CA2228503A1 - Use of griseofulvin for inhibiting the growth of cancers - Google Patents
Use of griseofulvin for inhibiting the growth of cancers Download PDFInfo
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- CA2228503A1 CA2228503A1 CA002228503A CA2228503A CA2228503A1 CA 2228503 A1 CA2228503 A1 CA 2228503A1 CA 002228503 A CA002228503 A CA 002228503A CA 2228503 A CA2228503 A CA 2228503A CA 2228503 A1 CA2228503 A1 CA 2228503A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
A pharmaceutical composition for the treatment of cancers or tumors in mammals is disclosed which comprises griseofulvin. A chemotherapeutic agent can be used in conjunction with griseofulvin as can potentiators. Griseofulvin can also be used to treat viral infections, either alone, in conjunction with other viral agents or with a potentiator.
Description
Use of griseofulvin for inhibiting the growth of cancers TECE~NICAL F~ELD
This i,.~.- is a pL~u~ fi~ ~I c--~ -- - that is useful for the ~ of cancers and tumors, p=-l;r~ in h~unan and warm blooded animals. The f~ --"- contains -~ h~. It can be used in A ~ with other c' --- -'~~~q~ ~ agents also.
S BACKGROU~ID OF T~E INVENTION
Cancers, i~ ;nE '~ ' ~ are the leading cause of death in animals and hurnans. The exact cause of l~ mi~ is not known, but links between certain activities such as smoking or c,~s u~ to w~_h-og_-~ and the ir~ nce of certain types of I ' - and turnors has been shown by a number of l~e~.h~.a.
Many types of ,1...... ~ ;c agents have been shown to be effective againsat cancers, tumors and I ' but not all types of cancer and tumor cells respond to these agents.
u"ru~ , many of these agents also destroy normal oells. The exact ~ for the action of these c' , - agents are not always known.
Despite a.l~ l~.,S in the field of canoer and l~ul~m~ n~.lta the leading t~ , ~ to lS date are r~ ti- n and ~1- -----11-- ~1~ and bone marrow ~ 'h. ..--~ll.. .a~ d~
are said to fight canoers that a~e p~uh.ukul~ a~.e~;~_. Such cytocidal or ~jt~at~li- agents work best on cancers with largc growth factors, i.e., ones whose oells are rapidly dividing. To date, 1~."~ ~A~ in p~uh-,~l~ estrogen. ~ ~uO_.t~,.une and i une, and some ~ ~,-ulu~l by a variety of ~ lahl.g agents, and anti ~- I"hnl;~ form the bulk of i ~ available 20 to ~ Ideally ~ ~ - agents that have ~ ;r..:/~ for '~ ~ ~, canoer and tumor oells while not affecting normal oells would be ~ el~ ~If-' -- ~~ U-lrU-i ' ~.y, none have been found and instead agents which target especially rapidly dividing oells (both diseased and normal) have been used.
Clearly, the d~ lo~..." .~ Of . .t~ lc that would target canoer or le -l-~mi:- oells due to 2~ some unique ~ r.;~ for them would be a b.cdkllu. _- Alt~..~h._l~, -'- that were .,~tolu~c to It ~ ~ or cancer cells while exerting mild effects on normal oells would be ~ ~ '- Therefore, ill is an object of this i,.~_.,tion to provide a ph-..--'- ~j..l;~ ~1 CC~ that is effective in treating '~ ' ~ with mild or no effects on normal blood oells More !q~ifi~lly, it is an object of this invention to provide a ~u--~ u~ g a 30 ph ~- ' carrier and a o~ia~,~r~ i" as defined herein along with a method for treating cancer, IP-.1,Pm;~ and tumors.
W O 97/05870 PCT~US96/12475 The u e of ~ c~rulvin in co~ l;n ~ with other ch~mr~th~ ;c agents which are effective in dc~lluyingth~e tumor is a novel method of tl~at~ nl Griseofulvin can also be used to treat viral infi~cti-~nc in the presence of a p SUMMARY OF THE INVENTION
S A ph~ ti~1 co~ ion for tll,atl~ -t of m~mm~llc, and in pa li-,ular, warmblooded animals and humuns, which are affected by I ' - Cc)--~ g a ph~ i carrierand an effective amount of ~;.i~vrul~in Griseofulvin has the formula:
CH30 ~ ~ ~
These ,~ c can be u ed to inhibit the growth of le~ r~;o turnors and cancer oells in hurnans or anim~ls by ~ t ~~;o~ of an effective amount either orally, rectally, topically or pa~ 11y, or illtla~ ,. These ~c l n~ do not ~ ri ~ ~11y a~fect hc-althy cells.
Pl~ can also be used in co- I~ with ~j.iacvr,llvin as can l~.. lh lS agents.
DEl'AILED DESCRIPTION OF T~E INVENTION
DE~INlTIONS:
As used herein, the term "co l ;~;~g" means various r~r can be ~ 1, 1~, in the pt~ of this invention Accul li~ly, the terrns "co~ g 20 , - 'Iy of n and ~c g Or are ~ d in the term ~ g As used herein, a "~ " ~ 11y ~ u c~ is one that is suitable for use with humans and~or animals without undue adverse side effects (such as toxicity, ilTit~tinn, and allergic response) co-- . ..~ te with a ~._ ' '- benefit/risk ratio As used herein, the term "safe and effective amount" refers to the quantity of a c~ ~''~ -.1 25 which is ~ r: .-t to yield a desired thf ~ ;c response without undue adverse side effects (wch as toxicity, ~ t~ n~ or allergic response) L('''~ with a ,~ )r ' I~ ~n-,r~ ;ak ratio when used in the rnanner of this i..~f.lliO... The specific "safe and effective amount" will, ~.liou~ly, vary with such factors as the particular co~i;l;o - being treated, the physical c~ l;l;o-- of the patient, the type of mamlr~ being treated, the duration of the lltiall..c.ll, the nature of co..,...,,_nl Wo 97/05870 PCT/US96/12475 therapy (if any), and the specific r~)". .I~I;nnc ~ .i and the structure of the CO"~1~UY~ or its d..iv~ti~
As used herein, a -~ t;~ -' addition salts" is salt of the anti ll .,L. - ~ C~..~l~....A
with an organic or hlOI~,diUC acid. These ~.ef...e;i acid addition salts are rhlnnA~oc, blu..~idc,s, S sulfates, nitrates, ph~y~ t. -, R~C ' S, finrmzlt~5~ tartrates, mzll ' , malates, citrates, ~ u ~h ~, salicylates, ~u-I,at. " and the like.
As used herein, a "~h~.~ e-~ l carrier" is a ph~ ly a "~ solvent, r ,, agent or vehicle for delivering the anti '~ ' ' agent to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of -d~ U"~ A in mind.
As used herein, "cancer" or "l ~ ~ " refers to all types of cancers or - ,' or ...~1;~.- -- ~ disease which attack normal healthy blood cells or bone marrow which produces blood cells which are found in ~., ~
As used herein, "viruses" includes viruses which cause diseases in war n blooded animals e HIV, i"n.,. ~-,~ ~hil~uvilu~c;~, herpes and the like.
As used herein, "g-i~ûrljlvin" means 7-Chloro-2',4,6-L-i.. _ll-u.~-6 ._lh,~ JilU
rt ~,..r~ 2-(3H),1'-[2~ lolt~ ] 3,4'~ione. It is an ~ .uducoi by p . 7r griseofu~vum As used herein "F~ ~ are ~ ' '- such as l.;l..ulidi-le and its cis-isomer which are used in c~ -- with ~ ~rulvi... r.. can suppress the immune system or 20 enhance the c~li~_"_~ of the drugs.
As used herein ~ nlh ~ ;c agents" includes DNA-' '._ Agents, Antime-tabolites, Tubulin-T 'v~ Agents, ITn..~ O~ agents and others, such as ~p--~gi~ -~ or h~.Lu~y~ ~.
B. GRISEOFULVIN
~ YJr~lViU~ has the following ~Uu.luc.
It is prepared according to the method Af ~ . ;I~A in U.S. 3,069,328 issued to TTn. L. ..
(1962) and U.S. 3,069,328 issued to Dorey et al. (1962) C CUEM OT~ERAPEUTIC AGENTS
The d~r~ ir agents are generally grouped a_ DNA~ Agents, A~ ;t~ C, Tubulin-Interactive Agents, IIo- I agents and others such as A.~ ~ or L r~UA~r~U~. Each of the groups of ~ agents can be further divided by type of 5 activity or co--.l~--u~l The rh~moth.._l,~ agents u_ed in c~ ;o~1 with 2~i~oîulvin include ~-- ~ ~l~f ~-, of all of these groups. For a detailed ~ of the ~ ...n~ f .~;r agents and their method of ad~ ul;on, see Dorr, et al, Cancer ~ th~rapy Hondboo~c, 2d edition, pages lS-34, Appleton rl~ Lange (C ~ , 1994) herein i..~.~,u.,~t~ by l~f~"~ c.
DNA-T '~,o Agents include the aL~cylating agents, e.g. Cicp1~'in C~,rc1r~l~hn~
10 All.1 ~, the DNA strand-bl~kà6_ agent_, _uch as Bl~...~, the ih.t~lr~lil.g 1O~ c.J.~ ~; ;e II inhibitors, e.g., Dactinomycin and Dw~u-l ' ' ); the r ' ~lating "~r;~ e II inhihi~rlrc such as, F~posi~1r and Tc~ ~s~i~, and the DNA minor groove binder Plc~ll., li...
The alkylating agents form covalent chrmir~l adducts with cellular DNA, RNA, andlS protein ---1( ' - and with smaller amino acids, gh~ hin~ and similar rhrmir~l~ Generally, these allylating agents react with a .~ ~ph;1ir atom in a oellular co~l ;n -~ such as an amino, carboxyl, r~ n.y,~l group in nucleic acids, proteins, amino acids, or g' ~-~' ~ - T_e ~ ' ~ and the role of these alkylating agents in cancer therapy is not well u~ ~.r~r~OA
Typical aL~l,~ing agents indude:
Nitrogen mustards, such as Ch1o1~ u~ C~lophr~ T " ~, Mechlo..l1--.--;1~ M~ h~ Uracil mustard;
AziAdine such as Thiotepa t; ~~ ~ esters such as ~ llf~n nitrosou~5,suchasC~.,... l ;..r Tr ~,S~ l~t~
F ' c , ' , such as ~i, ' ' GUIJOplf~lil-, ' ' r~l~.,li~_ alcylator, such as MilOl--yr i.-, and Plu~l,a~il.e, D~-~l,~ne andAlll.
DNA strand breaking agents include Bleollly~
DNA l~ nhih;tor~ include the following:
T ~ ' , suchas A.--~ e Da~;~inoll.. ~ , Daunorubicin, Do~o. ' ' ' Idall ' ' ~ and M;l.,._u~ulle., - ' ~lators, such as F~ f and Te-~ 1c The DNA minor groove binder is Plic~..~_h-.
The ~ l~l;t~, interfere with the ~lU hJ.,Iion of nucleic acids by one or the other of 3S t~o major ",~h~ Some of the drugs inhibit l,lu~lu~lioll of the deo~y-i~
lA~ t'_ that are the il ---" Pl~ U~ for DNA synthesis, thus inhihiting DNA
Some of the eu~ are S--n~ ly like purines or pynmi~ oS to be able to W O 97/05870 PCT~US96/12475 for them in the anabolic '- ' patl~ s These analogs ean then be ~ ~
into the DNA and RNA instead of their normal cu~ t-.~alLs. The ~ oi;t~ ~ useful herein inelude:
folate ~ such as M_lholl. and l-i...~,l..
S pyrimidine ~ l~o ~ " sueh as Fluo-uu c~ -il, Fluo.udco,~idine, CB3717, A7qr~ n Cy~;~.e, and Floxuridine purine ~ ~g. ;~1~ inelude M~.~ , . 6-Tl~ ;.f ~-J~hi.~,rl ;
wgar modified analogs inelude C~_~dl,i-.c, Fl ~ h;
'- ' ' .~1U~,LO- 1 ~ inelude h~u~a Tubulin T ~_ agents act by binding to specific sites on tubulin, a protein that pol~ .i~s to form cellular ~. i_-.hL '- Mi,-ulLL ' are eritieal eell structure units When the ~ ~,_ agents bind on the protein, the cell can not form l~iwulub~lC5 Tubulin I"t~.~,li,_ agents include Vi~ and V ~'- both q-l~ql- '' and Pa~,lila.~,l.
~Tnnntlnql agents are also useful in the l,~aL,...,.II of eancers and tumors. They are used in 15 ~ lly - ~-r ~ tuunors and are usually derived from natural sources. These include:
~,truO_.~" . ;_~ ~ e~,l.u~, and Ethinyl ~ct~tliol snd Diethylcti~
~hl." ~ GP.. and T<~ d~
I,,~,_;,lh,s sueh as II~uA~ ,~t~,.une caproate, Med-u.~ ,u~tu.unc, and Mct,_~tlul;
ai~uO_.~ sueh as l~;.lua~.u~ ui~c ~ r~ ~, nl~ui~yl--_:~t~.-O~C, I--~lI-ylt~tual~-u--_, Adrenal co.li,u~ ' are derived from natural adrenal eortisol or hydlu,OIliaOll.,. They are us~d beeause of their anti " y benefits as well as the ability of some to inhibit mitotie liv -- and to halt ~NA ~ -' These enmro~ c inelude, M_~l~ , and P-~
2S T~ e hormone ~~,1~;. o hormone agents or O ~'~ u~ih~-relea ing hormone are used primarily the l.~ ~ of prostate cancer These include leuprolide acetateand ~-~,li., acetate. They prevent the ~ , IllL~,aia of steroidâ in the testes .~nti~ ~' antigens include:
~ti~ u~, ni~, agents such as Tz~Tn~cifi~ n ' ug~,.. agents _uch as Flutamide; and allLiadl~aal agents such as l~litotqnt~ and ~. ;- .~1"~1;. -i 1c E~d-UA.~-W appear_ to act primarily through inhibit ~r of the enyme .;1~ liA~.
~ is an enyme which converts -~ t~ to rU~ ~r ~ ~ it~n~l aspartic acid and 3S thus blocks protein a.~lllL-,~;s in the tumor W O 97/05870 PCT~US96/12475 D. POTENTIATORS
The "~ can be any material which i.l.~.lu.es or increase the efficacy of the ph~ c.--~ or aets as an ;~ ~ o~ p~,~3r. One such F- is triprolidine and its cis-isomer which are used in cu~ inn with the ,~ ;c agents and t~e S ~i~orUlvi.,. Triprolidine is de~li~ in US 5,114,951 (1992). Another p is pr.-~ '~, lII Rr..,;~ 2_~11, ~ acid; [B-(2-ben7imiA ~-) p.l, acid; 2-(2-ca lu~ .,lllyl)brn7imi~ ~ propa_oll. Pl- ~ 'e is a non-specific active i,.. m ,~
agent against viral and bacterial infi~ti - - - and can be used with the co- ~1 n~ :~ io.~ claimed herein.
It is effective with gli~eorulvi-l alone in treating cancers, tumors, le.~ mi~ and viral jj.F~ or 10 cv~ ~ with ~ JI~ nll~ V~;C agents.
P~o~ - acid and its salts and esters can also be used in ~ ;"n with the r'~ 1 C~ IU)S;I;OnC claimed herein.
~ n~inYi,l~nr vitamins such as vitamins A, C and E and beta-carotene can be added to these cc.--~, oc;~
15 E. DOSAGE
Any suitable dosage may be given in the method of the i.,~ r The type of e ~
and the carrier and the amount will vary widely dr~nAing on the species of the warm blooded animal or human, body weight, and the type of cancer or tu~nor or viral infiection being treated.
Generally a dosage of between about 1 milli~m (mg) per kilogr~m (Icg) of body weight and about 20 8000 mg per kg of body weight is suitable for either the griseofulvin or the _h - , ~
agent. Plef~,.~l~ from 15 mg to about 5000 mg/kg of body weight is used. Generally, the dosage in man is lower than for small warm blooded m~mm~lc such as mice. A dosage unit may co ~1" ;~ a single ~ 1~ .A or mixtures thereof with other ,O...In, ~~lc or other cancer inh;t~iti~g ~ The dosage unit can also _r diluents, ~ d~ carriers, l;l u~-~r c and the 2S like. The unit may be in solid or gel fonn such as pills, tablets, capsules and the like or in liquid for n suitable for oral, rectal, topical, hlLI~.~ e.~JuS injection or pal~ r or injection into or around the bone marrow. The range and ratio of griseofulvin tochr ~ , ..t;r agent will depend on the type of cancer or tumor being treated and the p~ Li~,ul~
l~hr nntk .;~ agent.
30 F. DOSAGE DELIVERY FORMS
The ~h..,lh.,~ ;,, agents, griseofulvin and, optionally, the put~ are typically mi7~ed with a pl.~ lly ~ carrier. This carrier can be a solid or liquid and the type is generally chosen based on the type of a-l~ ion being used. The active agent can be C~ ~ 't~Cd in the form of a tablet or capsule, li~cnnlr, as an a~l~ t~Yi powder or in a 3S liquid form. F ~ r of suitable solid carriers include lactose, sucrose, gelatin and agar.
Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid _7_ forms indude granules, and bulk powders. Tablets may contain suitable binders, l~
diluents, ~' t~o ,, agents, coloring agents, navo~ g agents, flow-inducing agents, and melting agents. F - '-- of suitable liquid dosage forrns include ~ c or ~ in water, pha~ lly ~ ~.p! ' ~~ fats and oils, alcohols or other org nic solvents,; ~ e 5 esters, ~ c syrups or elixirs, ~ )nc, solutions and/or ~ - lr -~:o~c ~ t ~l from non-effervescent granules and ~,ff...~.~ prepA-r~ti~nc ,- COh~ A, from ~f~ l granules.
Such liquid dosage forms may contain, for, . 'e suitable solvents, yl~,~.vali~5, e..~ if~i-.O
agents, ~ ne agents, diluents, _.._ th~ PnPr~ and melting agents Oral dosage forms optionally contain na~v.~lt~ and coloring agents. Pal~ ~ ' and inlla~ u~ forms would 10 also include minerals and other m~Pri~lc to make them ~- It with the type of injection or delivery system chosen.
Specific ~ of pha. .-- ~ ;. al a ,ep~ ' 'o carriers and, ~~ ~ ~ that may be used to r_ ' ~,~ oral dosage forms of the present il.~ ioll are d~ A in U. S. Pat. No. 3,903,297 to Robert, issued Sept. 2, 1975.Tcchni~lu~c and ~ ~po~;~;o~ for making dosage forms usefill in lS the present invention are dr~-;I~d in the follo ving ~ e~. 7 Modern Pl-a. ~ ~ ul;- 5. Chapters 9 and 10 (13anker ~ Rhodes, Editors, 1979);T l~-~--al~ et al., Pl-a~ _l Dosa~ee Forms:
(1981); and Ansel, Il-llu lu-,lio-- to Pl.~ ...~ al Dosa e Forms 2nd Edition (1976).
G METHOD OF TREATMENT
The method of L.~ can be any suitable method which is effective in the ll~ of 20 the ~_ ' cancer or tumor type being treated. Treatment may be oral, rectal, topical, pa~e ' or i.~L...~_nvus ~I...;ni~u.-~ or by injection into the tumor or cancer. The method of applying an effective amount also varies d- ~ n-l;ug on the le~ Pmi-- cancer, tumor or virus being treated. It is believed that ~ ? ~l---~,..l by hllla~-~luus, 5uh~ n~ , or ;~
a~ of the ~;~rul~ill, r~ d with an a~.. upl;alt: carrier, a~ ' canoer ~ ' ' g 25 ~ . ' or ~ , ' or diluent to facilitate ~p~ on will be the l l~,fe,l~ method of ~ ~ ~ ~ ~ ~ th~ ' to warm blooded animals.
In addition to the use of ~hemnl~ agents and p ~isevr~ ill can be ~ ~ ~ ' with fi-ur;~ Jr;, L~ or other antiviral agents. P~ l h.,.~ - ~ and r.... .nF"~ :d ~ ~ include call~ ,; " " n U~o~ e, benomyl, ~;ly~hv~tu and pl-r c - ' 'e Example 1 In an acute HIV in vitro model, griseofulvin inhihi~Pd viral llr~ ~ by 98% at lOIIg/ml with a Ih .~ C index of 5.3. AZT, a known ~V drug, also inhihi~Pd viral l~
by 98% at lllg/ml with a ~h~ ;c index of 12,500. The Ih~,.a~ lic index is the ratio of toxic dose of drug to ~ ll~. ~- :-.--c dose of drug.
Example 2 In an in vivo mouse study for I ' '- (P388), ~.i~orulvin showed an increas~ in the survival time relative to a non treated control of 156% at 4000 mg/kg dose; 188% at 5000 mglkg dose; and 218% at 6000 mgAcg dose.
S Example 3 In an in vivo mouse study for, ~ (B16), ~fi~r~vi., showed an increase in the survival time relative to a nU~ control of 165% at 4000 mg/kg dose; 179% at S000 mg/kg dose; and 201% at 6000 mglkg dose. Cytoxan at 300 mg/kg showed an h.w~d survival rate of 192%.
Example 4 In an in vitro ~m..g for P~ , type A-l, cell line WI-38, g-;~rulvin was effective at 100 llg/ml. The positive control was A-36683 of Abbot Company, (S,S)-1,2-bis(S-methoxy-2~ --~yl)-1,2~~ J ol A-36683 has a ~ Jlir index of 1000-3200.
fi~l~,in has a i' , - ~- index of 1-2. (See S~hl~irhPr et al, Applied Microbiolo~y, ~, No.
15 1, 113-116 (1972).
Example 5 Solid tumors removed by patients are minced into 2 to 5 mm r -~ ~-1~ and ~
placed in McCoy's Medium 5A plus 10~/O heat hla~ newborn calf serum plus 1%
r llin/~ . Within 4 hours, these solid tumors are ,..f~ ly ,i;~ t-'~ with 20 scissors, forced through No. 100 stainless steel mesh through 25 gauge needles, and then washed with McCoy's medium as dc~cfil,cd above. Ascitic, pleural, p~ fi~ lial fluids and bone marrow are obtained by standard ~ c The fluid or marrow is placed in sterile co- ~
' ~ - g 10 units of ~/lc~va~ e free heparin per ml. of m~ gJl~nt fluid or marrow. After ~ ~~- '~ue~- ~ - at 150 x g for 10 minutes, the cells are haJ ~ d and washed with McCoy's medium 25 plus 10% heat h la~ calf serum. The viability of oell ~ ,c:.~c is J~ ~- ~---;---'A on a h~ te~ with trypan blue.
Cells to be cloned are 5 ~ ~ in 0.3~/O agar in enriched CMRL1066 _,"'~ ' with lS~/. heat in~li..~ ~ horse serum, pPnirillin {100 units/ml), ~ (2mg/ml), g' ~ ~ -(2mM), insulin (3 units/ml), ~ -e (0.6 mg/ml), and HEPES buffer (2mM). For the 30 ~ ~ exposure test each ~u~ is added to the above mixlure. Cells are placed in 35 mm petri dishes in a top layer of agar over an ullde~ . of agar to prevent growth of r.b.~~
Three plates are prepared for each data point. The plates are placed in a 37~C inr ~ - r, and are removed on day 14 for counting of the number of colonies in each plate. The number of colonies (defined as 50 cells) formed in the 3 r~ treated plates is Cw~uc;i to the number of~S colonies fonned in the 3 control plates, and the percent colonies S~ 'ViVil-g at the cc ~ - of ' can be; ~ ' Three positive control plates are used to ~i- t~ i-e s~ival rate.
W O 97/05870 PCT~US96/12475 g O.i' ~ s ' ~, - ' at 200 ~g/ml is used as the positive control. If there is <30% colonies in the positive control when cu~ d to the u..l.~t~.d control, the test is evaluated.
At con~ of 0.5 and S.0 llg/ml in a single dose e,~ ~oru~ was not effective (0/1) against tumors in this test. At c~ of S0.0 llg/ml in a; exposure S ~ ~ ~i~rul~ill was effective against colon, lun& n~ 1 cell, and ovarian cancers .
Over all S of 6 had SS0% survival.
This i,.~.- is a pL~u~ fi~ ~I c--~ -- - that is useful for the ~ of cancers and tumors, p=-l;r~ in h~unan and warm blooded animals. The f~ --"- contains -~ h~. It can be used in A ~ with other c' --- -'~~~q~ ~ agents also.
S BACKGROU~ID OF T~E INVENTION
Cancers, i~ ;nE '~ ' ~ are the leading cause of death in animals and hurnans. The exact cause of l~ mi~ is not known, but links between certain activities such as smoking or c,~s u~ to w~_h-og_-~ and the ir~ nce of certain types of I ' - and turnors has been shown by a number of l~e~.h~.a.
Many types of ,1...... ~ ;c agents have been shown to be effective againsat cancers, tumors and I ' but not all types of cancer and tumor cells respond to these agents.
u"ru~ , many of these agents also destroy normal oells. The exact ~ for the action of these c' , - agents are not always known.
Despite a.l~ l~.,S in the field of canoer and l~ul~m~ n~.lta the leading t~ , ~ to lS date are r~ ti- n and ~1- -----11-- ~1~ and bone marrow ~ 'h. ..--~ll.. .a~ d~
are said to fight canoers that a~e p~uh.ukul~ a~.e~;~_. Such cytocidal or ~jt~at~li- agents work best on cancers with largc growth factors, i.e., ones whose oells are rapidly dividing. To date, 1~."~ ~A~ in p~uh-,~l~ estrogen. ~ ~uO_.t~,.une and i une, and some ~ ~,-ulu~l by a variety of ~ lahl.g agents, and anti ~- I"hnl;~ form the bulk of i ~ available 20 to ~ Ideally ~ ~ - agents that have ~ ;r..:/~ for '~ ~ ~, canoer and tumor oells while not affecting normal oells would be ~ el~ ~If-' -- ~~ U-lrU-i ' ~.y, none have been found and instead agents which target especially rapidly dividing oells (both diseased and normal) have been used.
Clearly, the d~ lo~..." .~ Of . .t~ lc that would target canoer or le -l-~mi:- oells due to 2~ some unique ~ r.;~ for them would be a b.cdkllu. _- Alt~..~h._l~, -'- that were .,~tolu~c to It ~ ~ or cancer cells while exerting mild effects on normal oells would be ~ ~ '- Therefore, ill is an object of this i,.~_.,tion to provide a ph-..--'- ~j..l;~ ~1 CC~ that is effective in treating '~ ' ~ with mild or no effects on normal blood oells More !q~ifi~lly, it is an object of this invention to provide a ~u--~ u~ g a 30 ph ~- ' carrier and a o~ia~,~r~ i" as defined herein along with a method for treating cancer, IP-.1,Pm;~ and tumors.
W O 97/05870 PCT~US96/12475 The u e of ~ c~rulvin in co~ l;n ~ with other ch~mr~th~ ;c agents which are effective in dc~lluyingth~e tumor is a novel method of tl~at~ nl Griseofulvin can also be used to treat viral infi~cti-~nc in the presence of a p SUMMARY OF THE INVENTION
S A ph~ ti~1 co~ ion for tll,atl~ -t of m~mm~llc, and in pa li-,ular, warmblooded animals and humuns, which are affected by I ' - Cc)--~ g a ph~ i carrierand an effective amount of ~;.i~vrul~in Griseofulvin has the formula:
CH30 ~ ~ ~
These ,~ c can be u ed to inhibit the growth of le~ r~;o turnors and cancer oells in hurnans or anim~ls by ~ t ~~;o~ of an effective amount either orally, rectally, topically or pa~ 11y, or illtla~ ,. These ~c l n~ do not ~ ri ~ ~11y a~fect hc-althy cells.
Pl~ can also be used in co- I~ with ~j.iacvr,llvin as can l~.. lh lS agents.
DEl'AILED DESCRIPTION OF T~E INVENTION
DE~INlTIONS:
As used herein, the term "co l ;~;~g" means various r~r can be ~ 1, 1~, in the pt~ of this invention Accul li~ly, the terrns "co~ g 20 , - 'Iy of n and ~c g Or are ~ d in the term ~ g As used herein, a "~ " ~ 11y ~ u c~ is one that is suitable for use with humans and~or animals without undue adverse side effects (such as toxicity, ilTit~tinn, and allergic response) co-- . ..~ te with a ~._ ' '- benefit/risk ratio As used herein, the term "safe and effective amount" refers to the quantity of a c~ ~''~ -.1 25 which is ~ r: .-t to yield a desired thf ~ ;c response without undue adverse side effects (wch as toxicity, ~ t~ n~ or allergic response) L('''~ with a ,~ )r ' I~ ~n-,r~ ;ak ratio when used in the rnanner of this i..~f.lliO... The specific "safe and effective amount" will, ~.liou~ly, vary with such factors as the particular co~i;l;o - being treated, the physical c~ l;l;o-- of the patient, the type of mamlr~ being treated, the duration of the lltiall..c.ll, the nature of co..,...,,_nl Wo 97/05870 PCT/US96/12475 therapy (if any), and the specific r~)". .I~I;nnc ~ .i and the structure of the CO"~1~UY~ or its d..iv~ti~
As used herein, a -~ t;~ -' addition salts" is salt of the anti ll .,L. - ~ C~..~l~....A
with an organic or hlOI~,diUC acid. These ~.ef...e;i acid addition salts are rhlnnA~oc, blu..~idc,s, S sulfates, nitrates, ph~y~ t. -, R~C ' S, finrmzlt~5~ tartrates, mzll ' , malates, citrates, ~ u ~h ~, salicylates, ~u-I,at. " and the like.
As used herein, a "~h~.~ e-~ l carrier" is a ph~ ly a "~ solvent, r ,, agent or vehicle for delivering the anti '~ ' ' agent to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of -d~ U"~ A in mind.
As used herein, "cancer" or "l ~ ~ " refers to all types of cancers or - ,' or ...~1;~.- -- ~ disease which attack normal healthy blood cells or bone marrow which produces blood cells which are found in ~., ~
As used herein, "viruses" includes viruses which cause diseases in war n blooded animals e HIV, i"n.,. ~-,~ ~hil~uvilu~c;~, herpes and the like.
As used herein, "g-i~ûrljlvin" means 7-Chloro-2',4,6-L-i.. _ll-u.~-6 ._lh,~ JilU
rt ~,..r~ 2-(3H),1'-[2~ lolt~ ] 3,4'~ione. It is an ~ .uducoi by p . 7r griseofu~vum As used herein "F~ ~ are ~ ' '- such as l.;l..ulidi-le and its cis-isomer which are used in c~ -- with ~ ~rulvi... r.. can suppress the immune system or 20 enhance the c~li~_"_~ of the drugs.
As used herein ~ nlh ~ ;c agents" includes DNA-' '._ Agents, Antime-tabolites, Tubulin-T 'v~ Agents, ITn..~ O~ agents and others, such as ~p--~gi~ -~ or h~.Lu~y~ ~.
B. GRISEOFULVIN
~ YJr~lViU~ has the following ~Uu.luc.
It is prepared according to the method Af ~ . ;I~A in U.S. 3,069,328 issued to TTn. L. ..
(1962) and U.S. 3,069,328 issued to Dorey et al. (1962) C CUEM OT~ERAPEUTIC AGENTS
The d~r~ ir agents are generally grouped a_ DNA~ Agents, A~ ;t~ C, Tubulin-Interactive Agents, IIo- I agents and others such as A.~ ~ or L r~UA~r~U~. Each of the groups of ~ agents can be further divided by type of 5 activity or co--.l~--u~l The rh~moth.._l,~ agents u_ed in c~ ;o~1 with 2~i~oîulvin include ~-- ~ ~l~f ~-, of all of these groups. For a detailed ~ of the ~ ...n~ f .~;r agents and their method of ad~ ul;on, see Dorr, et al, Cancer ~ th~rapy Hondboo~c, 2d edition, pages lS-34, Appleton rl~ Lange (C ~ , 1994) herein i..~.~,u.,~t~ by l~f~"~ c.
DNA-T '~,o Agents include the aL~cylating agents, e.g. Cicp1~'in C~,rc1r~l~hn~
10 All.1 ~, the DNA strand-bl~kà6_ agent_, _uch as Bl~...~, the ih.t~lr~lil.g 1O~ c.J.~ ~; ;e II inhibitors, e.g., Dactinomycin and Dw~u-l ' ' ); the r ' ~lating "~r;~ e II inhihi~rlrc such as, F~posi~1r and Tc~ ~s~i~, and the DNA minor groove binder Plc~ll., li...
The alkylating agents form covalent chrmir~l adducts with cellular DNA, RNA, andlS protein ---1( ' - and with smaller amino acids, gh~ hin~ and similar rhrmir~l~ Generally, these allylating agents react with a .~ ~ph;1ir atom in a oellular co~l ;n -~ such as an amino, carboxyl, r~ n.y,~l group in nucleic acids, proteins, amino acids, or g' ~-~' ~ - T_e ~ ' ~ and the role of these alkylating agents in cancer therapy is not well u~ ~.r~r~OA
Typical aL~l,~ing agents indude:
Nitrogen mustards, such as Ch1o1~ u~ C~lophr~ T " ~, Mechlo..l1--.--;1~ M~ h~ Uracil mustard;
AziAdine such as Thiotepa t; ~~ ~ esters such as ~ llf~n nitrosou~5,suchasC~.,... l ;..r Tr ~,S~ l~t~
F ' c , ' , such as ~i, ' ' GUIJOplf~lil-, ' ' r~l~.,li~_ alcylator, such as MilOl--yr i.-, and Plu~l,a~il.e, D~-~l,~ne andAlll.
DNA strand breaking agents include Bleollly~
DNA l~ nhih;tor~ include the following:
T ~ ' , suchas A.--~ e Da~;~inoll.. ~ , Daunorubicin, Do~o. ' ' ' Idall ' ' ~ and M;l.,._u~ulle., - ' ~lators, such as F~ f and Te-~ 1c The DNA minor groove binder is Plic~..~_h-.
The ~ l~l;t~, interfere with the ~lU hJ.,Iion of nucleic acids by one or the other of 3S t~o major ",~h~ Some of the drugs inhibit l,lu~lu~lioll of the deo~y-i~
lA~ t'_ that are the il ---" Pl~ U~ for DNA synthesis, thus inhihiting DNA
Some of the eu~ are S--n~ ly like purines or pynmi~ oS to be able to W O 97/05870 PCT~US96/12475 for them in the anabolic '- ' patl~ s These analogs ean then be ~ ~
into the DNA and RNA instead of their normal cu~ t-.~alLs. The ~ oi;t~ ~ useful herein inelude:
folate ~ such as M_lholl. and l-i...~,l..
S pyrimidine ~ l~o ~ " sueh as Fluo-uu c~ -il, Fluo.udco,~idine, CB3717, A7qr~ n Cy~;~.e, and Floxuridine purine ~ ~g. ;~1~ inelude M~.~ , . 6-Tl~ ;.f ~-J~hi.~,rl ;
wgar modified analogs inelude C~_~dl,i-.c, Fl ~ h;
'- ' ' .~1U~,LO- 1 ~ inelude h~u~a Tubulin T ~_ agents act by binding to specific sites on tubulin, a protein that pol~ .i~s to form cellular ~. i_-.hL '- Mi,-ulLL ' are eritieal eell structure units When the ~ ~,_ agents bind on the protein, the cell can not form l~iwulub~lC5 Tubulin I"t~.~,li,_ agents include Vi~ and V ~'- both q-l~ql- '' and Pa~,lila.~,l.
~Tnnntlnql agents are also useful in the l,~aL,...,.II of eancers and tumors. They are used in 15 ~ lly - ~-r ~ tuunors and are usually derived from natural sources. These include:
~,truO_.~" . ;_~ ~ e~,l.u~, and Ethinyl ~ct~tliol snd Diethylcti~
~hl." ~ GP.. and T<~ d~
I,,~,_;,lh,s sueh as II~uA~ ,~t~,.une caproate, Med-u.~ ,u~tu.unc, and Mct,_~tlul;
ai~uO_.~ sueh as l~;.lua~.u~ ui~c ~ r~ ~, nl~ui~yl--_:~t~.-O~C, I--~lI-ylt~tual~-u--_, Adrenal co.li,u~ ' are derived from natural adrenal eortisol or hydlu,OIliaOll.,. They are us~d beeause of their anti " y benefits as well as the ability of some to inhibit mitotie liv -- and to halt ~NA ~ -' These enmro~ c inelude, M_~l~ , and P-~
2S T~ e hormone ~~,1~;. o hormone agents or O ~'~ u~ih~-relea ing hormone are used primarily the l.~ ~ of prostate cancer These include leuprolide acetateand ~-~,li., acetate. They prevent the ~ , IllL~,aia of steroidâ in the testes .~nti~ ~' antigens include:
~ti~ u~, ni~, agents such as Tz~Tn~cifi~ n ' ug~,.. agents _uch as Flutamide; and allLiadl~aal agents such as l~litotqnt~ and ~. ;- .~1"~1;. -i 1c E~d-UA.~-W appear_ to act primarily through inhibit ~r of the enyme .;1~ liA~.
~ is an enyme which converts -~ t~ to rU~ ~r ~ ~ it~n~l aspartic acid and 3S thus blocks protein a.~lllL-,~;s in the tumor W O 97/05870 PCT~US96/12475 D. POTENTIATORS
The "~ can be any material which i.l.~.lu.es or increase the efficacy of the ph~ c.--~ or aets as an ;~ ~ o~ p~,~3r. One such F- is triprolidine and its cis-isomer which are used in cu~ inn with the ,~ ;c agents and t~e S ~i~orUlvi.,. Triprolidine is de~li~ in US 5,114,951 (1992). Another p is pr.-~ '~, lII Rr..,;~ 2_~11, ~ acid; [B-(2-ben7imiA ~-) p.l, acid; 2-(2-ca lu~ .,lllyl)brn7imi~ ~ propa_oll. Pl- ~ 'e is a non-specific active i,.. m ,~
agent against viral and bacterial infi~ti - - - and can be used with the co- ~1 n~ :~ io.~ claimed herein.
It is effective with gli~eorulvi-l alone in treating cancers, tumors, le.~ mi~ and viral jj.F~ or 10 cv~ ~ with ~ JI~ nll~ V~;C agents.
P~o~ - acid and its salts and esters can also be used in ~ ;"n with the r'~ 1 C~ IU)S;I;OnC claimed herein.
~ n~inYi,l~nr vitamins such as vitamins A, C and E and beta-carotene can be added to these cc.--~, oc;~
15 E. DOSAGE
Any suitable dosage may be given in the method of the i.,~ r The type of e ~
and the carrier and the amount will vary widely dr~nAing on the species of the warm blooded animal or human, body weight, and the type of cancer or tu~nor or viral infiection being treated.
Generally a dosage of between about 1 milli~m (mg) per kilogr~m (Icg) of body weight and about 20 8000 mg per kg of body weight is suitable for either the griseofulvin or the _h - , ~
agent. Plef~,.~l~ from 15 mg to about 5000 mg/kg of body weight is used. Generally, the dosage in man is lower than for small warm blooded m~mm~lc such as mice. A dosage unit may co ~1" ;~ a single ~ 1~ .A or mixtures thereof with other ,O...In, ~~lc or other cancer inh;t~iti~g ~ The dosage unit can also _r diluents, ~ d~ carriers, l;l u~-~r c and the 2S like. The unit may be in solid or gel fonn such as pills, tablets, capsules and the like or in liquid for n suitable for oral, rectal, topical, hlLI~.~ e.~JuS injection or pal~ r or injection into or around the bone marrow. The range and ratio of griseofulvin tochr ~ , ..t;r agent will depend on the type of cancer or tumor being treated and the p~ Li~,ul~
l~hr nntk .;~ agent.
30 F. DOSAGE DELIVERY FORMS
The ~h..,lh.,~ ;,, agents, griseofulvin and, optionally, the put~ are typically mi7~ed with a pl.~ lly ~ carrier. This carrier can be a solid or liquid and the type is generally chosen based on the type of a-l~ ion being used. The active agent can be C~ ~ 't~Cd in the form of a tablet or capsule, li~cnnlr, as an a~l~ t~Yi powder or in a 3S liquid form. F ~ r of suitable solid carriers include lactose, sucrose, gelatin and agar.
Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid _7_ forms indude granules, and bulk powders. Tablets may contain suitable binders, l~
diluents, ~' t~o ,, agents, coloring agents, navo~ g agents, flow-inducing agents, and melting agents. F - '-- of suitable liquid dosage forrns include ~ c or ~ in water, pha~ lly ~ ~.p! ' ~~ fats and oils, alcohols or other org nic solvents,; ~ e 5 esters, ~ c syrups or elixirs, ~ )nc, solutions and/or ~ - lr -~:o~c ~ t ~l from non-effervescent granules and ~,ff...~.~ prepA-r~ti~nc ,- COh~ A, from ~f~ l granules.
Such liquid dosage forms may contain, for, . 'e suitable solvents, yl~,~.vali~5, e..~ if~i-.O
agents, ~ ne agents, diluents, _.._ th~ PnPr~ and melting agents Oral dosage forms optionally contain na~v.~lt~ and coloring agents. Pal~ ~ ' and inlla~ u~ forms would 10 also include minerals and other m~Pri~lc to make them ~- It with the type of injection or delivery system chosen.
Specific ~ of pha. .-- ~ ;. al a ,ep~ ' 'o carriers and, ~~ ~ ~ that may be used to r_ ' ~,~ oral dosage forms of the present il.~ ioll are d~ A in U. S. Pat. No. 3,903,297 to Robert, issued Sept. 2, 1975.Tcchni~lu~c and ~ ~po~;~;o~ for making dosage forms usefill in lS the present invention are dr~-;I~d in the follo ving ~ e~. 7 Modern Pl-a. ~ ~ ul;- 5. Chapters 9 and 10 (13anker ~ Rhodes, Editors, 1979);T l~-~--al~ et al., Pl-a~ _l Dosa~ee Forms:
(1981); and Ansel, Il-llu lu-,lio-- to Pl.~ ...~ al Dosa e Forms 2nd Edition (1976).
G METHOD OF TREATMENT
The method of L.~ can be any suitable method which is effective in the ll~ of 20 the ~_ ' cancer or tumor type being treated. Treatment may be oral, rectal, topical, pa~e ' or i.~L...~_nvus ~I...;ni~u.-~ or by injection into the tumor or cancer. The method of applying an effective amount also varies d- ~ n-l;ug on the le~ Pmi-- cancer, tumor or virus being treated. It is believed that ~ ? ~l---~,..l by hllla~-~luus, 5uh~ n~ , or ;~
a~ of the ~;~rul~ill, r~ d with an a~.. upl;alt: carrier, a~ ' canoer ~ ' ' g 25 ~ . ' or ~ , ' or diluent to facilitate ~p~ on will be the l l~,fe,l~ method of ~ ~ ~ ~ ~ ~ th~ ' to warm blooded animals.
In addition to the use of ~hemnl~ agents and p ~isevr~ ill can be ~ ~ ~ ' with fi-ur;~ Jr;, L~ or other antiviral agents. P~ l h.,.~ - ~ and r.... .nF"~ :d ~ ~ include call~ ,; " " n U~o~ e, benomyl, ~;ly~hv~tu and pl-r c - ' 'e Example 1 In an acute HIV in vitro model, griseofulvin inhihi~Pd viral llr~ ~ by 98% at lOIIg/ml with a Ih .~ C index of 5.3. AZT, a known ~V drug, also inhihi~Pd viral l~
by 98% at lllg/ml with a ~h~ ;c index of 12,500. The Ih~,.a~ lic index is the ratio of toxic dose of drug to ~ ll~. ~- :-.--c dose of drug.
Example 2 In an in vivo mouse study for I ' '- (P388), ~.i~orulvin showed an increas~ in the survival time relative to a non treated control of 156% at 4000 mg/kg dose; 188% at 5000 mglkg dose; and 218% at 6000 mgAcg dose.
S Example 3 In an in vivo mouse study for, ~ (B16), ~fi~r~vi., showed an increase in the survival time relative to a nU~ control of 165% at 4000 mg/kg dose; 179% at S000 mg/kg dose; and 201% at 6000 mglkg dose. Cytoxan at 300 mg/kg showed an h.w~d survival rate of 192%.
Example 4 In an in vitro ~m..g for P~ , type A-l, cell line WI-38, g-;~rulvin was effective at 100 llg/ml. The positive control was A-36683 of Abbot Company, (S,S)-1,2-bis(S-methoxy-2~ --~yl)-1,2~~ J ol A-36683 has a ~ Jlir index of 1000-3200.
fi~l~,in has a i' , - ~- index of 1-2. (See S~hl~irhPr et al, Applied Microbiolo~y, ~, No.
15 1, 113-116 (1972).
Example 5 Solid tumors removed by patients are minced into 2 to 5 mm r -~ ~-1~ and ~
placed in McCoy's Medium 5A plus 10~/O heat hla~ newborn calf serum plus 1%
r llin/~ . Within 4 hours, these solid tumors are ,..f~ ly ,i;~ t-'~ with 20 scissors, forced through No. 100 stainless steel mesh through 25 gauge needles, and then washed with McCoy's medium as dc~cfil,cd above. Ascitic, pleural, p~ fi~ lial fluids and bone marrow are obtained by standard ~ c The fluid or marrow is placed in sterile co- ~
' ~ - g 10 units of ~/lc~va~ e free heparin per ml. of m~ gJl~nt fluid or marrow. After ~ ~~- '~ue~- ~ - at 150 x g for 10 minutes, the cells are haJ ~ d and washed with McCoy's medium 25 plus 10% heat h la~ calf serum. The viability of oell ~ ,c:.~c is J~ ~- ~---;---'A on a h~ te~ with trypan blue.
Cells to be cloned are 5 ~ ~ in 0.3~/O agar in enriched CMRL1066 _,"'~ ' with lS~/. heat in~li..~ ~ horse serum, pPnirillin {100 units/ml), ~ (2mg/ml), g' ~ ~ -(2mM), insulin (3 units/ml), ~ -e (0.6 mg/ml), and HEPES buffer (2mM). For the 30 ~ ~ exposure test each ~u~ is added to the above mixlure. Cells are placed in 35 mm petri dishes in a top layer of agar over an ullde~ . of agar to prevent growth of r.b.~~
Three plates are prepared for each data point. The plates are placed in a 37~C inr ~ - r, and are removed on day 14 for counting of the number of colonies in each plate. The number of colonies (defined as 50 cells) formed in the 3 r~ treated plates is Cw~uc;i to the number of~S colonies fonned in the 3 control plates, and the percent colonies S~ 'ViVil-g at the cc ~ - of ' can be; ~ ' Three positive control plates are used to ~i- t~ i-e s~ival rate.
W O 97/05870 PCT~US96/12475 g O.i' ~ s ' ~, - ' at 200 ~g/ml is used as the positive control. If there is <30% colonies in the positive control when cu~ d to the u..l.~t~.d control, the test is evaluated.
At con~ of 0.5 and S.0 llg/ml in a single dose e,~ ~oru~ was not effective (0/1) against tumors in this test. At c~ of S0.0 llg/ml in a; exposure S ~ ~ ~i~rul~ill was effective against colon, lun& n~ 1 cell, and ovarian cancers .
Over all S of 6 had SS0% survival.
Claims (10)
1. A pharmaceutical composition for treating cancer and tumors comprising a pharmaceutical carrier and from 1 mg/kg to about 8000 mg/kg per body weight.
2. A pharmaceutical composition according to Claim 1 comprising a potentiator.
3. A pharmaceutical composition according to claim 1 and 2 comprising a pharmaceutically acceptable carrier and a safe and effective amount of griseofulvin and a chemotherapeutic agent.
4. A pharmaceutical composition according to claim 1,2 or 3 wherein said chemotherapeutic agent is selected from the group consisting of DNA-interactive Agents, Antimetabolites, Tubulin-Interactive Agents, Hormonal agents, Asparaginase or hydroxyurea.
5. A pharmaceutical composition according to claim 1, 2 or 4 wherein said chemotherapeutic agent is selected from the group consisting of Asparaginase, hydroxyurea, Cysplatin, Cyclophosphamide, Altretamine, Bleomycin, Dactinomycin, Doxorubicin, Etoposide, Teniposide and Plcamydin.
6. A pharmaceutical composition according to claim 1, 2 or 4 wherein said chemotherapeutic agent is selected from the group consisting of Methotrexate, Fluorouracil, Fluorodeoxyuridine, CB3717, Azacitidine, Cytarabine, Floxuridine, Mercaptopurine, 6-Thioguanine, Fludarabine, Pentostatin, Cyctrabine, and Fludarabine.
7. A method of treating cancer or tumors in warm blooded mammals comprising administering a composition according to claims 1, 2, 3, 4, 5 or 6.
8. A method of treating viral infections in warm blooded mammals comprising administering a composition according to claims 1, 2, 3, 4, 5, or 6.
9. A unit dosage composition for treating viral infections in animals or humans comprising a pharmaceutical carrier and from 1 mg/kg to about 8000 mg/kg of body weight.
10. A unit dosage composition for treating cancer or tumors in animals or humans comprising a pharmaceutical carrier and from 1 mg/kg to about 8000 mg/kg of body weight.
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| US183995P | 1995-08-03 | 1995-08-03 | |
| US60/001,839 | 1995-08-03 | ||
| US67418196A | 1996-07-16 | 1996-07-16 | |
| US08/674,181 | 1996-07-16 |
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| CA2228503A1 true CA2228503A1 (en) | 1997-02-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002228503A Abandoned CA2228503A1 (en) | 1995-08-03 | 1996-07-30 | Use of griseofulvin for inhibiting the growth of cancers |
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| EP (1) | EP0841914A2 (en) |
| JP (1) | JPH11511136A (en) |
| KR (1) | KR19990036137A (en) |
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| AU (1) | AU713031B2 (en) |
| BR (1) | BR9609920A (en) |
| CA (1) | CA2228503A1 (en) |
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| HU (1) | HUP9903506A3 (en) |
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| PL (1) | PL324905A1 (en) |
| SK (1) | SK14298A3 (en) |
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| WO (1) | WO1997005870A2 (en) |
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| US6479526B1 (en) | 1995-04-12 | 2002-11-12 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of viruses and cancers |
| US6262093B1 (en) | 1995-04-12 | 2001-07-17 | The Proctor & Gamble Company | Methods of treating cancer with benzimidazoles |
| US6177460B1 (en) | 1995-04-12 | 2001-01-23 | The Procter & Gamble Company | Method of treatment for cancer or viral infections |
| US6265427B1 (en) | 1995-06-07 | 2001-07-24 | The Proctor & Gamble Company | Pharmaceutical composition for the method of treating leukemia |
| US5770616A (en) | 1995-06-07 | 1998-06-23 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of cancers |
| US6686391B2 (en) | 1995-08-04 | 2004-02-03 | University Of Arizona Foundation | N-chlorophenylcarbamate and N-chlorophenylthiocarbamate compositions |
| US5900429A (en) | 1997-01-28 | 1999-05-04 | The Procter & Gamble Company | Method for inhibiting the growth of cancers |
| US6506783B1 (en) | 1997-05-16 | 2003-01-14 | The Procter & Gamble Company | Cancer treatments and pharmaceutical compositions therefor |
| US6245789B1 (en) | 1998-05-19 | 2001-06-12 | The Procter & Gamble Company | HIV and viral treatment |
| DK1098641T3 (en) * | 1998-07-27 | 2016-08-15 | St Jude Pharmaceuticals Inc | Chemically induced intracellular hyperthermia |
| WO2000027428A1 (en) * | 1998-11-09 | 2000-05-18 | Idec Pharmaceuticals Corporation | Treatment of hematologic malignancies associated with circulating tumor cells using chimeric anti-cd20 antibody |
| US6423734B1 (en) | 1999-08-13 | 2002-07-23 | The Procter & Gamble Company | Method of preventing cancer |
| US6407105B1 (en) | 2000-09-26 | 2002-06-18 | The Procter & Gamble Company | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| US6462062B1 (en) | 2000-09-26 | 2002-10-08 | The Procter & Gamble Company | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| US6608096B1 (en) | 2000-09-26 | 2003-08-19 | University Of Arizona Foundation | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| US6380232B1 (en) | 2000-09-26 | 2002-04-30 | The Procter & Gamble Company | Benzimidazole urea derivatives, and pharmaceutical compositions and unit dosages thereof |
| JP4779298B2 (en) * | 2001-06-25 | 2011-09-28 | 味の素株式会社 | Antitumor agent |
| EP2008652A1 (en) * | 2007-06-28 | 2008-12-31 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Griseofulvin analogues for the treatment of cancer by inhibition of centrosomal clustering |
| EP2204367A1 (en) * | 2008-12-22 | 2010-07-07 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Griseofulvin analogues for the treatment of cancer by inhibition of centrosomal clustering |
-
1996
- 1996-07-30 EP EP96926807A patent/EP0841914A2/en not_active Withdrawn
- 1996-07-30 BR BR9609920A patent/BR9609920A/en unknown
- 1996-07-30 IL IL12309496A patent/IL123094A0/en unknown
- 1996-07-30 KR KR1019980700805A patent/KR19990036137A/en not_active Application Discontinuation
- 1996-07-30 SK SK142-98A patent/SK14298A3/en unknown
- 1996-07-30 JP JP9508495A patent/JPH11511136A/en active Pending
- 1996-07-30 TR TR1998/00244T patent/TR199800244T2/en unknown
- 1996-07-30 MX MX9800945A patent/MX9800945A/en unknown
- 1996-07-30 WO PCT/US1996/012475 patent/WO1997005870A2/en not_active Application Discontinuation
- 1996-07-30 CA CA002228503A patent/CA2228503A1/en not_active Abandoned
- 1996-07-30 PL PL96324905A patent/PL324905A1/en unknown
- 1996-07-30 HU HU9903506A patent/HUP9903506A3/en unknown
- 1996-07-30 CZ CZ98305A patent/CZ30598A3/en unknown
- 1996-07-30 AU AU66834/96A patent/AU713031B2/en not_active Ceased
- 1996-08-02 AR ARP960103861A patent/AR003176A1/en not_active Application Discontinuation
-
1998
- 1998-01-30 NO NO980420A patent/NO980420L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JPH11511136A (en) | 1999-09-28 |
| AU6683496A (en) | 1997-03-05 |
| IL123094A0 (en) | 1998-09-24 |
| HUP9903506A2 (en) | 2000-06-28 |
| BR9609920A (en) | 1999-07-06 |
| MX9800945A (en) | 1998-04-30 |
| NO980420L (en) | 1998-04-03 |
| SK14298A3 (en) | 1998-09-09 |
| TR199800244T2 (en) | 1998-09-21 |
| WO1997005870A3 (en) | 1997-04-17 |
| AU713031B2 (en) | 1999-11-18 |
| CZ30598A3 (en) | 1998-06-17 |
| PL324905A1 (en) | 1998-06-22 |
| AR003176A1 (en) | 1998-07-08 |
| HUP9903506A3 (en) | 2000-07-28 |
| EP0841914A2 (en) | 1998-05-20 |
| KR19990036137A (en) | 1999-05-25 |
| NO980420D0 (en) | 1998-01-30 |
| WO1997005870A2 (en) | 1997-02-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |