- ~ n ~ :3rvg,l~ t;J~ ) c~ re~
~l 1 2 3 4~ 5 6 ~lo~
a~ 18~5 8~410.3 11.9 11.3 6.2 8.9 52 ~) 1.6 3~3 2.1 5-5 4.~7 10.2 8~5 2 24.0 2g.6 23~.9 16.5 4.4 ~.9 6.~ 73 ~c~o -s~ ....
3 11.D, 10.. 9 11,4 1~.1 . 1~;J5 2207 ~1,7 -~) 10,8 7.~ 4.3 both ~u- 2 togai 2 toge-2 to- 75 ~ed ther ther ~e~
.'.; thsr b) 3~Z 2.7 1.0 -3.4 -~.5 -3.0 -3.5 .:
~)1Z~5 6.2 4.3 1.9 i.2 o 0 100 b) . 0.~ 5.0 2.7 2.5 0 0 100 ~ .
6 12.0 12.2 4.~ 0.,8 0 ~: 0 0 100 necro- .. ;. .
7 a)16.5 7.3 4.3 3 tumor~ 3 to~- 3 ~0~2-~u~ ~d ~hor ther 2 5 ~ n t o o ~
b) 3~7 2.9 1.6 -13.4 -20~0 -21~5 -c~ 1.û 1.9 3.7 -19~2 ~)10.1 8.9 0 ~ec- 0 0 . 0 0 100 b31.2 1.0 ~o~i~1.0 1~2 1.9 1.5 9 ~)11. 0 2, 5 necr. 0 0 0 0 100 . b)4.2 3.4 3J0 1,5 0.9 1.0 o~6 ~G
o 9.~ 11,5 ~2.3 7.1 5.~ ~.7 3.6 61 ~,., "., , ,_.__A_.,. .. ~ .. .....
No ~ oxe` 1 6 17 17 i 7 q7 17 17 1 ~)r tumor~
23 FEB '94 14:59 P.24 2 ~ 7 ~1 ~ble 6 ~cont~nued~
Rat ~Jo. Ini- ~t intervals o~ ~w~ck~ 7~ r~;
tlal 1 2 3 d, 5 6 ~ze_ ~ ~ __ .. ~_ 5 ~ ra~
ria~- 9.,~ 7.0 5.5 5~3 3.7 4~4 5~ w:l.t;h-~on (1.0~ (0.~- (0- ~0- (0- (0- (0- out ran 24.0) 29.6) 23.~ 19.2) 15.5) 22,7) 31.7) e~-g~ 2 ) 1 ~d t.urn, ~yt~r.- re .~;r.
ol,~m0an 3) 5 P ~oomp~ ~ ulith r~ær.
rison ~rl"h ini- ~0~%
I;~al d~-t~) ;>0,05 ~0,05 <0.05 <0.01 ~0,01~0.01 (C-II. Untr~t~d ~nlm.c~ls too~ltrol) _ ~1.5 18.. 4 21~8 30.5 ~2.5 .~isd 2 . 9. 3 22,, 1 33 . 4died 3 12.5 13.3 18,1 21.0 2~'3.7 3B~3 died 4 12.0 19.2 30.5 42.8 50.8 59.~ died 9.5 15.~ 21.7 3g.2 43~6 di~d .- .
G ~ 3.4 5~4 a.2 ~.6 . 15c1 b) 5.6 7.0 8.9 10.0 .12,2 dlod No~ ~
~umox~ 7 7 7 6 6 2 ~JI (Yar~-~,tion 9.1 14,,5 20,7 25,5 32.1 ~) ~2.4) (5271) ~3624) (~2.6) 50.2~ ~.. ,... ~ ~-P ~cor1pn--ri30n ~Ji.'ch <0.05 ~0.05 <,o.os <o,o1~,0~01 itial ~ ;Jotc~ 'lhe~ 2-3 ~ or~ :Eusod ~nto one, th~ ~ati~tic~l -~ree,tm~nt toolr 5 tltO a¢count 2 or 3 1;wnors-2" ~Iho tumor ~ze equal to 0 (r~3x~s~on) wa~ con-~id~rcd ~ one tuT~o~
,, ., . . .... ~
23 FE~ ' 94 15: 01 P ~ Z5 2~.6.~7li 5. In contr~t to other cyto~tatic dru~s, the alle-ged pharmaceutical durin~ the ~roce~s o~ t~nor re~res3ion can e;cert an anal~et~.c ~f~ct as w~ ~ollo~d in th~ ex-periment~ signi~ic~nt incre~3e in th~ thre~ho~d of the pain e~:citabilit~ and,co~equently, ~ d~cr~a~e in tl~e pain sen3~ti~ity in ani.mal~, In the ab~ence of re~-r~3ion th~ an~lgcti~ f'eot: o~ 1, and thi~3 m~.y b/3 used clinically ~or the evalu.~iion o~ the ef~ec~ o~ t~e-rapy.
6. In contra~t to tha prototypo, ~h~ allo~d pharm~-¢eutical may exert the ~ntibl~tic e~ec~ on the lon~
terr.l growing cancer ~umor3 partially or completely lo~-ing their ~usceptibility to androgen~ which may be r-m e~per~mcntal ~odel o~ cl~nicall~ n~slected c~lc~r pxoce~s.
15 In thi9 ca3e the antitumoral prepar~'~ion cont2ins, in tur~ h D~-Yaline, ~1 ~n~bolic dru~ r,~eth~nclro~t~n:~
lone ana a k~o~m ~ntituberculo~i~ drug phthi~3~id ~',~ch h~ preYiously never been u~ed as antitor.lul~al d~u~s. In this ¢ompo~ltion, the new an~titumoral pr~p~tio~ exer~-20 1~ the anti~la3tic e~ect on largn .u-qed (2-3~ Qnd tre-mendous ~ingle ~:~erimentally induced tumorY (tlp to 2~, o cm3) c~uses the re~re~3ion o~ the ~umor~ acco~p~nie~ ~y xequent necro~e~. In this ca~a th~ liquid s~ructureles~
tumor m~e~ pora our, and healin~ o~ normal tissue~ '~;3-~_ 25 gin~ at thi8 s~to ~ee ~ble 6 70 I.~orphological le~on3 ~ch OCC~ in ~h9 t1~no~
t~3ue ~nd rG3ult in rcgre~3i.0n al30 ha~ their peculi~r f~atuxe~s unde~ thQ in~luence o~ th~ d ~a~in~ the~peu~ic e~eo~ o~ any chcmloal dru~ and ~ven irradiation the~e 30 oocurs marked ~ibe~ ~ormation, wherea~ the ~lle~erl ph~
m~ceutical influce~ chan~e3 due rao3tly to the l~si~ o~ :
ths cell~ o~ p~rench~ra ~nd ~roma o~ t}le tu~..or ti~ue, necroly~is with ~ub~equent re~orption (sae ~ig. 1~.
On t~e ba~is o~ ~h~ a~orementioned expeximent31 da~
and, a~pecially, taking into account complete harml~s~nos~
of t~P n~w antitumoral preparation teated and coniirmed in nor~al anim~l~ within the ~rama~ork o~ the com~l~ted ~ .
Z3 FE~3 '54 15: 03 P.Z6 21~.6;~711 ...... , . _._ _ _ _ 21 -pharm2cob~010~;ic21 pre-clinics.l trial~ we propo~e îor cli-nloal application a new a~t.itul~or~l pilarmaceutic~l con~
ting of a mechenical mi~c t~ ~ of 2 4 ~; o~ DI.-valine smirlo Qcid and a low non-therapeu1;1c~1 do~e o.o~o-o.02s e meth~Jl-testosteron~ per day ~or trea~nt o~ hormono-~u~ce~tible cQncer tumor~ in women, ~nd a phar~ceut~c~l con~i~tin~
o~ a mechanloal ml~ture o~ 2-4 ~ o~ D~-v~line, 0.005-0.010 ~ meth~ndro~tenolo~e an~ 0.~-0.5 g phthi~azid dai-ly *or tr~at~ent of canc~r tumors wh~ch ha~e ~artially or completel~ 109t their hor~none-susc3ptib~1ity, ~he dGily ~c3e3 o~ the propo~ed pharmaceutical for clinical u~s h~ve beon calcul~t~d ~rom the do~e~ u~ed e:~-p~rimental~y.
Thu~, the do~e for D~-~alir!~ ~a~ calculatad to be 2-4 ~ takin~ into accol~t the e~perimental do~a o~ 500-550 m~ .bod~ ei~ht of anLmal~ and at l~a3t 10 timc~
lower intensity o~ arnino acid metaboli~m in man; con~equ-~n~cly, a~ouv 50-55 mG~e~ body wei~ht o~ man oE D~-valine ~hould be u~ed or 2-4 g daily for a peraon ~Je~hi 50-70 ~^
~o doQos- o~ r, ~ t~::ro cl~laulut~d tn a di:EIerent way, since human and ~nimal sen3it~ y to t`,~a~ que~'v does r.ot corr late ~ith di~erence~ ~n the macabo~ ~stn lnten~ity, ~_ 25 A do~e o~ mcthyltestosterone 20-25 m~ or 0.020-~025 -:
5 ta~let3) per day wa~ o~lculated on tha ba3i~ OL
e:cperimOntal ~nd ¢linical data acoordin~ to which ~t3 oxperi~.esltal nonther~peutic do~s ~5 r~v~k,¢ bod~r w~ ht) ~e 5 time~ lo~ than th~ th~rapeutio one - ~5 rr.g~ an~
~al body weight. ~ on~ take~ into account that nand-rogen therap~ in clinic~l case~ o~ m~mmary ~la~ro ~pula-te~ ~ dose o~ methylte~to3terone of 100 mg ~r.d more daily ~ee ~uakin, Ya,I1., in t~Hormone therapy o~ rna~nary ~land cancer'~ .edi~in~" ~ubli~ers, ~,I., 1969, p. 6~-73), the non-t;1c~apeutic do~e should bs about ~0-25 rn~ daily. Sin-ce the dose o~ met'nGndro~nolone c~n~ot be calculated o~nthe b~si~ o~ ~ens$ti~i~y to it o~ the tumor ti~sue be-23 FE~ '94 15:05 P.Z7 .--`
. . _ . _ . . . _ cau~ it h~ ~evor been ussd a3 an ~tit~or~l d~u~, ~re ~de ou.~ c~lculation~ ~rom ths d~ta in the literatu~e (See IlPhar~aceuLical~r, I,l.D, rla~h'.iov~y, ~I,Iedizi~a~ b-lishers, r~,, 1985, pa~t l, p. 317; and dircct cli~ical ob3e~vations in treating ~ol~eex~. It wa~ thus est~b-li~hed that in ne~lected casc~ wi~h CoMplOte 1039 0~`
hormone ~u~ceptibility by the twmors it wa3 necessary to u~e methanQro~l~enolone in a da~ly doso o~ 5-10 m~ in co,~oinatlon ~th phthiYazid enh~ncing tl;~ col1ductive e~`ect o~ thi~ hormo~c. ~or phthivazid the d~ly dOBe c~lculat;ed ~:~om the experiiner.tal oIle with due con~ l-ders,tion o~ 10-fold lo~r~r met~ooli~m inte~lty in ilumuns _. ~3 compared ~ith ~r~all ms~nmal~ .. a dose ~or an e~peri-mental ~imal ~ra~) wa~ 45-50 mg/lcg body wei,~r,ht, ~or m~
15 it would be 4.5-5 mgJ]~ bod~ ;ht, or ~c~r a person .lei~.in~. 60-S0 k~ or mo~ it would b3 about 300-500 m~
~G. ;,-0. ~ ~ ) p~r d~y.
r';le st;udies oi:` tii~ antibl~ ic pt~op~rti~es o:E tll^
n~tr pharmac~ulic~l in the clinic, ~nliy i~ incur~bl~
20 ~rolu~teer paticnt~ yield~ the ~ollotrin~ data ~lgni~lc~
tl~,r dis l;i~gui~hin~, it fror:~ th~ prototype.
1~ r~ direct antiturnoral e~ ect o~ e propc3ed ph~rm~ccutical in the ~'orm of a mechanical mixture o .:
~-valine Q~d a lo~,~r nontherap~utic~l do~e o~ methylte~to-. 25 ~terone is att~3ted by the re~ults o~ c.~.tologi~l e.ca~l-~~ nat~o~ of ~lr~tion ~p~clr~en3 ~ror.3 tho ca~-ity ol the utorus ~ter ~dr,lini~tration o~' thi~ pha~n~c~utlc~l ln c~
3e~ O~ 9nOOarClllO~I~ O~ t~e ut~rus body in ~em~le ~ol~-t~era ~ivon no ~peci~ic treatment in thc ~re-operat~.on 3Q pariod ~rit,n th~ e:~c~ption o~ ~-valine in combin~ion ~rit'r. a lo~r doae o~ T3ethylte~to~terone. In all 9 patisnl~
~hi3 treat~er.~ resulted in a ~i~n~'~lca~ reduc~ion o~ ~he tumor, sizes a~ ~ell a~ c~s~tion o~ pai~ ar.d blood~ sec-retion~. In ~piration ~peciTnens collec~ed fxorn ~ever~l of ~h~se ~atients at dif~'erent inter~ (10 d~3, 2 we~
4 weeX3) we ~i`ound dy~trophic~lly alte~od ~deno¢~cino~n cell~ ~,'it~ n~ican~ valuolction o~ ~hi~ cytopl~m ~
nuclei, "cor~ododl~ outline~ of'. ~ nuclei, 1~9i~ of ~O;~B
23 FEB '94 15;07 ~,Z~
2 ~
r.uclei and me.r'~ed v~Lcuole d,~-stro~h;y (s2a ~
. In 1~e~7ec1;ed c~ei~ roco~ni~eul ~ corlpl~tel~ c~r-~ble, ~di~inia'"r~ on o:~ the r.o-~r prap,~.rQtion ~3 a mictu~e OI' DI--valin~ wit~ methylt~to~arona 03~ wi.,h mo.,'.q~Ld~;~o-5 ~1;c~lololle ~lld phth~ v~id Y~e~ulteù il~ ni.~.~i.c~t I~7~olon-gation o-~ tlle 3urvlv~1 time o~ th~ p~tient with 5at~ ac-tiO~ f ~ul~j ac l;i~ condition ~qnd in ~o~e ca~cs ~ith ~he ot~-j~ctive siltibl3st:lc ~ec1; - ~301ut~0n o~ ~h~ tumori~.
3. The action o~ t:~le ral,/ e;ltitumoral pllN:;~rllacoutlc lO Ll.~3 earl~ a~ with~n th~ Iir~t 7-10 ds.ys comt~l~Jel~J elir~i-nat~3(l t`ne pa'n ~drome e~n in t`~o~3c ca a3 l~h~re ~3tl Oll~
._ n~rcotica halped only ~Jlthill a limitad tir.~e, Ior i~ t~n-ce in .ne~s,~lected CA3e~ ritll meta~ e.~ i~to bone~, ekcO
4. q`he actlon of the new ph~r.maceu~ical ~n ~1L~ CCU5~-15 3~ t~eat~ent i~ X10-t 2ccompaxli~d b~J a~r S1nS o~ .;o~
ci ~,y tt.l~TllGd~ T;liC ~ o t~ n~u~ ,, vo.
5 . I;~ e co~ OL ~ t~ t t.lJi ti~ tll~3 n~ p7 ce~ttical~ "he ~tltumnr re~i~t~.~ crea~ed '3VG11 ;n i;l-our~bl~3 p~ti~nts ag m~:ht3~tt3d b~r the improvecl~nt in tl 20 perip~lt r~l blood compositiion, ~;cic~llL g~ill, lclpro~d ~7)e~
tit~ cr~3a3ea r,~orkin~; c~- p~cit;y.
iflt~.~rL', ~tl~2n~ 0~ w pl~ t~u';.'c2'~
co~sist3 i~ tne pos~i'oilit~;r o it~ 3uccas~3~ul usi3 in Ollt-pa7;:L~l.lt W~lrC~ liC~! collsl~tar~bly dlst,inrrui.~lAe,~3 ',l.o ne.;
25 ~harm~ceu~,ical ~'ro;~ the ina~or~t~J o~ e k~o~im o;~ ol;;~ler,~-p~3ut1ca1 dru~ 3r'~ 3e~rere .~ide-s~îect~ . ~r.tl ~ er~3b~
r~quirir,~, ho~pl'.,~l co~ition~ for tlLei~ ~pplic~io~.
S:ido ;3f:~cJ,s ~scnu,~ o~ .c nL"r.1~tE~a1le~ o~ the .no~ pl~ ~2couJ.ic~15 30 th~.ro are r~o ~ r~ic~lt, comp~1c~,c10r s. 4 10n~ ~ 'uorr:~ ~u~
to 2 clnn~ ) admini3traliio~ o:E m~thy1iie~3tos "erone Ln lo~r ~!o~ 12y cau~3 ';t~ ' m.s~11f~3~,~qt10n3 oL ~r.t.rl1i~m ~`nic'r rzpid1y d1sappear P~l"er met'1~r1t~,3 '~,o~terox1~ a~ 13t~, i cn 1~; ~ia^~n'~_n~l~d.
`~5 T~` ~he r.e~;J ph.~.rn~ceu~u~ca1 i~ adl~lnis',,~Y~ac~ XC9~ e ~o~nt3 and tho pro~.ein die'., i~ ~ot ob~er~d, J"ner~e ~a"r . ..
~ .................
23 FE~3 '94 15:12 P.23 -- 24 ~
. . .
occur ~nsi~ icant nau~eQ, ~r0~33 0:~ app9tlte, 10~ 3 0~
welxht. ~hc~ ns o:E ~mino acld di.~bQlance di~3~ppoar ~ ';er l~oduc1;ion o~ uhe ~ ,r doso o:~` l)L-v~lln~ on~, ob~erva~ce o~ 'l,he p~ot;~i~ dietv Contraindic~tion~
1, Prac~eding an~ro~e:n tllerap~
Ir ~uch Cll'3eS Q lcl;l do3~ o..~ me ~l~"rl~e~tc3tero~ o:F' ~l~.o l~t, therap~r ~chedule ca,lmo~ real- se l.JI~ i'ec l; o:~
3)I.-~Llinc conduc~oir ln ths '~-.lCi" ti~sue c~ 3.
10 ~ t~ 3~uic ~ c~ r~! J;tl~i^a~ scl~¢dul~-,, r.l~J;~ ros~onolon~ ~d p.tl~,l~vazid3 T;laJ~ ux,e~
2. q~fl ~e.~ 0~ r.~et~ a l~ .;s7 b~c~a -~pld ~ lo11 oi 'I;U~10~.~ rl~v~ re,ClllJ~¢~ 11 tl~s ~t~113 o~ ',h~ lood ~C~3~31~ I?rO~lt~;r~ Jv~-~
1-~ b~ .n,~
3.. ~ iou~ ~0:ri.13 ~:~ a+,~ o.~ o .. o~ rb ~C~Jv I~ ?..,U~ a~l d~mt~ t ~ Oc~ai~.3 ~vlt~ ~v~ vr~iGil u; X~ ~t3rl~u ~ 3-r~tio;~a~ lnt~r~re~luio~l~ b^u~ Li1aC~LU.~L~S~ i~
s"~r~oclate~ l t.'2~ px'op~rty- 0;' 01'~3dOmillQI~ t~ 'J'~)O'~ t-~
2C ~?'' ~ lin~ ~r~ o ClC-~ (1 .o ~n~3 ~l~m~.r;~ u~ o:? '.,'.1'3 ~dUr L~ . nc~t to t't~ tu~o~
. r~lore~orc the ~p~l'; "Q',.iOll o~ Lhe Y~ Xr.~aCeUtlC~
13 po~stblo only ~:,.tn;~ co~ le';,o .'ne~?.ii~.c" o~ .v~llO~
25 da~,ræ ~I;er ope;~2t;0n) ~nci ce~3at~ o~.~vh~ ,3t~ ta 25 co~:d~i!vion~ :3lood tr~.,n~t~u!vlon (e3~C~ lLi~r~lUl;v~P~ æO
. vr~nrl ~3:~Iec'., clo~ o th~i ol ~h~ o~
~,~?.l~ .L't~ S3C~ .h~r2:~ 1;}1~ ~n~;r~ v~ -;Oi.1. o~ i'!.t3 ,,,l;a~ coll~ical ~.u,~ 1, b a ~llsco;~ tl~ cd .~or ~ t '.;.;c.
~ u~ 3 l~ a~ n~, t.:~ U~3 o:P ~ 3'i:~c~ a-`~ c'~-30 1~ h~3 s~:Lt mcL.~ cll~ 3t be ~ol~l~cl~
5~ I~o o~ .r æ~:~;,l';ul.lo~ g~; ~ho~ . c;.
'~.Ju ~rltll J;~ i n~t p~ a~ lc~
., D~ ., t'l~ L~2~ J; ~irl~ J~ pl~ c~u~ '.cl~l ~v ~a v .o~ o:? c, 4LlC;. i}o.C~.Lo~ .u., (,0,;~ ,3, ~hy "o~
3 j ;~ . v.&~ ul~. u L~q~, hcl~o !~ o l ~ , c0,;~ ac r~c . ~
.
' 23 FEB 'g4 15:12 P 30 2 ~ 7 ,~
-- 2 5 -- _ ~xample~
r''ilC ln~nt. o~ U.'3'1;'L',o'',~?tl b;y I;1Le "ollowinG ~pcci-~ic ~.nmt~le s o~ th~ mo~al t~ o~erJ;.ie~ o~ ~h~ allcged new pha~maccutic,71 1. Pa'~ion~ 37r.il~0v.3~ A. 75 ~ r~ ol~, ca~c his-to~y ~o, 127~3~a. i3.r,~70~E~to~ ~roto;~-~r WEl:3 C~O`lC o:
31. 05~1977 ~t; the g~ colo~ departt.~ lt; o f ~o~to~r R~ e~
~rch Institu~e ol` oncolo~ L me~as4~sis f~om ~,hc ~;r~3a-t~3r omentum w~ tal;en ~o~ hi~tologic.al Q~lal~r~is Mo., 10 104~47-~343- Clandul~r ~ol~.d. o~ra~?~r cnn~or Clinical cliagnosl~: o~rary crncer Of ~ a~ i. I;h i1tv~ e t.ulnor $row1;1~ arld oul;,oro~.rtn i~to th~ in'.,~E tilte~, with Ir.et~lta~3~3 into the omentv.m and in the livar, ~ith ~citic ~luid accu~ulation in lh~ ~domin~l c~vit~r.
In th~ ~o,st~oper~tio.ll perlol, ~ cou~e o~ c~te.no-th~rapy (i~ thio_t~pQ) ~s~ v~n aa ~ rc.~ult o l,ih:ich no s.acito3 ~ccwnu~te~1 ~ut th~ ~umox ~ro~rl;h cont~ m In ~uly, thc p~tient ~sa~ dl~chax~e~ ~rotn th~ ho~
~td pre~crlbad 3ytnptom~tic. trentrn~nt.
In lal;~3 July, 1977, a~ a voluntc~r, khc pavi~
welænin~; 5~ 3~;, be~an tho tr~tment ~,rlth t~1~ pro~e;3~l ph~rmac~utic~l ln t'n~ ~orm o~ ~: mixtur~ o:~ 2 ~ DL~ re ill combin~l~,ioxl Wi1;h 25 ~lg ~0.025 ~;) or 5. tab~ r~l~3~}i;irl-1t,0~ t~.ront3 per d~J, ~it`~ ~trict o'~ .r.ce o.i` t`tle 2 5 m~ with ~..hc c~iYi~ion o~` the d~ily do~e :3 nto ~ 3inr;1 ~ ,.. . . .
ono~i l;a'.sen b~:~or~ ; 0.5 ~ D~-v~lin~ q~rr:~ m:l;1: en-tarall~J and 1 t~blot o:E i~ethyl~ 1;osterorle subl:in~ ,lly ~l. I;imt3~, arld 1 liubl~u o~ rnt3t,h~rl1;e~to~3'.~ n~i ~ublinr,u~lly r~ nicldl~ ;ho d~ itho~l~; DI~v~l~n~. 'I.'}1~3 t~ur~tlon ~0 o ~` t}~e cour~i e - 2 mon l;hs .
Dv~inf~ thi.~ t:i sr.~ 1;h~? pai:n~3 in 1 e lo~ b~orn~n nr~d ilL th~ r.x~E3 o~ t~ c~s~l ccr;sple~cl~, th~ ~7aSI~.~.'O-illt:e.~liinal trs.ct furction ~o~m~liz~d ~con~tipaLion~
l:)lood~- ~ecxatic~3 di~ e.re~.), the ~etl.te is~pro~re~, wei,~h~ r~ 4~5 }c~, the ~tre~l~th ~ld ~ror1cln~ capa C ~ wexe r~toxed, ~o t~ mor waa palp~ted.
O~rlng to thi~ 5tnt;l~s the p~lU-~ ~nt; ~ 3 ho~pitall~ecl.
23 FEB '9~ 15:14 P.~ll 2 ~ 3. ~ ~ 7 ~
..... __ . 2 6 on~ month l~ter for the 2nd coWr~3Q OI chemothcrap~r (im, thio-t~pa, a total do~s o~ 200 m~), G~ecolo~ical ax~mi_ nations ~e-u e~l~3d no n~opl~ia, In ~ ch ~d Ju~y, 1973, propllylQctically ~ ~ore cour-5 8c~3 oi~ thio-tepQ wero ,jiven which pro~uco~ ~tabl~ leuko-pen:La, In ~u~;us t, 1 Y78 a ~acond cour.qo o~` the pxop~d phar-maceut:i cal ~raa ~ive~ by thc ~arle 3ch~dul~ ~o~ 1 ~ontih~ 5~he blood ar~l~r3is ~ no;~m.~l. On the 7th da,.,~ o~ tll~ trcatl~e~lt 10 ~hc pati2nt hafl severe pairl~ in the liver a~ea Y~hich pe~-,t~a :E or 2~ h.ours but then dis~ppc~red compl~ r. ~yn~-~olo ~i c~l ~xal~inat ion rc voalad ~o ~loopl~ h~ pat i~nt ~elt w~ll. No ~r~atm~3nt ~s ~;iVOn unl;il April next ~e~r gener2l c~ndit;ion was satls~aciiory, ~aineû soms v~ t, 15 ~mecolo~;lce.l ~:~nin~tion~ Y~e~r~ale~l nothin~s.
In late April-r.lay, ~979, ~he Yl~S ~iverl a 5th (})~c~hy lflctlc) courr~3 of 1;hio--i.opa, im~, toler~ted ~3a'l,1'3~ ,ct;ox'i.-ly.
Tn .June, 1979, ~}la W3~3 gi~ren a 3rd ~proph,yl~ctio ) c~i-20 u~ o~ the n~w phQrm~.ceutic~l but ir.~ ancther daily do~eb~caus~ o~ Lc~lt chantro o~ wai~;ht in 2 l,r~r~
~:EroTl 54 kg to ~a k~ hc ,~;aine~l 14 k,~;~r Sh~ we.
re2l 3 ~ Ct~re o~ 3 ~ ine a~ 25 ~ er~lylte~ n~
dall~r in 4 ~in~ do~cs, ~ri.th th~3 c~ne (lie.'. r,h~ cotlr~3e ~5 l~t~ 2 month~3. ~h~rs a~p~re~ 3$,~,n~ic~.1; 3i~3 ~
~_ virillty ~rhich opprec~c~l t;he p~tiCll~ b~cau:~e o~ l:lb~,do m~li~e~ tatio2i3, :3ec~qe o~ th:L,q, ,s~.e d~cli~cd ~ur';hcr pro~hy~ao1iic admi~i~ l;rQtion o:l~ the n~w p~rTn~cauti¢al~ ~a-~it7 in 1979, i:~ ~pxin~ d ~UtUt~l 0~ 1980 she w~ iv~n 3 3t~ l~O~C pl~)ph~ c ~G.~C c~ u:",~ ,r ch~v~r.ctllfl~y ~ri lih cyclollo.~v-phar,o ~hio~ ~he toleral;ed Wi-Gh mor~3 di~'~iculty, n ~a~rtl~r~r ~~ rar~.h 1~1~1 the ~2ti~vnt ~SU~L:er~ ;ro ults. S~e d~erl r,,~tll the 3econa, ~itho~ ny ~ o~
noopl~si~ w]rtvh ~ad ~t~n c~l;abli~h~d, ~t a ~ 0lo~ic~
35 c~ in~tion on-~ Ir.oTlth 1~vfo-la d~nt.l~ he re:!.avive~ r~fus~d th~ alltop,sy.
r~h-- ocn~.lu~3lon 9~. incre,n~c ln ~ht) perio~l of ~cti.~re li~e hy 4 ~ear~ a~tt~r recognition o~ ker cor:ditiorl ,c~
: .' ' - '~ ,;: ' ' :~ '' : ''', . ' '' ~: ~ '' ~ ' ' '~ ~ . . :
`'` ,,,, ::'.'' '' ' ' :' ,~ '.. '.. ,,.. . .. ~; .. ' .. ,. ' ','', " . ;: ,.. ..
23 FEB ' 94 15: 16 P . :32 :. , . c~o~plQt~ly l~c~urnble cnnn~t b~3 r~8~rdGd t~ b~ dll~ to th~
~3ucce~s Or t~a~ltlonal c~ncer chem~t~apy ~1~ e rl~7w .
pharmaceut~oal not only correct~d ths ~ida o~f00t~ o~
c}lemical drug9 but cle~rly ~aoilitat2d the ~ntiblQ~tic 5 e~fect~
2. Patien1; Tlc~henko , lq.A., 28 ycars old , ca~e hi~-~or~r No. 1151a~x, admittoc~ to ~ynecolo~ical departm~t o~
Ros-tov R~sear¢h In~ti'~uto of oncolo~ .0~ Tllo ~ta~
tu~ at ad~ ion: wi~hin 2 month~ e~eat ~rllar~s~3ment o~
10 the abdomen, ~;re~t ~ei~;hli los~, evenin~ tcmpcr~t~ out 39C, ~3u~ 0c~tl0n, X-r~,y o~' the che~t ~eveQlad a met,a-st~is lnto ine pulmon~ y pleura. ~:ndol~ilphat~c polycho-`~ mother~py ~va~ ~tarted bllt did not allev~at~ th~ condit~on o~ '"he patl~nt.
1~ ~n 31.,08.~9 a~ explor~tory l~p~ro~omy r~a~ per~ox~ d wi'l,}l a~acuation OI 15 1 o.~ asci~lc ~'lu~ ~ro~ the ~ lo-;ni ~ c~vit~r ar.d ~,he al)out 2 lit~c~ o~ :Elu~ d i~2~0m tj}
pleu~al c~ityv "~ha dia~no~ oY~ry c~nca~ o~ IV ~t~g~ lrrit~ oU'L-20 growt}l o* the twnor~ lnto tha ~nte~tina~ ~nd with mct~ta-o~ into the gr l;e:r ornantum, liver, paritonow~ pleura~met~ t~o plcurit~). Hi~tolo~l¢al an~lysi~ ~o~ 26~62s ! ~l~ndul~r-o~pi~lary canoe~. , On 13.09.89 a preparation o~.platinum ~B~ inoo~lated intr~pe~itone~lly. ~ter ~hl~ th~ condition o~ t~e p~-ti~nt d3texIorated e~e~ more, she Y~a~ conside~ed to ba in-cuxabl~ and ~ di~oh~r~d ~rom th~ ho~pital in the ~re-terminal oondition~ :
On ~6.09.ag ohe be~n, ~ ol~teer, the treatment ~th the n~7 pharmaceutical in the outpat~ent department~
Ths daily do~e ~th the pati~nt'~ wei~ht a~out 70 k~) consisted o~ 3 ~ aline in combination ~th 25 mg O.025 ~ or 5 tablets) methylte~tosterone. The daile do-line F~ublin~u~llg 2 time~ i~ the mlddle o~ tha d3y ~e70 -Z3 FEE3 ' 94 15: 18 P . 33 2 ~
moal~ he pat~ent ~trictly obæerved the dlet wlth thc exce~3 o~ protein, liTTited amount o~ caxbohydxat~ and complet~ ~x¢lu~ion o~ ~mal ~at and phosphol~pid~ ish hard~roo, e~;g yolk), u~in~" no ~ore Jchs~ 1-2 1;able ipoon-5 ~ul~ o~ ~regetable oil daily.
~ '~thin the ~irst 10-15 d~y~ o~ treatmen~ with ',he new pha~maceutical the ~ollov/~n~ ch~nge~ occured 1~1 the condltio~; o~ ,.he pal;ient s 1. Vomit;in~ ~topped and lnt~s~inal oY~cuQ~lon OOCIIr-10 red indep~ndently;
2. ~he body ~empe~aturc beca~e noxlln~l;
3~ e ur~ no oolour ~c~ne li~hter ~pre~ioll~J.y _ dar~c beer ~olour);
~ r~ ~0 ækin coloux ohan~ed from dra~-green illtO ye7-15 l~ Yhi te.
5, ~h~ er ~nl~r~ed ~ htly ~nd pexiodia311y ~Ta~
pairlLul;
6. sn'nyc~.~dia Qppe~red ~ro~ ~ime to t~r~lC~;
7. ~e ~atiant ~howed ~ood ~pp~tite:~nd intore~t ~or li~e, e cour,q~ o~ 1:reatment ~va3 1 ~onth becau~ the pa~ :
~ient ~va~ con~idered to be cur~bla ~nd w~ ~r~clltl~ ho~pi-taliæ~d o~ 23,10~9 ~or a repoated i~txaper~ton~ ac- .
tion o~ ~latinu~ prep~x~tion~ he patlen~ bo~e the in3~c-tion o~ th~ pl~Jcir.u~ preparation eaaior than th~ ~ir~
time~ but th~rea~aln appe~r~d ain~s o~ cardio-pulmon~y - .
in~u~c~nc~
A~ter tlae diachar~e from th~ ho~pitQ1~ on 09~11.89 tho pa~ient ~g~in 1~e~n to ~t th~ tre~t~iarl~ w~t}l the ne~
ph~rln~outlcal, ~ 2~month cou~ o~mbe~-D~cemb~r, 19~9)~
ChQnge~ i~ thi~ p~riod: ~
1. Sigr~ o~ c~rdio-pulmonnr~ insu~f~ciency dl~ppe-ar~d.
2~ Pexio~lc~lly oc~urir~ p~ in tne liver ~topped ~-but the live-r Yla3 3till onl~ed~
3. ~o s~ gn~ o~ aaoite~ eith~r in th~ abdolnial~l or in pleur~l cQvi~y.
~ 'he ~ppe~lJ~e ~ 3~il-l ~ood, ~aln in '~7~ 4 k~
:~
23 FEE3 ' 94 15: 20 ~ . 34 i 7 ~
2 ~
5. ~h~ patient t~ko~ ac~ive pa:rt ~n liîe, w~nt~ to go to uork but she get~ ti~ed quic'cly~
I~l J~nu~ry 199~, she ~IQ~ ho~pitnlizec~ ~or 3 w~k-co-ur~e of ~y~temic chemotilerQpy ~im, thio-1;o~ u~ich wa~
5 tol~rat~cl ~ti~r~Cto~ly, without diso:rd.er~ hc-modyna-, wlthou~ nau~c~ ~d vomitlng, Bu~; the cour~s ~a3 notcorlpl~ ~.ed arld di~¢ontin~l~d b~c~u~e o~ .~ se~rs sllcrgia ede~na o~ ~u~cke'~ tgp~ t t;hi~ time ~?ai~ in t~ ight ~nd le~t h~ochondrium.
Earl~ 'ebru~ry, ~990 ~ tt,t~o-month COU'n'~2 (,~ l'U
ary~ arch) o~ ~;re~tment w:ith t;he new pharrJI~oeutioal Y~S
st~rted in ~hc Sam9 dose~ cs before. A~t~r the cour~s:
1. ~he ob~octiv~ ~t~tu~: a~ ~ho~rn~ by ~ ologic~1 ex~;nin~ti~n, ln the ~mQll pelvi~ ~ll tunoral ~ormatio~3 15 w:th the e~cceptio~ of ~, ~mall tWllOX on the ri~ht ~lde ~Q:~` the ~ e o~ ~ child ~ t ) rc~olve~; no ~i~ n~ o~
mot~Qtic ~?lsuritis.
2. q~he ~ub~ ective ~tatus i~ gOoa. Plan.s to ~e1i ~.ar-riodO Early .in April sh~ ~Y~ rnal~ried; reIu~ed a~ny ~x~a,t-20 m~nt ~or ~pril ~n~ ~IQ~ ense~ ~b~ent for ~ mcnu':s ~t~--te~d on I,t.~y 1.
In the mid-~ay, 1990, h~ e~e~,:the~ ppe~od 3i~n~ .
o~ metn~t~tic pleurit~: hard bl~cathillg, ~luid l~ t~o l~t.
~_ lu~ up ~o t~e 3xd ~ Cllan~e9 ~2i th0 ~all p~ v ~om ~3~ 18, 1990, shs Yra~ ~iYon a.cours~ o~ s~t~
mic ch~motherapy with c~cloplio~hane ~ n ~n . ~utpP tient w~rd w~th no result: pleuritl~ progre~ d ~'luid up to the 5th rib~, .
on Jlme 4, 1~0, the ~*h co~ O~ til~3xa~ th the 3 ne~ pharmaceutl~ l W~3 ~rted wlth a dail~ dose of D~
line 3 ~ Qnd. mct.hylt~tc3te~0ne 3 ta~lo~ .()15 g), b~cau-the patient, duo to a very hi3h l~bido, re~u~d to take 5 tablet~ pet~ dn~ (0,0.25 g), int~r~ g ot~er~ 3e ~o di~con-t~r.u~ any therapy~ I~ 2 week~ o~ the J,ire~tme~ pleuri~
decrea~e~ n to th~ 3~d ri~), re,Q~ir~tior, b~camo ~-~ier.
~ y th~ l~c~u~e~ o.~ ~he physici~n-~n-char~, chc~otile-23 FEEI ' 94 15: 2;~ P . 35 ~ 2 ~ 7 ~1 . . .
rapy ~th cyclopho~phQne (2 wo~k~) was ~ltexnated ~th the treatment u~in~ the ne~r pharm~ceutical t2 week~), ~ter t~Yo suoh alternation~ the patient refu~ed to ta~e more chemotherapy v~th cyclopho~ph~ne because each time it cau~ed very ~trong aller~ic edema o~ pude~dal lip~
a~d l~r~nx not ~110Y~ at~d by t~lo n~t~r pl~rm~o~u tloal.
¦ For ~ year ~Au~ust, 1990 ~ Au~u9t, 1991) the p~tient carried out ind~pendent treatment ~Yith the new ph~maceuD
tical in oourse~ o~ 1-2 months i~ the sQme do~es w~th approæ~m~tely one-month inter~als, However, the ~enerQli-z~tion of the pro¢es~ continued slowly: there ~ppeQred ~ :
a meta~ta~i~ in tl1e le~t brea~t, in the i~t~rpleural area there a¢cumulated the ~luid which in thi~ period w~s removed 3 time~
S~nce it appeared de~inite that mnlignant neopla-~ia9 by the end of that year ~illing the ~mall pelvi~
h~d complotely lo~t ~uscept~billty to hormono~ ,on Au~ ust 13, 1991, the treatment with the m~chQnical mlxturc ~a~
startod: 3 ~ o~ D~ linc, 0.005 g meth~ndro3tenolone, : :
and 0.3 ~ phthi~azid per day, All t~l~ mixture ~Ya3 ~
ded into 2 sin$1e dose~ in the morn~n~ ~nd the evening;
eQch con~i~ting o~ 1.5 ~ Dl-valine ~nd 1~2 tablet methen- :
dro~tenolone, 1/2 tablet phthi~azid ~ith warm milk on an ampty ~tom~cll~ ~ cour~e o~ 1 month. . `:
_, 25 ~hl3 treat~ent app~rently cau~ed oxtensive necrotic generation of meta~ta~es in the i~terpleural cavity: the temperatuxe rOSQ ~ig~ by the e~enin$, se~are coughing deYeloped, hard breathinB. Vomiting occurred onco in 1-~
da~r~ ~ th~ Yomitu~ containln6 dark 3truoturele~ masse~
a~ter th~ the iever dropped~ breathin~ b~came ea~iar, but coughing did not ~top.
~r the p~tient 13 raquest is sep~ember 1991 9he WQ9 q again gi~en a 1-month cour~e o~ treatment ~th D1-~allne ~ (3 g~) in combinatlon ~th 0,015 g methyltestosterone.
j~ 35 Cou~hing ~lightly decrea~ed, ~omiting ~topp~d, hoY~er, ~ the ~el1eraliæ~tion of the proCe39 con'i~ued: the metas-j t~is in the bre~t bc~n to grow out into t'ne back mu~-cl es .
~j .
~ ~cl: ~4 1~i~4 P.3ti 2 ~ 7 ~1 ~ arl~ in octob~r another course ~as started with a mixture o~ D~-valine, methandrostenolone ~nd phthivazid in the ~ e dose~ e couEhing incr~ased, ~requen~ epl-~ode~ o~ su~ocat~on de~eloped,a.ttempts at the ~luld pump~ng out showed the absencc o~ the latters apparentltr .
the cavity ~ra~ ~illed with tumor ma~se~. Cardiac weak-nes~ increased. No paln~. ~he patient ~ldom le~t the house because Or dif~lculties in climblng the ~tairs, but at home she read, ~Yrote, ~reely ~o~ed about the room.
On ~ovember 8, 1991 the patient dled of a heart Qttack ~or 30-40 mln, She had lived mo~e than 2 ye~
~rom the time she had baen con~idered to be i~curable.
The conclu~ions ~ e succe~ in prolon~ation of the acti~e li~e ~ thi~ youn~ woman c~nnot be as~ociated with the treat-~ent ~ith the new phar~aoeutical elone because in the 19~ year she receivad the con~entional chemotherap~t cour-~e~ ~rhich ~he coul~ hardl~ tolerate each time.
2, ~he turning point towards tlle n~w ~eneralization ~ the process fell on April-~.lay when all the traatme~t ~28 dis~ontinued. ~hi~ ~hould no~ ha~a been done. Slnce our treatment t~as onl~ YoluntarJ w~ had no rl~ht to in-~i~t.
. . . 3~ ~h~ u~e o~ the miæture o~ D~-vallne, methanaro- 2~ stonolone and phthi~azld, in our oplnlon, ~'rQ~ too delay-ed ~nd the time had probably been 105t ~or it~ optimal - e~fect.
~ he new pharmac~utlcal v~th the antitumoral activity in th~ ~or o~ ~ mixture o~ DIr~al~ne and ~mall doses of 3o methylte~to~terone ~!~a3 lnit~all~ tried ~n 33 patient~
(volunteer~) t~th malignant tumor~ of genitalia con~ir-med hi~tologicall~ as cancer of the ~ollo~Jin~ localiza-tion~: ~ali~nant ovar~ cancer~ - 9 patients, malignant tumor9 o~ the uterus bod~ - 21 patient~, cance~ o~ the uterine tube - one patient, cervical cancer - 2 patient~.
~ ith the sxeption of 9 patient~ ~lith the uteru~
~od~ c~ncer in the II~ tage o~ the d-lsea3e ~o~
23 FE~ '94 15:27 P.~37 2 ~
_ _ _ the ne~ ~harmaceut~cal wa~ u~ed a~ the fir3t ~tase of tre~tlten~ ln the pre;operation pe~iod, all the ot~cr pa-tients wore in the III-IV ~ta~e o~ the disea~e a~d ~y the time o~ treatment ~rith th3 new pharmaceutic they had been given the convention~l tre~tment or chomoth~rapy alone, ~thout ~ny o~ect, having larg~ immovable tumor ccn~lomerates in the ~mall pelvi9 oe esudate3 into ~2-riou~ ca~ities, ~ome o~ them had xelap~es of th~ di3e~ise a~ter ine~fective combinea treatment.
~i~.o~t o~ tho p~tient~ treated ~!~th the new pharDtaceu-tical a good (tumor~ re~olved) or ~Qti~f~¢tory e~ec~
Complete lack o~ e~ect w~ ob3erved i5 5 p~tients only.
ln ~our of th~m the tumor~ w~re de~ln~tely ho~to~e-un3us-coptible: cervical c~ncer, uterine tube cancer, sarcoma 15 On the uteru~ body, and the ~th patient wQs pre~ented ~or tre~tme~t in a ~ery ~e~re o~ndit~oll du~ to r~p~d ~enerallzation o~ the proce~s.
~ he propo~ed pharmaceutical wa3 al30 tested in 5 incurable p2tients suf~exin~ ~rom tha mammPry gl~nd can-.~ 20 ¢~r ~th metast~es into bo~e3, ~th groi~n~ out meta~ta-j se~ int;o the s~u~cles o~ in o~ the chest t~/ho were dis-ch~rged for ~ ptomatic treatment in a vér~ ~evare condi-tlon a~er ine~cti~e irrad~at,$on therap~ and 10-12 cour-se~ o~ chemotherapy~
`~ 25 In one o~ these o~e,q, a~ter a long-term hospital . treatment ~t~3tases lnto the bon~ o~ ~e slmll~ pol~
ribs led to the pre-terminQl condition.o~ the patient I and ~ha was brought ~rom the ho3pital on tha stretoher~.
~h~ o~ct o~ th~ tre~tment witll th~ me¢hanical mixt,ura 30 o~ 2 g DIrvaline and 20 m~ metl1ylte~to~qt~rone w~3 both ~ubJRcti~e and ob~¢ti~e. S~e~est pains usuall~ accompa-nyin~ ~uch meta3ta3isin~ which coild only ba ~topp~d ~or 11/2-2 hour~ b~ trimep~ridine h~drochloride tpromedol3, be~Qn to ~ub~ide ~nce the 3rd day of treatment and co~-1 3~ pletel~ di~appeared w~thin 2 weelc~. A~ ~ r~ult, ~ a ! month the patient started to get up fro~ the bed Qnd ~ru~u~lly b~c~ms invol~ed i~ th~ ~cti~e life. Ever~ 2 month~, the ~ected par~,~ o~ the ~keleton were ex~.lined ~1 1-.~
~ 33 -by roentgen, Si~ns o~ beginning reparation o~ th~ bone ti3~ue were observed ~n ~kull end pel~l~ bone9. ~7ith ~hort interr~l3 o~ 1-1'k weeks the p~tient too~ thc treatment in the outpctient ~ d ~Ol' 8 ~onth~, unt~l she d~ed o~ throm-boemboli~m ag a reeult o~ lon~-term uncontrolled taking o~ calcium chloride for 3 months, ~ ntil the la3t day thi~ pQtient actl~aly did the house wor~, went shoppin~ ~ld to th~ ma~l~etl In 3 cases, t~eatmsnt with the mechan~cal mixture of lo D~valina, methQndro~tenolon3 and phthivazid resulted in temporary but well ~arl;ed sub~ectiva imp~o~ement in ~he oondition o~ the patients which finally ended a~er an-- other course o~ chemo~herapy b~c~use they were a~ai~
hospotalized into ohemo-ho~mone therapy department o~`
Ro~tov ~es~arch In~titu'e o~ Oncolo.~y.
In one oa~e, ~uch ~ub~ective considerable i~npro~e-ment s topped sharpl~ durin~, the trea "ment with the pro-po~ed pharmaceutical beca,u3e o~ tha ~,res~ condition o~
the patient de~reloping due to her personal problem~, She 20 ~la~ not hospltali~ed.
q~lle observationa c~L~ried out b~r the author ~ho~ed the trea~nt ~rith t~le propo~ed phnrmE~cauti¢al t;o ~ re mQinly s~tia~actory r~sult~ e~en e.~,er prevlously per~or-~ed ine~octiYe chemo~-radlation therapy.
llhe tec~nical re~ult o~' th~ in~relltion con~ s in the ~ollo~ ing.
I`he phar;nacoloeical properti~s o~ the propo~od pharm3.cautical ~tudied e:cporimentall~r ~n i~duoed hori~ono-~iusceptible tumor~ o~ mamn~r canc~r in ~ antl in nor-30 mal animals, a~ well QS the dat~ obtained clinic~ in treatlttent OI ~rolunteer~ in incur~l~ case~ atte~t to i~9 co~nplete harJ;tle~ne~s, sufficl~ntly t~tar~:ed ant,lblas~lc prop~rtie~ with simultanaou~ s~imulation of the defence foroos of the bod~r ~d an~1~et1c effect.
.,~
~ r~ 4 l~:Jl P~39 7 ~ ~ :
:
34 ~
A P~A~CEU~ICAL E~R~ING AN~ ORA~ AC~ Y ~: -~gend~ for Pl~ures Pi~ D~,~A-i~duc~d ma~m~xy glQnd cancsr in x~t~ :
1. Control - glandular-sol~d can¢er o~ th~ ma~mary gland in rQt (untre~t~d). Ma~ni~i¢at-ion x 160.
2. ~cpe~imont - a~ter tre~tment ~it~ D~-valino in mlxture witl1 m~thylte~to~terons ~reg- -~
re3sion). I,larlced dy~trophic le~ioi1s ~ ~
in tumox oells: predomi~ant ~aouola-tion o~ the cytopl~m and ly9i~ 0 both nucleu~ end ¢ytopla~m. i.~gni-~ic~tio~ x 200, ~ig. 2 - Adcnoc~rcinoma o~ hum~n uterine body.
~pir~tion ~rom the uterin~ cavity tcytolo~y) 1~ ~s~ore ~reatm~nt. Ro~ette ~truoture~ from elon-gatsd a typical c~119 0~ the c~ dor ~hap~
(magnific~tion ~ 600, im.).
2.. ~ra~me;1t ~or 2.weeks ~ith D~-valin~ and me~hyl-te~to~terone~.~acuolation o~ th~ cytopla~m and nuolei o~ t~moi- c~ell~ ~mn~ni~lc~t:Lon :1~600, lm) 3~ ~e~4m3n4 for 4 v~eeL~ vri'Gh DI~Yalin-3 and methyi~-t~s~nf~t:erono~ J~la~kod ~3broh~r;o~ ;u~le~s fu-- ~on o~ ~mall ~a~uole~ ln cytop~m ~nd nucle~
o~ tumor cell~ (m~gni~ication ~,6,p,o, im.). .
4~ ~rea~me~t ~or 10 day3~ A ~ayer oi d~stroph~callg chan~d cancer cellss l~oorrodod" outl~s o~ the nucl~, ly~ o~ individual nuolel (ma~n~c~-tiOl~ X 60o, lm.).
. . .
phtllivnæld ~a~ ~ound cmplrlcall~ to b~ 45-50 ~k~ bod~
wo~ht. A co~sidera~le ~ncrea~e or dccre~ o~ the do~e eith~r does not af~eo~ th3 tumor growth or may even ~nhan-c~ it.
~'able 1 A phr~aceutical e~ertin~ antotumor~l acti~lty ~ ite random-bred ra~ ~th induoed m~mnary glQnd cancer.
~reatme~t: D~aline (550 m~tkg) ~nd methandro-~~ ~tenolone ~25 m~ ) in com~ari~on with untre~ted t~nor-bo&ri~ ~nim~13 (condi-tional tumor size~ in cm3) 15 ~,~ Initial I n t e r v a 1 9 I~o. dat~ Je~lc 2 ~leek~. 3 weelss 4 ~q~
CON~RO~ GROUP ~untrea~d) 1 4 7,~ 20.2 37.3 died 2 ~9 5.7 7.0 .13.3 20~
20 3 a~ 6,o10,2 16.0 25~1 d~ed b) 5,05vO 5.3 B.2 4 5.16.6 7.l 7.~ ~.0 ; 5 7-312.5 19,0 30.2 42.0 ..
6 a.o9.6 20,0 ~6.0 di~d 25 7 ~,84,5 9.5 14.2 23.0 . 56 ~ 2 7 ~ 3 1 0. 3 t~h 5,.3~.7 11~6 ~n.2 20.7 ~ean and ~ariat-- io~ ran- .
30 ~ 3.~-~.0 4.5-1~.5 5.3-~0 7.~-37.3 a.O-42~0 P: compari~on <~0.05 <0.01 <0.01 <0.01 ~th lniti~
,~
P R O G P. E S S I O IT
. ' ~::
. ~
23 FE~3 '94 14: 43 P. 13 ~_ 2~3 ~3 ~1 ~
Tablc 1 ~cont~nued) : :~
R~t~. Initi~l I n t e r ~ a 1 s .~,, No, tlata 1 r~ek 2 weëk~ 3 weelc~ 4 ll;e~Ls ~ re~
re~-~o~
EXP~I?.~ r~ I, GROUP (DIJ~ ne L~nd metllandro~
~tenolon~ ) 4D6 ~4 3.4 2"1 2~0 56 210.5 11.2 6,9(nec- 6.1 5~ 52 ro-35.5 5.7 ~7 2.8 . ~ 2~3 ~o 4 7,2 3.4 ~.6 2.7 ~ 2,1 71 55.2 ~.0 2.~ 2,5 ~ 2.~ 57 61.7 5.8 5.5 5.8 ~ 5.5 30 7G.6 6.3 5.6 ~.6 4,2 36 6.3 ~,0 .~0 4,3 , 3.3 50 1~ 9 4.5 3.7 3,6 2.8 ~i 2.0 53 mo 1;~ o 6. 5 5. 3 ~ ~ 3- 7 ~ ?,. ~ 52 moan . . . . ~.
ana VQ~
ria~ion 4 ~j 3~0 11,2 2~-649 2.~-6.1, 30-71 P - ~>o,05 <0,05. <0,01 -. ~0.
. 2 0 . PL E ~ P~ E S S I 0 P - corapar~on o~ eaeh ~r~e~: witll th~`~it~l da~a.
oompars.t~e analg~ w~th th~ pr7~otyp~ - oil-~olub-1~ synthe~lc te~-.,ost~rons dcriYati~s~ ~lnisterad ~ n-t0r~ donc on the baæi3 o:f th~ Rxpo~m~ntal d~ta sho-25 ~Jed the ne~r s,ll.e~,Gd ant~tur.~or dru,s,r to b~ Ri~;nilicantl~r erent Irom t}la kno~vn on~
1~ ~rl~ alle~ea antitumor dru~; e~rl~ the anti~la~ tic e~Ieot b~ t}lo close interaction of 2 componenl;~ OI a rnech~-nical ~tu~c: DL-valine arnixlo acid capable o~ roduci~
30 Qn idependellt cytolysi~ e~ect onl~r ~xl indl~r~du~l mar,lma-$aTn c~ cer c~ in Yitro and a~ ~ndro~.3en o~pi3ble o~ per-~orm~n~ in ~ ~T~ nollthor9,peutlc do3e J~113 role o~` t,h~ con-.
~ , . .
~ " " ~
-23 FEB ' 94 14: 44 P . 14 - ^` 21~.6a7 1 ductor o~ 3 ~no ~cid i~to .,h~ cell3 o~ ~ ~ol~d m~nuna-lia~ tn~liænant t~nor.
2. ~he ~ e~ the m~chanic~l mix.turo ~Yith D~-~aline aclino arCl~ contal~n, in co,npaxison wlth tho pro-tot~,rpe ~25-~',0 m/l~), Q lottr (5-10 m~X~) ~o~ltl~er~peutic do~e o~ a 1;e~to~JI,3ron~ deri~rati~e, methyltesto3teron~, e~orting no ant~bla~tic e~fecl; ~Yithout Dl,-v&line,.
3, ~o n~YJ ~nl;itumor dru,~ d~ers oon~iderably ~OT:~
th~ p~otot~rp~ al30 by ~highly ~`ecti~,-e antibla~tic s,c~
10 l;ion:
a) in t:he pxo~ence o~ se~roxal tutnor.s in ~ anin~Ql, tha '~m~in" tumor~ ~ioh ha~e ac}~oved ~ con~roll~ble ~e ~4~0 cm3) under~o resolut~on :~il"St 01' ~ m~Ulta~l~lOUi~ly ~Jil~.h l'ædditional~1 onos;
b) ~o disconti~u~tion of re~re3~10n, or occux e~ce oi' xel:~ia3ion ~ollowed b~ ir~ttexsible tumor ~J,ro~th i.~ o~-8erved upon adminis~rD.tion o~ ~he ne~l prep~tion;
C) llo r~lap~es o~ turnor growth ~ ob~erved ~:~ter oo~plete resolu~io~ ther~ol;
d~ in repe~ted u~o o~ the ne~J preparation, no l0313 o~ sen3it;i.vi.,3~ to ~ t i~ ob~erved;
a) daily ~dmi~istration îor 30 ~ay~ o~ "he propo~od preparat~on producs~ the re~;~es~ion ef:E~ct r~lated ~Lth the de~oe OI tumor hormone-~3u300ptibilit~J and meth~Jltestost~
25 rone dos~ Yith a do~e of 5 ~g/kg per cent o~ general Y~eg- :
~e~sion ~ 89% ~10%.o~ tu~or~ did not re~ol~e - 2 out o~ :
17); cot:lplot~ re~re~sion tdi~pp~aranc~ 0~ tunors) wa~ ob-~arved lrri~ G55~ of tuDIo~ (11 out ~ l7? and p~rtial re~
ra~ioll (b~J 53%~85$ o~ the in~t~ e o~ the t;umoY~) :
30 ~rith 2~%, th~t ~ r tumor~ out o~ 17 tsee ~s.bl~ 2~; rrith ~o~e o* 10 mgJI;g ~oneral re$~e~sion rla3 ob~erved urith 100S~U of tl,;mor9~ thal; is, all the t~ or~ ~93ol~red on tlls ~ r~go by ~30~?7, oo.~r.plet:e r~:Tr~ssion with 20%, a~l in ~0%
o~ the tumor~ r~olution achie~Yed 61% to 955~ o~ tho i~$-35 ti~l size o~ 1;he tumor wihin 30 day~ o~ tn~ e~p~rirnont (~e ~,3~1~ 3). ::~
4. ~.h~ Qlle~3ed a~ltitUmor preparal;ion, in co~tr~3t l;o 23 FE~ ' 94 14: 46 P . 15 2 ~ ;3 7 ~
the prototype and other kno~m oyto3tatic~, alon~S~ld~ r,ri1;}
~he re~ol~in~ e~ect OIl ms.lign~ll; I;w~or i~ al~o capable i;o enh~ce the de~e~ce ~orce3, ~,1. r~ tanca to ~lmor o~ tlle tumor bee,rer, ~ indlcated by:
a) ~ ni~icant incr~a~e in the boày ~r~i~h~ OL tho a~imal Rccompany~ng t~3 re~re~io~ t~ee ~able 4~;
b ~ ha~mopoieei~ ~timul~tion lea~l~g ~c. normali~at-;io~ .ereof ln tlle courF~e o~ twno~ re~re~iorl tsee ~'able 5);
c ) a si~ni~iG~nt increa~e ~2-3-~old) OI t;h~ ~u~
~ral ti~le oi~ the arims,ls in ca~e~ e~ C~1t l~
tumor e~ect achiev~d in 30 d~y~ o~ tll~ e~perl~ent Q~
cor~pared with that oî cont~ol (un,,~e~l;ed) ~nl~ a~t;er t~ ination o~ the e~p~ritnent.
. ~able 2 A phQrm~c~utical e~;ert;lnz antiLurl~.ora~ ac ~i~rity Induced m~ ary ~ nd c~cer ~n r~ndom-b~d ~/hit~ ~erns,le rat~. Cond~tio~l tu~lor ~i~ec3 ~in cm3) in ti3:~tms~t l,~it'n 5 m~sJ~;~; snethylteeto~terone ~r.d 5~
Re,t.I~litlal ~umor ~ze~ ~Liver ~n~,e~v~l.s o~.
~o. da~,a 1 week 2 w~ek,s 3 w~ek~ 4 wo-elc~
CO~ROh GP~OIJP (u~.,rea'~s~) ~.D, .7,5 11.5 ,c ~ 21.,3 '2 4.6 6,~ 7.1.~ 7.1 7.3 3 7.2 ~ 8.4.1~ 14.~ 17.2 7.~2 12.0 1~.2~ 30.5 5~.~
~,1 9.3 22.1 ~ 3Z.4 di~d G 3.9 ~,22 23.~ iecl - 7 3.8 5~3 ~ 15.a 21 . 30 ~ 3 3.S 5,~ 5.9 6.7 9,6 : 0 1, ~ 2 .. 7 4 . 7 9 , 7 9 6 ." ~12, 5 13 . 3 1 S . 1 21 ~'~3 G.3 2~5 35.5 ~led . ~O.Oe' ~QtS~ 10 ~5 I.lorS ~' __ ___ !~
23 FE2 '94 1~: 47 P 16 2 ~ 7 ~
....... ~ _ -- 1 1 ~
~abl~ 2 ~conl;inuod3 . _ Rat.Initial ~umor gi~se~ ter intervs,l~ o~
No. d~ta 1 week 2 wsek~ 3 week~ ~, w~ei~
Arithm~tic 5.2 7.5 12.7 13.7 ~0~8 mean and ~raria~ion ranses (3. 8-7 . 2 ) tl . 8-12~ 5 ) ~2 . 7-23- 4 ) (4 69-; t~ 3-P in compari~on ~0.05 ~01r01 ~0.01 ~0.01 wlth initial 10 datc, (be 1rre~1~9 in ¢ontrol eroup ) P in compariBon 15 o:~ control end experlm~nt~l ~ 0,05 ~0.01 ~0.01 ~;0.01<0.
anlm~l~ (by ~teeks ) E~ JT~L GROUP (treated ~ith the p~apax- :
~tion) R~t~Initi~l ~or ~3iZ9S a~tex intcr.tr~l~ o~ :
~JO. dF''I;Q 1 ~'IL'~3 2 l~r}~3 3 r,rl~ 4 ~Jk~ % re~-~e3~3-0~1 1 4~ 2~0 0,81 O 0 100 2 4~2 2~2 0~7 0-4 100 3 4~1r 1~0 0~0~1r 0 0 100 4 4~0 0~8 0,0~ 0 0 100 5 a) 5.6 ~.~ û o O 100 3~ b) 1.0 0.8 0 0 0 100 ,6 ~,~9 ~,7 3~8 2v8 1.0 80 7 4.~ ~0.4 0.1 0; 0 100 :8 a) 6.4 5.3 ~.8 2.9 3.0 53 : : b) 0~2 0 0 0 0 100 9 : 4~7 3.5 1.1 0~1 o 100 ~' ' ~ ~ .-: ", . . . , : ,- ,.
Z3 FE13 ' 94 14: 49 P . 17 ~a~l~ 2 (oo~t~nuod ) R~. Ini~i~l D.r.o-~ ~Iz~ ~% r~
5, 7 3 . 2 2 ~ 2 1 . 0 0- 10~
11 7.6 G.5 3.9 3.5 2,074 . 5 1~ ~7 3,,2 2,3 1.2~ ~75d5 13 7,8 4.G 5~1 2,0 0 100 14 a) 6.2 7.3 7~5 ~.7 10.7 3 ~, 2, 5 3 5_ .
~o. O:e , .
_ rats~tu mor~ 1 __,_ ,__ "_ ,_ , ,"_ _ __ _ , ... ,, _~, ._.. __ , .,.. _, ~.. , _ ~ithmoti~c ll~7 3 2.1 1~5 : 1~2 82rj~
'Q,at~Ldn ~o~ 2-7 . 8 3 tO-7 . 3 ) tO-7 . ~ ) ~0-~. 7 ~ ~0-l o. 5 ) (o-1 oo ) rQnge~ j, . ... mor3 p in coT~pari~ , I;um.
son t~i"h in~- <0,01 <0.01 ~o.ol <~,01 ~>50S~
t~ al data 2 tum.
(by ~e~ks in . ~with-20 ~:~?cr~r~ental .. out . ~;roup) . ~ s~ sn~
b) se~rer~ ~ur.~or~ ~ n o~o ~nt:.
.:
. .
23 FE13 '94 14:50 P.lE
, 2.~ 3 .. - 13 -T~ble 3 A pharm~ceutlc~l ex~rtin~ a~titumor~l acti~ity Induced ~mm~ry ~lQnd a~ncer in random~bred white mic~
(conditional tumor ~iz~ in cm3) tx~nted Y~th 10 m~/1Cs ~ethylt~sto~t~rone and 550 mg~1cg ~-v~line _ 5 R~t. Initial ~umor si~e~ a~ter intor~al~ o~ _ ~Jo~ data 1 w~k 2 week~ . 3 we~ 4 woelc~
G~NTR0~ G~OUP. ~un~reatsd) 1 4 7.8 20.2 37.3 died 2 3,9 5~7 7.0 13.3 20,2 10 3 a) 6.0 10.2 16.0 25.1 di~d ~) 5-0 5-~ 5.3 ~-2 . :
5.1 6.6 7.1 7.8 8.1 7.3 1~5 19.0 30.2 42.0 6 8.0 9.6 2000 36.0 di~d 15 7 3.~ 4.5 9.5 1~2 23~0 a ~.5 6.2 7.1 8.3 10.3 ~ : .
Ax~thm.
meQ~ ~nd 5.3 8.7 11.6 20.~ 20.7 Yari~tion 20 r~n~e~ ~3.~-B.0)(4.5-12.5~ ~5-3-20? (7.8 37.3)(a.0-~200) a~ com- ~ .05 <0,01 <0,01 c~0.01 pQred ~th ~nitial data _ P ~ 0 ~ R E S S I 0 ~J _ _ ~at. Initial Iu~or ~ize~ a~ter in~erv~l~ o~
~,o. ~a 1 ~Jee~ 2 ~reeks 3 we~k~ 4 ~eeks qO re~-r~_ ~ion _ _ .___ _ ~P~RIL~TTA~ GRoUP (D~-~alln~ ~n~ me'h~l-te~o~tero~e) 30 1 6.8 3~20.7 0.8 O.B 88 2 ~.o 4.3~.0 3~ 6~
3 4,2 3.o2.3 o.~ 0 100 ~ 7,o 8.66.9 3.9 2.0 71 :~
7.3 7.45.0 2,~ 2.5 66 Z~ FE~ 'g4 14: 52 P. 19 & ~i 7 ~able ~ ~continued ) 6 6.7 ~.1 2.4 0.9 o.6 ~5 '1 7~,1 5.0 2,2 1.0 0.9 a7 ~.Z 6.~ 5,0 3.3 2.~ ~6 9 5,~ ~-o 2,3 1.6 0 100 7-5 7.8 5.G 4.1 2,9 61 ., ,,, ~, ,.. .. .~.. .... ~ .
AritlLm. 6. 3 5~ 4 3~ 6 2 . 1 1~ ~ 80 m~n a~d ~rLo.~ion 10 r~ges ~4.2-8.2) (~.o-~.6) (o~7-6~9) - . tO-2.9) (0~ ~-4.1 ) (61 -1 00) P a~ com- .
pared ~th ?0.05 <0.01~<0.01 ~0.01 2 tu~n~, .
inLtial . ~: 1007 1~ d~ta . ~ll " ' O i,~
.~ 50%
1~ ~ G R E ~ ~ I 0-~
5~bl~ ~
A p~l~rmaceutical e~rtin~ titumoral ~ctL~rity Induced m~rn~ry 6land cancer in r~ndom-bred ic.l~2le ~, ~ rat~ . Uei~ht chan~e~ (in ~,) o~ e~p~r.l~1;al ra1;~ ~
~,r~ated ~,~th 5 mg ~eth~3.testosteron~ ~nà 550 m~
25D~-~alinc p~r k~ bo~y ~lei~ht and c~trol a~l~m~
(u~;ro~ted ) during on~ month -.~
~;ti'$R~J~ OUP (A~ imal~ th ~nor re:l,r2s~io~) '.Y3~ we~
~lo~ Pl ~ wa~c 2 3 4 ~a w~el;s ~ck~ w~3k~ 1 mon-1 220 230 2~0 245 250 ~3 2 260 265 270 270 275 +15 3 24 0 225 260 260 265 ~25 4 200 210 215 220 220 ~20 35 5 200 210 220 235 2~0 ~40 . ..... ............. ~ ' F~
23 FE13 ' 94 14: 53 P . 20 - ~5 --~s;bl~ 4 (continued) .
6 160 1~30 18; 190 195 ~15 7 200 210 215 220 230 ~30 ~3 240 2~0 245 250 2G0 ~20 ~ 220 220 230 235 2~0 ~20 2~0 255 260 260 255 ~15 1 1 170 1~0 190 190 200 ~30 Ari~hmet. 213 ~20 230 234 239 ~23 variation(160-260) ~1a~2~t5)5 27()9 (195-275) P a~ r.OT;lpQ-~o,o5 ~,0.
red YJit~l ~ init;~al tby w~eXs~
15CONI~R0~ GROUP (with pro~re~ion) R~t.Ini- ln 1 in 2 in 3 ln 4 ~rteeka ~ i;t los~
~o, tial w~elc wee'.ca wl~ we$~ht~ o~ in 1 Tnonth tD~ ani- with ~al mor mal mal tu-wi~h- wlth- mor out out tumor tu-~ ~ mor~ _ _ 2go220 240 24 0 25020 Z30 -20 -0 2 250230 230 2~0 240 6 23~ -16 -10 3 220215 290 2~5 2002~ 1~0 -40 -20 4 240230 220 235 23050 1~0 -60 ~10 200.190 195 190 1~020 160 _~.o-20 6 2602~0 250 230 24020 220 _~o -20 Arit~;~. 23G22~ Z37 23~ 200 _36 -13 mea~ and ~rari~t-3 ion ~200_~190~ .,5- (190- (160-234~ (0-20) ran~ es ~60) 260) 2 9o) 285) P as ~o~- ~0.05 ~0~05>0.05 <t)45 pared with . init~ al tbY -weck~ ) , _ . _. _.__,.. ... .............................. ~, Z3 FE13 ' 9~ 14: 55 P . 21 2 ~ 7 i~
.. ..... _ ..
qlable 5 A pharmaceutical exertin~ itumoral ac~ivit~
Stimulation o~ he:mopoie~ ccompanying ~unor ~e~
sion in ~emale rat~ witll induc~d manunary gland cancer tr~ted w~th DI-Yaline aIld msthylte~tosterone (~;ho ~on-parametrical method o~ ~atl tical tr~atme~t by the "I" criterion of Wilcockson-;tla~n-Witney. ~he me~n valu~ and vari~t~on r~n~ ar~ presented), AniT~al Hemoglo- Erythrocyte,~ ~ucoc~e 10 ~roup3 bir by in 1 ~m3 in 1 mm Sally~
~' - te~t _ _ _ ... ...... . ...... .. .
--~ 2 3 I
-r~ormql ~7 4534000 5300 (10 anim~,l3)(84-90) ~402000û~4920000) t4000-6600) II
Controls `76 4165000 ,'9650 w~lh tu~or~ ~4~-96) (3100000-4~00000) :(7~00~12000) 20 (untreat~d) .
P in compari~
son OI ,~rou~s ~ .0 ~ 05 > . O . o~ ~0 . 01 ~ I snd II
III . ;~
~5 ~ .pQ~imental ~ 91428 . -.~057 ~rith tur;lor~, (66-g4) (3820000-4710000) .:(6900-13500) treQtod P ir~ compari- ~ ,~ ~
~on o~ $roup~ ~0.05 >0.05 ~0.05 II end III
. _ ,_~_._ .__. ___._", .. _ .. ~_ .. _.__.. " .. ,, . ___.............. ~ .
P i~. compar~-~on o~ ~oups ~o.05 >0~05 ~0.01 I a~d II-~
. . _ ,__ _ . ~,,__. ~
: ITotes ~ increas~, - Y decrease 9 r- - unchallged~
. ~:
23 FEE~ '94 14:56 P.22 ~` 2 ~ 7 ~
.... .~ ._ ~able 5 (continu~d) Animal ~o~ino-Stab So~,m~n- l~lono- ~ympho $roup~ phil~form~ te~i cyte~ cytes 1 5 6 _ 7 ~ _, 9 __ _ Normal 2,9 3. 4 38,7 5.6 5~.2 (10 a~imals) ~o-6~ t2-7~s) (19-56) (2-8) (36-6B?
II
~ontrol,q 2~6 7.2 62 1c7 27.~
l,~th tumo~ (o-5~ 0) (4-11 )(56 6B)(1-r~) ~22-35) -- tUntreated ) ~ __," ,,_ " ,,,,,_,_ p in comp~ri- ~ + t ~on of group~>0,05 ~0,01 ~0.01~0.01 . ~o.ol 15 I and II ~_~ __.~....~ .... - -III
~cp~r~ental 2. 0 3. 6 45 4.7 43 ~Yit}l 'tllt;lOY'g ~ ~0, 5-4. o) (2, 0-5. 0) (31 61 ) t2-~) (31 59) treated 20 P in comps,ri~
~on o~ ærouP~ > 0.05 <.Q.5 <0.05 <,0.05 <0.01 P in compari- ~ ,_ ~ .. ~ ~
son o~ ~roups ~ 0 . 05 ~ 0 . 05 ~ 0 . 05 ~ 0 . 05 > 0 . 05 25 I ~nd III
~ ,............................................ .
I~o~e~: ~ a lncreQi~e, ~ ~ d~or~a~e, ,-~ a unch~l3od, `i.' ' ' ., ' ' ": .' , ,.:. ., . , . '' ~ ' . . ...
- - Z3 FE~ ' 94 14: 58 P . Z3 2~ ..37~
~able 6 A ph~rmacoutical e~csrt~n,~ ~ntitumo~l aoti~rity ~lle e~ect oi~ ~ mixture o~ D~-valin~ ~550 m~/k~), methandro~tenoloIle (25 ~g~lcg) and phthivazid t50 clg/l;~) on l~r3e .~ tumo:r~ (or on several tu~
mor~ ~n one animal) of induo~d ms3n.~ary gl~nd cancer ~n ra~dom-bred white rat~ . tConditional tumor ~ize~
in cm3) . . , ~ . . . _ . ~
I. It~eated Qnim3l~ (e~,~porimenta,l) R~t Mo . Ini - At- ~ n ~ :3rvg,l~ t;J~ ) c~ re~
~l 1 2 3 4~ 5 6 ~lo~
a~ 18~5 8~410.3 11.9 11.3 6.2 8.9 52 ~) 1.6 3~3 2.1 5-5 4.~7 10.2 8~5 2 24.0 2g.6 23~.9 16.5 4.4 ~.9 6.~ 73 ~c~o -s~ ....
3 11.D, 10.. 9 11,4 1~.1 . 1~;J5 2207 ~1,7 -~) 10,8 7.~ 4.3 both ~u- 2 togai 2 toge-2 to- 75 ~ed ther ther ~e~
.'.; thsr b) 3~Z 2.7 1.0 -3.4 -~.5 -3.0 -3.5 .:
~)1Z~5 6.2 4.3 1.9 i.2 o 0 100 b) . 0.~ 5.0 2.7 2.5 0 0 100 ~ .
6 12.0 12.2 4.~ 0.,8 0 ~: 0 0 100 necro- .. ;. .
7 a)16.5 7.3 4.3 3 tumor~ 3 to~- 3 ~0~2-~u~ ~d ~hor ther 2 5 ~ n t o o ~
b) 3~7 2.9 1.6 -13.4 -20~0 -21~5 -c~ 1.û 1.9 3.7 -19~2 ~)10.1 8.9 0 ~ec- 0 0 . 0 0 100 b31.2 1.0 ~o~i~1.0 1~2 1.9 1.5 9 ~)11. 0 2, 5 necr. 0 0 0 0 100 . b)4.2 3.4 3J0 1,5 0.9 1.0 o~6 ~G
o 9.~ 11,5 ~2.3 7.1 5.~ ~.7 3.6 61 ~,., "., , ,_.__A_.,. .. ~ .. .....
No ~ oxe` 1 6 17 17 i 7 q7 17 17 1 ~)r tumor~
23 FEB '94 14:59 P.24 2 ~ 7 ~1 ~ble 6 ~cont~nued~
Rat ~Jo. Ini- ~t intervals o~ ~w~ck~ 7~ r~;
tlal 1 2 3 d, 5 6 ~ze_ ~ ~ __ .. ~_ 5 ~ ra~
ria~- 9.,~ 7.0 5.5 5~3 3.7 4~4 5~ w:l.t;h-~on (1.0~ (0.~- (0- ~0- (0- (0- (0- out ran 24.0) 29.6) 23.~ 19.2) 15.5) 22,7) 31.7) e~-g~ 2 ) 1 ~d t.urn, ~yt~r.- re .~;r.
ol,~m0an 3) 5 P ~oomp~ ~ ulith r~ær.
rison ~rl"h ini- ~0~%
I;~al d~-t~) ;>0,05 ~0,05 <0.05 <0.01 ~0,01~0.01 (C-II. Untr~t~d ~nlm.c~ls too~ltrol) _ ~1.5 18.. 4 21~8 30.5 ~2.5 .~isd 2 . 9. 3 22,, 1 33 . 4died 3 12.5 13.3 18,1 21.0 2~'3.7 3B~3 died 4 12.0 19.2 30.5 42.8 50.8 59.~ died 9.5 15.~ 21.7 3g.2 43~6 di~d .- .
G ~ 3.4 5~4 a.2 ~.6 . 15c1 b) 5.6 7.0 8.9 10.0 .12,2 dlod No~ ~
~umox~ 7 7 7 6 6 2 ~JI (Yar~-~,tion 9.1 14,,5 20,7 25,5 32.1 ~) ~2.4) (5271) ~3624) (~2.6) 50.2~ ~.. ,... ~ ~-P ~cor1pn--ri30n ~Ji.'ch <0.05 ~0.05 <,o.os <o,o1~,0~01 itial ~ ;Jotc~ 'lhe~ 2-3 ~ or~ :Eusod ~nto one, th~ ~ati~tic~l -~ree,tm~nt toolr 5 tltO a¢count 2 or 3 1;wnors-2" ~Iho tumor ~ze equal to 0 (r~3x~s~on) wa~ con-~id~rcd ~ one tuT~o~
,, ., . . .... ~
23 FE~ ' 94 15: 01 P ~ Z5 2~.6.~7li 5. In contr~t to other cyto~tatic dru~s, the alle-ged pharmaceutical durin~ the ~roce~s o~ t~nor re~res3ion can e;cert an anal~et~.c ~f~ct as w~ ~ollo~d in th~ ex-periment~ signi~ic~nt incre~3e in th~ thre~ho~d of the pain e~:citabilit~ and,co~equently, ~ d~cr~a~e in tl~e pain sen3~ti~ity in ani.mal~, In the ab~ence of re~-r~3ion th~ an~lgcti~ f'eot: o~ 1, and thi~3 m~.y b/3 used clinically ~or the evalu.~iion o~ the ef~ec~ o~ t~e-rapy.
6. In contra~t to tha prototypo, ~h~ allo~d pharm~-¢eutical may exert the ~ntibl~tic e~ec~ on the lon~
terr.l growing cancer ~umor3 partially or completely lo~-ing their ~usceptibility to androgen~ which may be r-m e~per~mcntal ~odel o~ cl~nicall~ n~slected c~lc~r pxoce~s.
15 In thi9 ca3e the antitumoral prepar~'~ion cont2ins, in tur~ h D~-Yaline, ~1 ~n~bolic dru~ r,~eth~nclro~t~n:~
lone ana a k~o~m ~ntituberculo~i~ drug phthi~3~id ~',~ch h~ preYiously never been u~ed as antitor.lul~al d~u~s. In this ¢ompo~ltion, the new an~titumoral pr~p~tio~ exer~-20 1~ the anti~la3tic e~ect on largn .u-qed (2-3~ Qnd tre-mendous ~ingle ~:~erimentally induced tumorY (tlp to 2~, o cm3) c~uses the re~re~3ion o~ the ~umor~ acco~p~nie~ ~y xequent necro~e~. In this ca~a th~ liquid s~ructureles~
tumor m~e~ pora our, and healin~ o~ normal tissue~ '~;3-~_ 25 gin~ at thi8 s~to ~ee ~ble 6 70 I.~orphological le~on3 ~ch OCC~ in ~h9 t1~no~
t~3ue ~nd rG3ult in rcgre~3i.0n al30 ha~ their peculi~r f~atuxe~s unde~ thQ in~luence o~ th~ d ~a~in~ the~peu~ic e~eo~ o~ any chcmloal dru~ and ~ven irradiation the~e 30 oocurs marked ~ibe~ ~ormation, wherea~ the ~lle~erl ph~
m~ceutical influce~ chan~e3 due rao3tly to the l~si~ o~ :
ths cell~ o~ p~rench~ra ~nd ~roma o~ t}le tu~..or ti~ue, necroly~is with ~ub~equent re~orption (sae ~ig. 1~.
On t~e ba~is o~ ~h~ a~orementioned expeximent31 da~
and, a~pecially, taking into account complete harml~s~nos~
of t~P n~w antitumoral preparation teated and coniirmed in nor~al anim~l~ within the ~rama~ork o~ the com~l~ted ~ .
Z3 FE~3 '54 15: 03 P.Z6 21~.6;~711 ...... , . _._ _ _ _ 21 -pharm2cob~010~;ic21 pre-clinics.l trial~ we propo~e îor cli-nloal application a new a~t.itul~or~l pilarmaceutic~l con~
ting of a mechenical mi~c t~ ~ of 2 4 ~; o~ DI.-valine smirlo Qcid and a low non-therapeu1;1c~1 do~e o.o~o-o.02s e meth~Jl-testosteron~ per day ~or trea~nt o~ hormono-~u~ce~tible cQncer tumor~ in women, ~nd a phar~ceut~c~l con~i~tin~
o~ a mechanloal ml~ture o~ 2-4 ~ o~ D~-v~line, 0.005-0.010 ~ meth~ndro~tenolo~e an~ 0.~-0.5 g phthi~azid dai-ly *or tr~at~ent of canc~r tumors wh~ch ha~e ~artially or completel~ 109t their hor~none-susc3ptib~1ity, ~he dGily ~c3e3 o~ the propo~ed pharmaceutical for clinical u~s h~ve beon calcul~t~d ~rom the do~e~ u~ed e:~-p~rimental~y.
Thu~, the do~e for D~-~alir!~ ~a~ calculatad to be 2-4 ~ takin~ into accol~t the e~perimental do~a o~ 500-550 m~ .bod~ ei~ht of anLmal~ and at l~a3t 10 timc~
lower intensity o~ arnino acid metaboli~m in man; con~equ-~n~cly, a~ouv 50-55 mG~e~ body wei~ht o~ man oE D~-valine ~hould be u~ed or 2-4 g daily for a peraon ~Je~hi 50-70 ~^
~o doQos- o~ r, ~ t~::ro cl~laulut~d tn a di:EIerent way, since human and ~nimal sen3it~ y to t`,~a~ que~'v does r.ot corr late ~ith di~erence~ ~n the macabo~ ~stn lnten~ity, ~_ 25 A do~e o~ mcthyltestosterone 20-25 m~ or 0.020-~025 -:
5 ta~let3) per day wa~ o~lculated on tha ba3i~ OL
e:cperimOntal ~nd ¢linical data acoordin~ to which ~t3 oxperi~.esltal nonther~peutic do~s ~5 r~v~k,¢ bod~r w~ ht) ~e 5 time~ lo~ than th~ th~rapeutio one - ~5 rr.g~ an~
~al body weight. ~ on~ take~ into account that nand-rogen therap~ in clinic~l case~ o~ m~mmary ~la~ro ~pula-te~ ~ dose o~ methylte~to3terone of 100 mg ~r.d more daily ~ee ~uakin, Ya,I1., in t~Hormone therapy o~ rna~nary ~land cancer'~ .edi~in~" ~ubli~ers, ~,I., 1969, p. 6~-73), the non-t;1c~apeutic do~e should bs about ~0-25 rn~ daily. Sin-ce the dose o~ met'nGndro~nolone c~n~ot be calculated o~nthe b~si~ o~ ~ens$ti~i~y to it o~ the tumor ti~sue be-23 FE~ '94 15:05 P.Z7 .--`
. . _ . _ . . . _ cau~ it h~ ~evor been ussd a3 an ~tit~or~l d~u~, ~re ~de ou.~ c~lculation~ ~rom ths d~ta in the literatu~e (See IlPhar~aceuLical~r, I,l.D, rla~h'.iov~y, ~I,Iedizi~a~ b-lishers, r~,, 1985, pa~t l, p. 317; and dircct cli~ical ob3e~vations in treating ~ol~eex~. It wa~ thus est~b-li~hed that in ne~lected casc~ wi~h CoMplOte 1039 0~`
hormone ~u~ceptibility by the twmors it wa3 necessary to u~e methanQro~l~enolone in a da~ly doso o~ 5-10 m~ in co,~oinatlon ~th phthiYazid enh~ncing tl;~ col1ductive e~`ect o~ thi~ hormo~c. ~or phthivazid the d~ly dOBe c~lculat;ed ~:~om the experiiner.tal oIle with due con~ l-ders,tion o~ 10-fold lo~r~r met~ooli~m inte~lty in ilumuns _. ~3 compared ~ith ~r~all ms~nmal~ .. a dose ~or an e~peri-mental ~imal ~ra~) wa~ 45-50 mg/lcg body wei,~r,ht, ~or m~
15 it would be 4.5-5 mgJ]~ bod~ ;ht, or ~c~r a person .lei~.in~. 60-S0 k~ or mo~ it would b3 about 300-500 m~
~G. ;,-0. ~ ~ ) p~r d~y.
r';le st;udies oi:` tii~ antibl~ ic pt~op~rti~es o:E tll^
n~tr pharmac~ulic~l in the clinic, ~nliy i~ incur~bl~
20 ~rolu~teer paticnt~ yield~ the ~ollotrin~ data ~lgni~lc~
tl~,r dis l;i~gui~hin~, it fror:~ th~ prototype.
1~ r~ direct antiturnoral e~ ect o~ e propc3ed ph~rm~ccutical in the ~'orm of a mechanical mixture o .:
~-valine Q~d a lo~,~r nontherap~utic~l do~e o~ methylte~to-. 25 ~terone is att~3ted by the re~ults o~ c.~.tologi~l e.ca~l-~~ nat~o~ of ~lr~tion ~p~clr~en3 ~ror.3 tho ca~-ity ol the utorus ~ter ~dr,lini~tration o~' thi~ pha~n~c~utlc~l ln c~
3e~ O~ 9nOOarClllO~I~ O~ t~e ut~rus body in ~em~le ~ol~-t~era ~ivon no ~peci~ic treatment in thc ~re-operat~.on 3Q pariod ~rit,n th~ e:~c~ption o~ ~-valine in combin~ion ~rit'r. a lo~r doae o~ T3ethylte~to~terone. In all 9 patisnl~
~hi3 treat~er.~ resulted in a ~i~n~'~lca~ reduc~ion o~ ~he tumor, sizes a~ ~ell a~ c~s~tion o~ pai~ ar.d blood~ sec-retion~. In ~piration ~peciTnens collec~ed fxorn ~ever~l of ~h~se ~atients at dif~'erent inter~ (10 d~3, 2 we~
4 weeX3) we ~i`ound dy~trophic~lly alte~od ~deno¢~cino~n cell~ ~,'it~ n~ican~ valuolction o~ ~hi~ cytopl~m ~
nuclei, "cor~ododl~ outline~ of'. ~ nuclei, 1~9i~ of ~O;~B
23 FEB '94 15;07 ~,Z~
2 ~
r.uclei and me.r'~ed v~Lcuole d,~-stro~h;y (s2a ~
. In 1~e~7ec1;ed c~ei~ roco~ni~eul ~ corlpl~tel~ c~r-~ble, ~di~inia'"r~ on o:~ the r.o-~r prap,~.rQtion ~3 a mictu~e OI' DI--valin~ wit~ methylt~to~arona 03~ wi.,h mo.,'.q~Ld~;~o-5 ~1;c~lololle ~lld phth~ v~id Y~e~ulteù il~ ni.~.~i.c~t I~7~olon-gation o-~ tlle 3urvlv~1 time o~ th~ p~tient with 5at~ ac-tiO~ f ~ul~j ac l;i~ condition ~qnd in ~o~e ca~cs ~ith ~he ot~-j~ctive siltibl3st:lc ~ec1; - ~301ut~0n o~ ~h~ tumori~.
3. The action o~ t:~le ral,/ e;ltitumoral pllN:;~rllacoutlc lO Ll.~3 earl~ a~ with~n th~ Iir~t 7-10 ds.ys comt~l~Jel~J elir~i-nat~3(l t`ne pa'n ~drome e~n in t`~o~3c ca a3 l~h~re ~3tl Oll~
._ n~rcotica halped only ~Jlthill a limitad tir.~e, Ior i~ t~n-ce in .ne~s,~lected CA3e~ ritll meta~ e.~ i~to bone~, ekcO
4. q`he actlon of the new ph~r.maceu~ical ~n ~1L~ CCU5~-15 3~ t~eat~ent i~ X10-t 2ccompaxli~d b~J a~r S1nS o~ .;o~
ci ~,y tt.l~TllGd~ T;liC ~ o t~ n~u~ ,, vo.
5 . I;~ e co~ OL ~ t~ t t.lJi ti~ tll~3 n~ p7 ce~ttical~ "he ~tltumnr re~i~t~.~ crea~ed '3VG11 ;n i;l-our~bl~3 p~ti~nts ag m~:ht3~tt3d b~r the improvecl~nt in tl 20 perip~lt r~l blood compositiion, ~;cic~llL g~ill, lclpro~d ~7)e~
tit~ cr~3a3ea r,~orkin~; c~- p~cit;y.
iflt~.~rL', ~tl~2n~ 0~ w pl~ t~u';.'c2'~
co~sist3 i~ tne pos~i'oilit~;r o it~ 3uccas~3~ul usi3 in Ollt-pa7;:L~l.lt W~lrC~ liC~! collsl~tar~bly dlst,inrrui.~lAe,~3 ',l.o ne.;
25 ~harm~ceu~,ical ~'ro;~ the ina~or~t~J o~ e k~o~im o;~ ol;;~ler,~-p~3ut1ca1 dru~ 3r'~ 3e~rere .~ide-s~îect~ . ~r.tl ~ er~3b~
r~quirir,~, ho~pl'.,~l co~ition~ for tlLei~ ~pplic~io~.
S:ido ;3f:~cJ,s ~scnu,~ o~ .c nL"r.1~tE~a1le~ o~ the .no~ pl~ ~2couJ.ic~15 30 th~.ro are r~o ~ r~ic~lt, comp~1c~,c10r s. 4 10n~ ~ 'uorr:~ ~u~
to 2 clnn~ ) admini3traliio~ o:E m~thy1iie~3tos "erone Ln lo~r ~!o~ 12y cau~3 ';t~ ' m.s~11f~3~,~qt10n3 oL ~r.t.rl1i~m ~`nic'r rzpid1y d1sappear P~l"er met'1~r1t~,3 '~,o~terox1~ a~ 13t~, i cn 1~; ~ia^~n'~_n~l~d.
`~5 T~` ~he r.e~;J ph.~.rn~ceu~u~ca1 i~ adl~lnis',,~Y~ac~ XC9~ e ~o~nt3 and tho pro~.ein die'., i~ ~ot ob~er~d, J"ner~e ~a"r . ..
~ .................
23 FE~3 '94 15:12 P.23 -- 24 ~
. . .
occur ~nsi~ icant nau~eQ, ~r0~33 0:~ app9tlte, 10~ 3 0~
welxht. ~hc~ ns o:E ~mino acld di.~bQlance di~3~ppoar ~ ';er l~oduc1;ion o~ uhe ~ ,r doso o:~` l)L-v~lln~ on~, ob~erva~ce o~ 'l,he p~ot;~i~ dietv Contraindic~tion~
1, Prac~eding an~ro~e:n tllerap~
Ir ~uch Cll'3eS Q lcl;l do3~ o..~ me ~l~"rl~e~tc3tero~ o:F' ~l~.o l~t, therap~r ~chedule ca,lmo~ real- se l.JI~ i'ec l; o:~
3)I.-~Llinc conduc~oir ln ths '~-.lCi" ti~sue c~ 3.
10 ~ t~ 3~uic ~ c~ r~! J;tl~i^a~ scl~¢dul~-,, r.l~J;~ ros~onolon~ ~d p.tl~,l~vazid3 T;laJ~ ux,e~
2. q~fl ~e.~ 0~ r.~et~ a l~ .;s7 b~c~a -~pld ~ lo11 oi 'I;U~10~.~ rl~v~ re,ClllJ~¢~ 11 tl~s ~t~113 o~ ',h~ lood ~C~3~31~ I?rO~lt~;r~ Jv~-~
1-~ b~ .n,~
3.. ~ iou~ ~0:ri.13 ~:~ a+,~ o.~ o .. o~ rb ~C~Jv I~ ?..,U~ a~l d~mt~ t ~ Oc~ai~.3 ~vlt~ ~v~ vr~iGil u; X~ ~t3rl~u ~ 3-r~tio;~a~ lnt~r~re~luio~l~ b^u~ Li1aC~LU.~L~S~ i~
s"~r~oclate~ l t.'2~ px'op~rty- 0;' 01'~3dOmillQI~ t~ 'J'~)O'~ t-~
2C ~?'' ~ lin~ ~r~ o ClC-~ (1 .o ~n~3 ~l~m~.r;~ u~ o:? '.,'.1'3 ~dUr L~ . nc~t to t't~ tu~o~
. r~lore~orc the ~p~l'; "Q',.iOll o~ Lhe Y~ Xr.~aCeUtlC~
13 po~stblo only ~:,.tn;~ co~ le';,o .'ne~?.ii~.c" o~ .v~llO~
25 da~,ræ ~I;er ope;~2t;0n) ~nci ce~3at~ o~.~vh~ ,3t~ ta 25 co~:d~i!vion~ :3lood tr~.,n~t~u!vlon (e3~C~ lLi~r~lUl;v~P~ æO
. vr~nrl ~3:~Iec'., clo~ o th~i ol ~h~ o~
~,~?.l~ .L't~ S3C~ .h~r2:~ 1;}1~ ~n~;r~ v~ -;Oi.1. o~ i'!.t3 ,,,l;a~ coll~ical ~.u,~ 1, b a ~llsco;~ tl~ cd .~or ~ t '.;.;c.
~ u~ 3 l~ a~ n~, t.:~ U~3 o:P ~ 3'i:~c~ a-`~ c'~-30 1~ h~3 s~:Lt mcL.~ cll~ 3t be ~ol~l~cl~
5~ I~o o~ .r æ~:~;,l';ul.lo~ g~; ~ho~ . c;.
'~.Ju ~rltll J;~ i n~t p~ a~ lc~
., D~ ., t'l~ L~2~ J; ~irl~ J~ pl~ c~u~ '.cl~l ~v ~a v .o~ o:? c, 4LlC;. i}o.C~.Lo~ .u., (,0,;~ ,3, ~hy "o~
3 j ;~ . v.&~ ul~. u L~q~, hcl~o !~ o l ~ , c0,;~ ac r~c . ~
.
' 23 FEB 'g4 15:12 P 30 2 ~ 7 ,~
-- 2 5 -- _ ~xample~
r''ilC ln~nt. o~ U.'3'1;'L',o'',~?tl b;y I;1Le "ollowinG ~pcci-~ic ~.nmt~le s o~ th~ mo~al t~ o~erJ;.ie~ o~ ~h~ allcged new pha~maccutic,71 1. Pa'~ion~ 37r.il~0v.3~ A. 75 ~ r~ ol~, ca~c his-to~y ~o, 127~3~a. i3.r,~70~E~to~ ~roto;~-~r WEl:3 C~O`lC o:
31. 05~1977 ~t; the g~ colo~ departt.~ lt; o f ~o~to~r R~ e~
~rch Institu~e ol` oncolo~ L me~as4~sis f~om ~,hc ~;r~3a-t~3r omentum w~ tal;en ~o~ hi~tologic.al Q~lal~r~is Mo., 10 104~47-~343- Clandul~r ~ol~.d. o~ra~?~r cnn~or Clinical cliagnosl~: o~rary crncer Of ~ a~ i. I;h i1tv~ e t.ulnor $row1;1~ arld oul;,oro~.rtn i~to th~ in'.,~E tilte~, with Ir.et~lta~3~3 into the omentv.m and in the livar, ~ith ~citic ~luid accu~ulation in lh~ ~domin~l c~vit~r.
In th~ ~o,st~oper~tio.ll perlol, ~ cou~e o~ c~te.no-th~rapy (i~ thio_t~pQ) ~s~ v~n aa ~ rc.~ult o l,ih:ich no s.acito3 ~ccwnu~te~1 ~ut th~ ~umox ~ro~rl;h cont~ m In ~uly, thc p~tient ~sa~ dl~chax~e~ ~rotn th~ ho~
~td pre~crlbad 3ytnptom~tic. trentrn~nt.
In lal;~3 July, 1977, a~ a voluntc~r, khc pavi~
welænin~; 5~ 3~;, be~an tho tr~tment ~,rlth t~1~ pro~e;3~l ph~rmac~utic~l ln t'n~ ~orm o~ ~: mixtur~ o:~ 2 ~ DL~ re ill combin~l~,ioxl Wi1;h 25 ~lg ~0.025 ~;) or 5. tab~ r~l~3~}i;irl-1t,0~ t~.ront3 per d~J, ~it`~ ~trict o'~ .r.ce o.i` t`tle 2 5 m~ with ~..hc c~iYi~ion o~` the d~ily do~e :3 nto ~ 3inr;1 ~ ,.. . . .
ono~i l;a'.sen b~:~or~ ; 0.5 ~ D~-v~lin~ q~rr:~ m:l;1: en-tarall~J and 1 t~blot o:E i~ethyl~ 1;osterorle subl:in~ ,lly ~l. I;imt3~, arld 1 liubl~u o~ rnt3t,h~rl1;e~to~3'.~ n~i ~ublinr,u~lly r~ nicldl~ ;ho d~ itho~l~; DI~v~l~n~. 'I.'}1~3 t~ur~tlon ~0 o ~` t}~e cour~i e - 2 mon l;hs .
Dv~inf~ thi.~ t:i sr.~ 1;h~? pai:n~3 in 1 e lo~ b~orn~n nr~d ilL th~ r.x~E3 o~ t~ c~s~l ccr;sple~cl~, th~ ~7aSI~.~.'O-illt:e.~liinal trs.ct furction ~o~m~liz~d ~con~tipaLion~
l:)lood~- ~ecxatic~3 di~ e.re~.), the ~etl.te is~pro~re~, wei,~h~ r~ 4~5 }c~, the ~tre~l~th ~ld ~ror1cln~ capa C ~ wexe r~toxed, ~o t~ mor waa palp~ted.
O~rlng to thi~ 5tnt;l~s the p~lU-~ ~nt; ~ 3 ho~pitall~ecl.
23 FEB '9~ 15:14 P.~ll 2 ~ 3. ~ ~ 7 ~
..... __ . 2 6 on~ month l~ter for the 2nd coWr~3Q OI chemothcrap~r (im, thio-t~pa, a total do~s o~ 200 m~), G~ecolo~ical ax~mi_ nations ~e-u e~l~3d no n~opl~ia, In ~ ch ~d Ju~y, 1973, propllylQctically ~ ~ore cour-5 8c~3 oi~ thio-tepQ wero ,jiven which pro~uco~ ~tabl~ leuko-pen:La, In ~u~;us t, 1 Y78 a ~acond cour.qo o~` the pxop~d phar-maceut:i cal ~raa ~ive~ by thc ~arle 3ch~dul~ ~o~ 1 ~ontih~ 5~he blood ar~l~r3is ~ no;~m.~l. On the 7th da,.,~ o~ tll~ trcatl~e~lt 10 ~hc pati2nt hafl severe pairl~ in the liver a~ea Y~hich pe~-,t~a :E or 2~ h.ours but then dis~ppc~red compl~ r. ~yn~-~olo ~i c~l ~xal~inat ion rc voalad ~o ~loopl~ h~ pat i~nt ~elt w~ll. No ~r~atm~3nt ~s ~;iVOn unl;il April next ~e~r gener2l c~ndit;ion was satls~aciiory, ~aineû soms v~ t, 15 ~mecolo~;lce.l ~:~nin~tion~ Y~e~r~ale~l nothin~s.
In late April-r.lay, ~979, ~he Yl~S ~iverl a 5th (})~c~hy lflctlc) courr~3 of 1;hio--i.opa, im~, toler~ted ~3a'l,1'3~ ,ct;ox'i.-ly.
Tn .June, 1979, ~}la W3~3 gi~ren a 3rd ~proph,yl~ctio ) c~i-20 u~ o~ the n~w phQrm~.ceutic~l but ir.~ ancther daily do~eb~caus~ o~ Lc~lt chantro o~ wai~;ht in 2 l,r~r~
~:EroTl 54 kg to ~a k~ hc ,~;aine~l 14 k,~;~r Sh~ we.
re2l 3 ~ Ct~re o~ 3 ~ ine a~ 25 ~ er~lylte~ n~
dall~r in 4 ~in~ do~cs, ~ri.th th~3 c~ne (lie.'. r,h~ cotlr~3e ~5 l~t~ 2 month~3. ~h~rs a~p~re~ 3$,~,n~ic~.1; 3i~3 ~
~_ virillty ~rhich opprec~c~l t;he p~tiCll~ b~cau:~e o~ l:lb~,do m~li~e~ tatio2i3, :3ec~qe o~ th:L,q, ,s~.e d~cli~cd ~ur';hcr pro~hy~ao1iic admi~i~ l;rQtion o:l~ the n~w p~rTn~cauti¢al~ ~a-~it7 in 1979, i:~ ~pxin~ d ~UtUt~l 0~ 1980 she w~ iv~n 3 3t~ l~O~C pl~)ph~ c ~G.~C c~ u:",~ ,r ch~v~r.ctllfl~y ~ri lih cyclollo.~v-phar,o ~hio~ ~he toleral;ed Wi-Gh mor~3 di~'~iculty, n ~a~rtl~r~r ~~ rar~.h 1~1~1 the ~2ti~vnt ~SU~L:er~ ;ro ults. S~e d~erl r,,~tll the 3econa, ~itho~ ny ~ o~
noopl~si~ w]rtvh ~ad ~t~n c~l;abli~h~d, ~t a ~ 0lo~ic~
35 c~ in~tion on-~ Ir.oTlth 1~vfo-la d~nt.l~ he re:!.avive~ r~fus~d th~ alltop,sy.
r~h-- ocn~.lu~3lon 9~. incre,n~c ln ~ht) perio~l of ~cti.~re li~e hy 4 ~ear~ a~tt~r recognition o~ ker cor:ditiorl ,c~
: .' ' - '~ ,;: ' ' :~ '' : ''', . ' '' ~: ~ '' ~ ' ' '~ ~ . . :
`'` ,,,, ::'.'' '' ' ' :' ,~ '.. '.. ,,.. . .. ~; .. ' .. ,. ' ','', " . ;: ,.. ..
23 FEB ' 94 15: 16 P . :32 :. , . c~o~plQt~ly l~c~urnble cnnn~t b~3 r~8~rdGd t~ b~ dll~ to th~
~3ucce~s Or t~a~ltlonal c~ncer chem~t~apy ~1~ e rl~7w .
pharmaceut~oal not only correct~d ths ~ida o~f00t~ o~
c}lemical drug9 but cle~rly ~aoilitat2d the ~ntiblQ~tic 5 e~fect~
2. Patien1; Tlc~henko , lq.A., 28 ycars old , ca~e hi~-~or~r No. 1151a~x, admittoc~ to ~ynecolo~ical departm~t o~
Ros-tov R~sear¢h In~ti'~uto of oncolo~ .0~ Tllo ~ta~
tu~ at ad~ ion: wi~hin 2 month~ e~eat ~rllar~s~3ment o~
10 the abdomen, ~;re~t ~ei~;hli los~, evenin~ tcmpcr~t~ out 39C, ~3u~ 0c~tl0n, X-r~,y o~' the che~t ~eveQlad a met,a-st~is lnto ine pulmon~ y pleura. ~:ndol~ilphat~c polycho-`~ mother~py ~va~ ~tarted bllt did not allev~at~ th~ condit~on o~ '"he patl~nt.
1~ ~n 31.,08.~9 a~ explor~tory l~p~ro~omy r~a~ per~ox~ d wi'l,}l a~acuation OI 15 1 o.~ asci~lc ~'lu~ ~ro~ the ~ lo-;ni ~ c~vit~r ar.d ~,he al)out 2 lit~c~ o~ :Elu~ d i~2~0m tj}
pleu~al c~ityv "~ha dia~no~ oY~ry c~nca~ o~ IV ~t~g~ lrrit~ oU'L-20 growt}l o* the twnor~ lnto tha ~nte~tina~ ~nd with mct~ta-o~ into the gr l;e:r ornantum, liver, paritonow~ pleura~met~ t~o plcurit~). Hi~tolo~l¢al an~lysi~ ~o~ 26~62s ! ~l~ndul~r-o~pi~lary canoe~. , On 13.09.89 a preparation o~.platinum ~B~ inoo~lated intr~pe~itone~lly. ~ter ~hl~ th~ condition o~ t~e p~-ti~nt d3texIorated e~e~ more, she Y~a~ conside~ed to ba in-cuxabl~ and ~ di~oh~r~d ~rom th~ ho~pital in the ~re-terminal oondition~ :
On ~6.09.ag ohe be~n, ~ ol~teer, the treatment ~th the n~7 pharmaceutical in the outpat~ent department~
Ths daily do~e ~th the pati~nt'~ wei~ht a~out 70 k~) consisted o~ 3 ~ aline in combination ~th 25 mg O.025 ~ or 5 tablets) methylte~tosterone. The daile do-line F~ublin~u~llg 2 time~ i~ the mlddle o~ tha d3y ~e70 -Z3 FEE3 ' 94 15: 18 P . 33 2 ~
moal~ he pat~ent ~trictly obæerved the dlet wlth thc exce~3 o~ protein, liTTited amount o~ caxbohydxat~ and complet~ ~x¢lu~ion o~ ~mal ~at and phosphol~pid~ ish hard~roo, e~;g yolk), u~in~" no ~ore Jchs~ 1-2 1;able ipoon-5 ~ul~ o~ ~regetable oil daily.
~ '~thin the ~irst 10-15 d~y~ o~ treatmen~ with ',he new pha~maceutical the ~ollov/~n~ ch~nge~ occured 1~1 the condltio~; o~ ,.he pal;ient s 1. Vomit;in~ ~topped and lnt~s~inal oY~cuQ~lon OOCIIr-10 red indep~ndently;
2. ~he body ~empe~aturc beca~e noxlln~l;
3~ e ur~ no oolour ~c~ne li~hter ~pre~ioll~J.y _ dar~c beer ~olour);
~ r~ ~0 ækin coloux ohan~ed from dra~-green illtO ye7-15 l~ Yhi te.
5, ~h~ er ~nl~r~ed ~ htly ~nd pexiodia311y ~Ta~
pairlLul;
6. sn'nyc~.~dia Qppe~red ~ro~ ~ime to t~r~lC~;
7. ~e ~atiant ~howed ~ood ~pp~tite:~nd intore~t ~or li~e, e cour,q~ o~ 1:reatment ~va3 1 ~onth becau~ the pa~ :
~ient ~va~ con~idered to be cur~bla ~nd w~ ~r~clltl~ ho~pi-taliæ~d o~ 23,10~9 ~or a repoated i~txaper~ton~ ac- .
tion o~ ~latinu~ prep~x~tion~ he patlen~ bo~e the in3~c-tion o~ th~ pl~Jcir.u~ preparation eaaior than th~ ~ir~
time~ but th~rea~aln appe~r~d ain~s o~ cardio-pulmon~y - .
in~u~c~nc~
A~ter tlae diachar~e from th~ ho~pitQ1~ on 09~11.89 tho pa~ient ~g~in 1~e~n to ~t th~ tre~t~iarl~ w~t}l the ne~
ph~rln~outlcal, ~ 2~month cou~ o~mbe~-D~cemb~r, 19~9)~
ChQnge~ i~ thi~ p~riod: ~
1. Sigr~ o~ c~rdio-pulmonnr~ insu~f~ciency dl~ppe-ar~d.
2~ Pexio~lc~lly oc~urir~ p~ in tne liver ~topped ~-but the live-r Yla3 3till onl~ed~
3. ~o s~ gn~ o~ aaoite~ eith~r in th~ abdolnial~l or in pleur~l cQvi~y.
~ 'he ~ppe~lJ~e ~ 3~il-l ~ood, ~aln in '~7~ 4 k~
:~
23 FEE3 ' 94 15: 20 ~ . 34 i 7 ~
2 ~
5. ~h~ patient t~ko~ ac~ive pa:rt ~n liîe, w~nt~ to go to uork but she get~ ti~ed quic'cly~
I~l J~nu~ry 199~, she ~IQ~ ho~pitnlizec~ ~or 3 w~k-co-ur~e of ~y~temic chemotilerQpy ~im, thio-1;o~ u~ich wa~
5 tol~rat~cl ~ti~r~Cto~ly, without diso:rd.er~ hc-modyna-, wlthou~ nau~c~ ~d vomitlng, Bu~; the cour~s ~a3 notcorlpl~ ~.ed arld di~¢ontin~l~d b~c~u~e o~ .~ se~rs sllcrgia ede~na o~ ~u~cke'~ tgp~ t t;hi~ time ~?ai~ in t~ ight ~nd le~t h~ochondrium.
Earl~ 'ebru~ry, ~990 ~ tt,t~o-month COU'n'~2 (,~ l'U
ary~ arch) o~ ~;re~tment w:ith t;he new pharrJI~oeutioal Y~S
st~rted in ~hc Sam9 dose~ cs before. A~t~r the cour~s:
1. ~he ob~octiv~ ~t~tu~: a~ ~ho~rn~ by ~ ologic~1 ex~;nin~ti~n, ln the ~mQll pelvi~ ~ll tunoral ~ormatio~3 15 w:th the e~cceptio~ of ~, ~mall tWllOX on the ri~ht ~lde ~Q:~` the ~ e o~ ~ child ~ t ) rc~olve~; no ~i~ n~ o~
mot~Qtic ~?lsuritis.
2. q~he ~ub~ ective ~tatus i~ gOoa. Plan.s to ~e1i ~.ar-riodO Early .in April sh~ ~Y~ rnal~ried; reIu~ed a~ny ~x~a,t-20 m~nt ~or ~pril ~n~ ~IQ~ ense~ ~b~ent for ~ mcnu':s ~t~--te~d on I,t.~y 1.
In the mid-~ay, 1990, h~ e~e~,:the~ ppe~od 3i~n~ .
o~ metn~t~tic pleurit~: hard bl~cathillg, ~luid l~ t~o l~t.
~_ lu~ up ~o t~e 3xd ~ Cllan~e9 ~2i th0 ~all p~ v ~om ~3~ 18, 1990, shs Yra~ ~iYon a.cours~ o~ s~t~
mic ch~motherapy with c~cloplio~hane ~ n ~n . ~utpP tient w~rd w~th no result: pleuritl~ progre~ d ~'luid up to the 5th rib~, .
on Jlme 4, 1~0, the ~*h co~ O~ til~3xa~ th the 3 ne~ pharmaceutl~ l W~3 ~rted wlth a dail~ dose of D~
line 3 ~ Qnd. mct.hylt~tc3te~0ne 3 ta~lo~ .()15 g), b~cau-the patient, duo to a very hi3h l~bido, re~u~d to take 5 tablet~ pet~ dn~ (0,0.25 g), int~r~ g ot~er~ 3e ~o di~con-t~r.u~ any therapy~ I~ 2 week~ o~ the J,ire~tme~ pleuri~
decrea~e~ n to th~ 3~d ri~), re,Q~ir~tior, b~camo ~-~ier.
~ y th~ l~c~u~e~ o.~ ~he physici~n-~n-char~, chc~otile-23 FEEI ' 94 15: 2;~ P . 35 ~ 2 ~ 7 ~1 . . .
rapy ~th cyclopho~phQne (2 wo~k~) was ~ltexnated ~th the treatment u~in~ the ne~r pharm~ceutical t2 week~), ~ter t~Yo suoh alternation~ the patient refu~ed to ta~e more chemotherapy v~th cyclopho~ph~ne because each time it cau~ed very ~trong aller~ic edema o~ pude~dal lip~
a~d l~r~nx not ~110Y~ at~d by t~lo n~t~r pl~rm~o~u tloal.
¦ For ~ year ~Au~ust, 1990 ~ Au~u9t, 1991) the p~tient carried out ind~pendent treatment ~Yith the new ph~maceuD
tical in oourse~ o~ 1-2 months i~ the sQme do~es w~th approæ~m~tely one-month inter~als, However, the ~enerQli-z~tion of the pro¢es~ continued slowly: there ~ppeQred ~ :
a meta~ta~i~ in tl1e le~t brea~t, in the i~t~rpleural area there a¢cumulated the ~luid which in thi~ period w~s removed 3 time~
S~nce it appeared de~inite that mnlignant neopla-~ia9 by the end of that year ~illing the ~mall pelvi~
h~d complotely lo~t ~uscept~billty to hormono~ ,on Au~ ust 13, 1991, the treatment with the m~chQnical mlxturc ~a~
startod: 3 ~ o~ D~ linc, 0.005 g meth~ndro3tenolone, : :
and 0.3 ~ phthi~azid per day, All t~l~ mixture ~Ya3 ~
ded into 2 sin$1e dose~ in the morn~n~ ~nd the evening;
eQch con~i~ting o~ 1.5 ~ Dl-valine ~nd 1~2 tablet methen- :
dro~tenolone, 1/2 tablet phthi~azid ~ith warm milk on an ampty ~tom~cll~ ~ cour~e o~ 1 month. . `:
_, 25 ~hl3 treat~ent app~rently cau~ed oxtensive necrotic generation of meta~ta~es in the i~terpleural cavity: the temperatuxe rOSQ ~ig~ by the e~enin$, se~are coughing deYeloped, hard breathinB. Vomiting occurred onco in 1-~
da~r~ ~ th~ Yomitu~ containln6 dark 3truoturele~ masse~
a~ter th~ the iever dropped~ breathin~ b~came ea~iar, but coughing did not ~top.
~r the p~tient 13 raquest is sep~ember 1991 9he WQ9 q again gi~en a 1-month cour~e o~ treatment ~th D1-~allne ~ (3 g~) in combinatlon ~th 0,015 g methyltestosterone.
j~ 35 Cou~hing ~lightly decrea~ed, ~omiting ~topp~d, hoY~er, ~ the ~el1eraliæ~tion of the proCe39 con'i~ued: the metas-j t~is in the bre~t bc~n to grow out into t'ne back mu~-cl es .
~j .
~ ~cl: ~4 1~i~4 P.3ti 2 ~ 7 ~1 ~ arl~ in octob~r another course ~as started with a mixture o~ D~-valine, methandrostenolone ~nd phthivazid in the ~ e dose~ e couEhing incr~ased, ~requen~ epl-~ode~ o~ su~ocat~on de~eloped,a.ttempts at the ~luld pump~ng out showed the absencc o~ the latters apparentltr .
the cavity ~ra~ ~illed with tumor ma~se~. Cardiac weak-nes~ increased. No paln~. ~he patient ~ldom le~t the house because Or dif~lculties in climblng the ~tairs, but at home she read, ~Yrote, ~reely ~o~ed about the room.
On ~ovember 8, 1991 the patient dled of a heart Qttack ~or 30-40 mln, She had lived mo~e than 2 ye~
~rom the time she had baen con~idered to be i~curable.
The conclu~ions ~ e succe~ in prolon~ation of the acti~e li~e ~ thi~ youn~ woman c~nnot be as~ociated with the treat-~ent ~ith the new phar~aoeutical elone because in the 19~ year she receivad the con~entional chemotherap~t cour-~e~ ~rhich ~he coul~ hardl~ tolerate each time.
2, ~he turning point towards tlle n~w ~eneralization ~ the process fell on April-~.lay when all the traatme~t ~28 dis~ontinued. ~hi~ ~hould no~ ha~a been done. Slnce our treatment t~as onl~ YoluntarJ w~ had no rl~ht to in-~i~t.
. . . 3~ ~h~ u~e o~ the miæture o~ D~-vallne, methanaro- 2~ stonolone and phthi~azld, in our oplnlon, ~'rQ~ too delay-ed ~nd the time had probably been 105t ~or it~ optimal - e~fect.
~ he new pharmac~utlcal v~th the antitumoral activity in th~ ~or o~ ~ mixture o~ DIr~al~ne and ~mall doses of 3o methylte~to~terone ~!~a3 lnit~all~ tried ~n 33 patient~
(volunteer~) t~th malignant tumor~ of genitalia con~ir-med hi~tologicall~ as cancer of the ~ollo~Jin~ localiza-tion~: ~ali~nant ovar~ cancer~ - 9 patients, malignant tumor9 o~ the uterus bod~ - 21 patient~, cance~ o~ the uterine tube - one patient, cervical cancer - 2 patient~.
~ ith the sxeption of 9 patient~ ~lith the uteru~
~od~ c~ncer in the II~ tage o~ the d-lsea3e ~o~
23 FE~ '94 15:27 P.~37 2 ~
_ _ _ the ne~ ~harmaceut~cal wa~ u~ed a~ the fir3t ~tase of tre~tlten~ ln the pre;operation pe~iod, all the ot~cr pa-tients wore in the III-IV ~ta~e o~ the disea~e a~d ~y the time o~ treatment ~rith th3 new pharmaceutic they had been given the convention~l tre~tment or chomoth~rapy alone, ~thout ~ny o~ect, having larg~ immovable tumor ccn~lomerates in the ~mall pelvi9 oe esudate3 into ~2-riou~ ca~ities, ~ome o~ them had xelap~es of th~ di3e~ise a~ter ine~fective combinea treatment.
~i~.o~t o~ tho p~tient~ treated ~!~th the new pharDtaceu-tical a good (tumor~ re~olved) or ~Qti~f~¢tory e~ec~
Complete lack o~ e~ect w~ ob3erved i5 5 p~tients only.
ln ~our of th~m the tumor~ w~re de~ln~tely ho~to~e-un3us-coptible: cervical c~ncer, uterine tube cancer, sarcoma 15 On the uteru~ body, and the ~th patient wQs pre~ented ~or tre~tme~t in a ~ery ~e~re o~ndit~oll du~ to r~p~d ~enerallzation o~ the proce~s.
~ he propo~ed pharmaceutical wa3 al30 tested in 5 incurable p2tients suf~exin~ ~rom tha mammPry gl~nd can-.~ 20 ¢~r ~th metast~es into bo~e3, ~th groi~n~ out meta~ta-j se~ int;o the s~u~cles o~ in o~ the chest t~/ho were dis-ch~rged for ~ ptomatic treatment in a vér~ ~evare condi-tlon a~er ine~cti~e irrad~at,$on therap~ and 10-12 cour-se~ o~ chemotherapy~
`~ 25 In one o~ these o~e,q, a~ter a long-term hospital . treatment ~t~3tases lnto the bon~ o~ ~e slmll~ pol~
ribs led to the pre-terminQl condition.o~ the patient I and ~ha was brought ~rom the ho3pital on tha stretoher~.
~h~ o~ct o~ th~ tre~tment witll th~ me¢hanical mixt,ura 30 o~ 2 g DIrvaline and 20 m~ metl1ylte~to~qt~rone w~3 both ~ubJRcti~e and ob~¢ti~e. S~e~est pains usuall~ accompa-nyin~ ~uch meta3ta3isin~ which coild only ba ~topp~d ~or 11/2-2 hour~ b~ trimep~ridine h~drochloride tpromedol3, be~Qn to ~ub~ide ~nce the 3rd day of treatment and co~-1 3~ pletel~ di~appeared w~thin 2 weelc~. A~ ~ r~ult, ~ a ! month the patient started to get up fro~ the bed Qnd ~ru~u~lly b~c~ms invol~ed i~ th~ ~cti~e life. Ever~ 2 month~, the ~ected par~,~ o~ the ~keleton were ex~.lined ~1 1-.~
~ 33 -by roentgen, Si~ns o~ beginning reparation o~ th~ bone ti3~ue were observed ~n ~kull end pel~l~ bone9. ~7ith ~hort interr~l3 o~ 1-1'k weeks the p~tient too~ thc treatment in the outpctient ~ d ~Ol' 8 ~onth~, unt~l she d~ed o~ throm-boemboli~m ag a reeult o~ lon~-term uncontrolled taking o~ calcium chloride for 3 months, ~ ntil the la3t day thi~ pQtient actl~aly did the house wor~, went shoppin~ ~ld to th~ ma~l~etl In 3 cases, t~eatmsnt with the mechan~cal mixture of lo D~valina, methQndro~tenolon3 and phthivazid resulted in temporary but well ~arl;ed sub~ectiva imp~o~ement in ~he oondition o~ the patients which finally ended a~er an-- other course o~ chemo~herapy b~c~use they were a~ai~
hospotalized into ohemo-ho~mone therapy department o~`
Ro~tov ~es~arch In~titu'e o~ Oncolo.~y.
In one oa~e, ~uch ~ub~ective considerable i~npro~e-ment s topped sharpl~ durin~, the trea "ment with the pro-po~ed pharmaceutical beca,u3e o~ tha ~,res~ condition o~
the patient de~reloping due to her personal problem~, She 20 ~la~ not hospltali~ed.
q~lle observationa c~L~ried out b~r the author ~ho~ed the trea~nt ~rith t~le propo~ed phnrmE~cauti¢al t;o ~ re mQinly s~tia~actory r~sult~ e~en e.~,er prevlously per~or-~ed ine~octiYe chemo~-radlation therapy.
llhe tec~nical re~ult o~' th~ in~relltion con~ s in the ~ollo~ ing.
I`he phar;nacoloeical properti~s o~ the propo~od pharm3.cautical ~tudied e:cporimentall~r ~n i~duoed hori~ono-~iusceptible tumor~ o~ mamn~r canc~r in ~ antl in nor-30 mal animals, a~ well QS the dat~ obtained clinic~ in treatlttent OI ~rolunteer~ in incur~l~ case~ atte~t to i~9 co~nplete harJ;tle~ne~s, sufficl~ntly t~tar~:ed ant,lblas~lc prop~rtie~ with simultanaou~ s~imulation of the defence foroos of the bod~r ~d an~1~et1c effect.
.,~
~ r~ 4 l~:Jl P~39 7 ~ ~ :
:
34 ~
A P~A~CEU~ICAL E~R~ING AN~ ORA~ AC~ Y ~: -~gend~ for Pl~ures Pi~ D~,~A-i~duc~d ma~m~xy glQnd cancsr in x~t~ :
1. Control - glandular-sol~d can¢er o~ th~ ma~mary gland in rQt (untre~t~d). Ma~ni~i¢at-ion x 160.
2. ~cpe~imont - a~ter tre~tment ~it~ D~-valino in mlxture witl1 m~thylte~to~terons ~reg- -~
re3sion). I,larlced dy~trophic le~ioi1s ~ ~
in tumox oells: predomi~ant ~aouola-tion o~ the cytopl~m and ly9i~ 0 both nucleu~ end ¢ytopla~m. i.~gni-~ic~tio~ x 200, ~ig. 2 - Adcnoc~rcinoma o~ hum~n uterine body.
~pir~tion ~rom the uterin~ cavity tcytolo~y) 1~ ~s~ore ~reatm~nt. Ro~ette ~truoture~ from elon-gatsd a typical c~119 0~ the c~ dor ~hap~
(magnific~tion ~ 600, im.).
2.. ~ra~me;1t ~or 2.weeks ~ith D~-valin~ and me~hyl-te~to~terone~.~acuolation o~ th~ cytopla~m and nuolei o~ t~moi- c~ell~ ~mn~ni~lc~t:Lon :1~600, lm) 3~ ~e~4m3n4 for 4 v~eeL~ vri'Gh DI~Yalin-3 and methyi~-t~s~nf~t:erono~ J~la~kod ~3broh~r;o~ ;u~le~s fu-- ~on o~ ~mall ~a~uole~ ln cytop~m ~nd nucle~
o~ tumor cell~ (m~gni~ication ~,6,p,o, im.). .
4~ ~rea~me~t ~or 10 day3~ A ~ayer oi d~stroph~callg chan~d cancer cellss l~oorrodod" outl~s o~ the nucl~, ly~ o~ individual nuolel (ma~n~c~-tiOl~ X 60o, lm.).
. . .
Claims
Claim A pharmaceutical preparation having an anti-tumor activity and comprising a mixture of 2 g to 4 g DL-valine and a low non-therapeuti-cal dose of 0.020 - 0.025 g methyltestosterone for treating hormone susceptible cancer tumors in women, or a mixture of 2 g to 4 g DL-valine, 0.005 - 0.010 g metandro-stenolone and 0.3 - 0.5 g phthivazide for treating cancer tumors which are not hormone susceptible.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
RU5049685/14 | 1992-06-26 | ||
SU4968514 | 1992-06-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2116574A1 true CA2116574A1 (en) | 1994-01-06 |
Family
ID=21584494
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA 2116574 Abandoned CA2116574A1 (en) | 1992-06-26 | 1993-06-28 | A pharmaceutical exerting antitumor acitivity |
Country Status (1)
Country | Link |
---|---|
CA (1) | CA2116574A1 (en) |
-
1993
- 1993-06-28 CA CA 2116574 patent/CA2116574A1/en not_active Abandoned
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Ozols et al. | Enhanced melphalan cytotoxicity in human ovarian cancer in vitro and in tumor-bearing nude mice by buthionine sulfoximine depletion of glutathione | |
US6309672B1 (en) | Anti-cancer therapy agent of arsenic hexoxide (As4O6) of a natural chemical substance and its pharmaceutical composition | |
SUHRLAND et al. | Intracavitary 5-fluorouracil in malignant effusions | |
Keung et al. | Potentiation of the bioavailability of daidzin by an extract of Radix puerariae. | |
JPH0651636B2 (en) | New anticancer drug | |
WO2003006036A2 (en) | Herbal formulation | |
KR950008767B1 (en) | Novel pharmacentical use of ebselen | |
Gamboa‐Vujicic et al. | Toxicity of the mitochondrial poison dequalinium chloride in a murine model system | |
Geisler | The use of high-dose megestrol acetate in the treatment of ovarian adenocarcinoma | |
KR101693828B1 (en) | Compostion comprising Yukmijihwangtang extract for treatment of renal cell carcinoma or liver cancer | |
CA2116574A1 (en) | A pharmaceutical exerting antitumor acitivity | |
EA007685B1 (en) | Pharmaceutical composition containing toluene sulfonamide and method of use thereof | |
US7261906B2 (en) | Anti-cancer therapy agent of arsenic hexoxide (As4O6) of a natural chemical substance and its pharmaceutical composition | |
CN100434077C (en) | Megestrol acetate capsule composition | |
WO2004009106A1 (en) | Preparation extracted from stephania tetrandra s. moor and the use thereof | |
CN104688748A (en) | Pharmaceutical composition containing ursolic acid and cyclophosphamide | |
Weigand et al. | Action and toxicity of vitamin B6 hydrochloride | |
Sriskandabalan et al. | Aspergillus infection of the epiglottis in a HIV positive patient. | |
CN105769849B (en) | A kind of pharmaceutical composition for treating oophoroma | |
CN116999417A (en) | Liquid preparation containing paeonol and apocynin | |
CN112891496B (en) | Traditional Chinese medicine compound preparation for treating liver cancer and application thereof | |
Nakano et al. | Antitumor activity of ascorbic acid in combination with antitumor agents against Lewis lung carcinoma | |
Xuan et al. | ID 121. Utilization Pattern of Lipid Modifying Agents in an Outpatient Pharmacy Department of a Private Hospital in Malaysia. | |
JPS61134315A (en) | Antipyretic and analgesic agent | |
Jackson et al. | Phase II study of vincristine infusion in refractory small cell carcinoma of the lung |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Dead |