CA2129282A1

CA2129282A1 - Method for the treatment of neoplastic disease utilizing taxol and tiazofurin

Info

Publication number: CA2129282A1
Application number: CA 2129282
Authority: CA
Inventors: George Weber; Katherine Y. Look
Original assignee: Individual
Current assignee: Indiana University Foundation
Priority date: 1993-09-29
Filing date: 1994-08-02
Publication date: 1995-03-30
Also published as: AU7719994A; WO1995008994A1

Abstract

ABSTRACT

A method of treating neoplastic cells using a combination of taxol and tiazofurin. Preferably, the taxol is administered in a dosage of approximately 110 mg/m2 to approximately 250 mg/m2 on a single day, followed by 31 days of rest, and the tiazofurin is administered in a dosage of approximately 1,800 to 4,400 mg/m2 over a period of about ten days, followed by 21 days of rest, and the taxol and tiazofurin administration cycles are in phase with each other.

Description

-EXPRESS ~L9IL LABEL TB234564286Us 21Z9~8Z
PATENT

S P E C I F I C A T I O N

OD FOR T~E TREAT~ OF NEOPI-ASTIC DISE~SE
~TILIZING T}~XOL AND TIAZO~JRIN

I . BAC~CG20UND OF l~E INVENTION
S A. Fi~3ld Of Th~3 Inv~3ntioIl The field of the present invention is the treatment of neoplastic cells utilizing chemotherapeutic agents.

B. Backgrou~d I~formatlo~
Control of cancer remains a much sought after goal. In 10 fact, Lung cancer i8 a major therapeutic problem, with 16B,OoO
new cases per year in the United States, 87~ mortality, and a continuing rise of incidence in both men and women. With regard to pancreatic cancer, which i9 the fifth leading cau~e of cancer deaths in the United States, and which carries a 90~ mortality 15 rate, 2~,000 new cases are diagnosed annually. Chemotherapy in this disease has so far been useful only as a palliative. It also is estimated that there will be 22,000 new cases of ovarian :-cancer in the United States in 1993. Thus, there is a need for .~
new therapies to treat and control cancers, including especially : :.
lung, pancreatic and ovarian cancers.
.:
Neopla~tic cells tend to grow and divide faster than :~
ordinary cells, and several anti-cancer drugs have been developed which interfere with cell divieion. Two such drugs, taxol (NSC
125975) and tiazofurin ~NSC 286193), interfere with the formation ; ....
of microtubules, structural elements employed in the formation of the mitotic spindle. Microtubules are produced through ;;
polymerization of alpha-tubulin and beta-tubulin, under the . .. ~, . .

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-influence of GTP (guanosine triphosphate) and microtubulin-associated proteins.
In the drawing whlch illustrates the invention, it can be seen that taxol and tiazofurin interfere with mitotic spindle formation at two distinct sites. Taxol exerts its anti-cancer action by binding to the microtubule and promoting precocious microtubule assembly. It does not inhibit the binding or the hydrolysis of ~TP. (ManEredi, 3.J. and Horwitz, S.B., "Taxol: An antimitotic agent with a new mechanism of action," Pharmac. Ther.
25:83, ls84; Schiff, P.B. and Horwitz, S.B., "Taxol assembles tubulin in the absence of exogenous guanosine 5-triphosphate or microtubule-associated proteins," Biochemistrv, 20:3247, 1981).
Tiazofurin exerts its anti-cancer action through conversion to an active metabolite, TAD (thiazole-4-carboxamide adenine dlnucleotide), which then inhibits IMPDH (inosine 5'phosphate dehydrogenase), the rate limlting enzyme of de novo GTP synthesis. Weber G., "Blochemlcal strategy of cancer cells and the deslgn of chemotherapy," H.A. Clowes Memorial Lecture, in Cancer Res 43:3466-3492, 1983; Weber, G., "IMP Dehydrogenase and GTP as Targets ln Human Leukemla Treatment" Purlne and PYrimidine Metabollsm ln Man VII, pp. 287-292 (Plenum Press, NY 1991; Cooney, D., et al., "The converslon of 2-be~a-D-rlbofuranosylthlazole-4-carboxamlde to an analog of NAD with potent IMP-dehydrogenase lnhibitory propertles,: Biochem. Pharmacol., 31:2133-2136, 1982).
Look, et al. found that the addition of 0.5 micromolar TA~ for 10 minutes to extracts of ovarian carcinoma led to 81% lnhlbitory effect of IMPDH actlvity. (Look, K. Y., et al., "Inhlbitlon by tiazofurln of inosine 5'phosphate 2'~ 29'~R'~
~ PATENT --203/1~4 dehydrogenase (IMPDH) activity in extracts of ovarian carcinoma,~
Gynecol. Oncol., 47:66-70, 1992). Micha et al. demonstrated an inhibitory effect of tiazofurin on growth of xenographs of huwan epithelial carcinoma in a mouse subrenal capsule assay. ~Micha ..
J.P., et al., "Action of 2-beta-D-ribofuanosylthiazole-4-carboxamide (tiazofurin) against untreated human ovarian cancers in the murine xenograph assay,~ Gvnecol. Oncol,, 21:351-355, 1985). .: :

Clinical development of taxol as an anti-cancer agent in ...
humans progressed slowly because of an initially limited drug ';;.
supply and because of taxol's poor solubility in aqueous solution. However, more recently taxol has been recognized as an important and highly promising drug. In a recent review, Chabner noted Phase I and Phase II investigations in taxol revealed clear indications of anti-tumor activity in otherwise refractory solid '.
tumors ~Chabner, B. A., "Taxol," in V.T. De Vita Jr, S. :. -Hellman, S. A. Rosenberg (eds.), "PPO Updates 5," Cancer Principlçs ~_P~aç5ice of Oncoloqv, 3rd Edition, pp. 1-10, 198 .~ .
Clinical development of tiazofurin as an anti-cancer agent also proceeded slowly. In the early clinical studies, the drug .j^
was given as a 10 minute bolus or as a continuous intravenous j~-infusion, each of which caused various toxicities. As a result, low and ineffective dose schedules were used in patients with solid tumors in Phase I trials. In more recent clinical investigations, tiazofurin was given in effective doses as a ,;
daily one hour infusion. In these investigations, good therapeutic results were obtained in end stage leukemic patients, particularly in patients in blast crisis with chronic :, : ..

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~ granulocytic leukemia, where a 77% response rate was seen.
7 (Tricot, B. et al. "Tiazofurin: Biological Effects and Clinical Uses," Int'l J. Cell Cloninq 8:161, 1990; Weber, G. et al. 1991 supra). This compares with a 25-50% response in such patients treated with conventional therapy.
The effectiveness of tiazofurin can be enhanced by the synergistic effect of allopurinol, (1,5-dihydro-4~-pyrazolo[3,4~d~pyrimidin-4-orle~. Allopurinol decreases xanthine oxidase activity, which increases plasma hypoxanthine concentration, which in turn competitively inhibits the activity of GPRT and further inhibits the synthesis of GTP. (Weber, G., 1991 supra; Weber, G., et al., "Enzyme-pattern-targeted chemotherapy with tiazofurin and allopurinol in human leukemia,"
Adv. in Enzyme Requl., 27:405-433, 1988).
II. SUMMARY OF THE INVENTION
The present invention ls directed to treating neoplastic disease, solid tumors, and leukemia, using a combination of taxol and tiazofurin. Accordingly, the present invention seeks to provide a combination drug treatment for neoplastic disease. The invention also provides commercial packages comprising a pharmaceutically effective amount of taxol and tiazofurin together with instructions for use thereof for treating neoplastic cells.
The invention additlonally provides a kit for treating neoplastic cells comprising at leas~ two separate containers, a first container containing a pharmaceutically effective amount of taxol and a second container containing a pharmaceutically effective amount of tiazofurin. Other advantages will appear hereinafter.

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III. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
As used herein, taxol refers to 5~20-epoxy-1,2~,4,7~, 10~,13a-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoa~e 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine, and pharmaceutically acceptable salts thereof (NSC 125975). As used herein, tiazofurin refers to 2-~-D-ribofuranosylthiazole-4-carboxamide and pharmaceutically acceptable salts thereof (NSC
286193).
A. Preparation And Adminstration Taxol is commerclally available, and is administered at the rate of between approximately 110 mg/m to approximately 250 mg/m2 in a three hour infusion, once every 31 days. The starting dose of taxol is preferably 175 mg/m2.
Tiazofurin may be prepared as described in United States Patent No. 4,680,285 or United States Patent No. 4,451,648. -~
Tiazofurin also may be obtained from the National Cancer Institute as a sterile drug for injection in clear vials. Each vial contains 1 gram prepared as a white lyophilized powder with sodium hydroxide to adjust the pH. A tiazofurin solution is reconstltuted by adding 4.6 ml of sterile water for injection USP
the contents of aach vlal. One ml of the resultlng solution will then contain 200 mg of tiazofurin with a pH of 6-8. The reconstituted solution is further diluted in 500 ml of 5% dextrose solutions, USP, or 0.9% sodlum chloride solution, USP.
Tiazofurin is preferably administered by one-hour infusion as described in Jayaram, H. e~ al., "Cllnical Pha.rmacoanalytic Study of Tiazofurin Administered as a One Hour ~. ~
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Infusion," Int. J. Cancer, 51(2):182-188, 1992). In such infusions, tiazofurin is dissolved or suspended in a ¦ physiologically compatible solution, in a concentration of at least 0.1% by weight. More preferably, tiazofurin would be present ln a concentration of aboot 10~ to about 90~ by welght.

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,`- PATEI~-Before a patient receives tiazofurin, baseline IMPD~I ` .
activity i9 determined. In patients with ascites, the ascites is removed by paracentesis, and at least 50,000,000 cells are assayed for IMPDH activity. Only those patients whose baseline IMPDH is elevated, æuggesting that the drug may have utility in ;~
view of its mechanism of action, receive tiazofurin. In such patients, tiazofurin is reconstituted and diluted as described above and is administered by infusion pump over one hour at a dose of 4,400 mg/m2 per day for the first two days. If the IMPD~ :
activity after two days is higher than 10% of baseline, the ;
tiazofurin treatment is discontinued. If the IMPDH activity ;
after two days is less than 10~ of baseline, the patient is maintained on tiazofurin at a dose of 2,200 mg/m' per day, given -as a one hour infusion for a total of 8 days. setween each cycle .:
there i9 a 21 day rest, such that an entire treatment cycle is 31 ~.
days.

In subsequent cycles, if patients present with persistent ascites, the ascites i9 resampled. If, however, the ascites has resolved or become cytologically negative, and there is no other evidence of disease progression, the patient is continued on therapy as this would suggest at least a partial response. .

On days that both taxol and tiazofurin are given, tiazofurin is preferably administered in the morning, and taxol is preferably administered in the evening. During the course of combined taxol and tiazofurin treatment as described herein, the :
patient~s hematology is carefully monitored. In the event of excesslve toxicity, administration of one or both of taxol and ;e~
tiazofurin is reduced or discontinued. In the event of severe .
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PATENT

anemia (hemoglobin concentration of less than 8 gm/lOOml), taxol showed reduced to a dosage of about 110 mg/m2. In the event severe leukopenia (less than lOOo absolute granulocyte count) tiazofurin should be reduced to a dosage of about 1800 mg/m'. ~.
';'' The approximately eight day maintenance dose of tiazofurin depends on how well tiazofurin is tolerated by an individual patient. If tiazofurin appears to be well tolerated, the maintenance dosage is increased to 3,300 mg/m2 from 2,200 mg/m2. ~' If tiazofurin appears to be poorly tolerated, the maintenance dosage is decreased to 1,800 mg/m2 from 2,200 mg/m2.

Allopurinol is preferably, but not necessarily used in ,.
conjunction with tiazofurin treatment. Allopurinol is commer- -cially available in 100 mg tablets. During the tiazofurin treatment, tha patient may receive 100 mg by month every four hours in order to attain plasma hypoxanthine levels of 40-80 micromoles. Should the allopurinol starting dose fail to achieve a hypoxanthine concentration of abut 40 ~m, the allopurinol dose can be increased to a maximum of 100 mg by month every three .hours. During the treatment, the amount of oral and intravenous .~0 fluids are limited to less than 3 liters per day to maintain plasma hypoxanthine levels, but at least 2 liters per day to minimize the risk of hypoxanthine renal stones. .
.
The aynergistic activity of taxol and tiazofurin in ;;
attacking microtubular synthetic processes of the m;.totic spindle .
has been tested in human ovarian, pancreatic and lung carcinoma , cells, and in rat hepatoma 3924A cells. As described below, ~?
taxol and tiazofurin proved synergistic in all foux cell lines 7 `
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~ 203/184 tested (p ~ 0.05). These results indicate that taxol and tiazofurin should also have synergistic effect in the clinical treatment of human solid tumors, including tumors of the ovary, pancreas, lung and liver. Such improved effectiveness should ..
s permit dose reductions which result in lower toxicity, decreased emergence of resistant clones, and more rational modulation of chemotherapy schedules. .

IV. EXPERIMENT~L DATA ON CELL LINES
The synergistic inhibitory action of taxol and tiazofurin on :.-cell proliferation was studied in vitro. The investigations focused primarily on human cell lines originally derived from solid tumors of the ovary, pancreas, and lung.

A. Cell ~i~s~ Studi~d -The cell lines studied were human ovarian carcinoma OVCAR-5, human pancreatic carcinoma PANC-l, human non-small cell ~ .
adenosquamous carcinoma H-235 cells and rat hepatoma 3924A cells. ::
All cells were maintained in RPMI-1640 medium, supplemented with 10S FBS (GIBCO, Grand Island, NY~, penicillin (100 U/ml) and streptomycin (100 ~g/ml). Cells were incubated in 5~ CO2 with .
95~ humidified air at 37C. For subcultures, cells were dispersed with 0.25~ trypsin containing 1 Mm EDTA at 37C for 10 :: .
min, then centrifuged, suspended in fresh medium and seeded in cul~ure flasks. Exponentially growing cells were seeded in 24-il well plates in triplicate at a density of 2 x 10' cells/ml/well ` .
and drugs were added alone or simultaneously 6 hr later. After 3 days ~OVCAR-5, 3924A cell~) or 4 days (PANC-1, H-125 cells) of drug exposure, cells were harvested and counted in a Coulter counter. ~, . 8 , :~
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B. Drugs Tested Taxol (lOmM) was prepared in DMSO (dimethyl sulfoxide) and diluted in PBS (phosphate balanced solution) for a 25 ~M stock solution and from this solution aliquots were dissolved in RPMI-1640 medium. The highest concentration of taxol (0.025 yM) contained 0.0019~ DMSO which had no effect on the cells.
Tiazofurin was dlssolved in PBS. Stock solutions were stored at -20C.
C. Evaluation Of Drug Ac$ion Means ~ SE of cells in triplicate samples were tabulated and percent inhibition was calculated and compared with control.
The Chou-Talalay method (Chou and Talalay, 1984) was used to determine the nature of the interaction of ~he ~wo drugs. In ~he tables below, Fa denotes the fraction affected, and CI denotes the combination index. CI of less than 1 indicates synergism, values greater than 1 denote antagonism, and values equal to 1 reveal summation (additivity) ~Chou and Talalay, 1984).
D. Re~ults Table I summarizes the effect of taxol and tiazofurin in the cell llnes tested. The doubling times of OVCAR-5, PANC-1, ~1-125, and 3924A cells were 15, 36, 27, and 15 h, respectively. The IC50 values reveal the marked differences in the activities of taxol and tiazofurin. Taxol is eEfective in nanomolar concentrations whereas tiazofurin requires concentrations 2 to 3 orders of higher magnitude (micromolar concentrations~ to be effective. In these studies only minor variations were observed over a period of 1 year in the doubling times and IC50 values ':', 9 ~9~
PATENT

Table II summarizes the effect of taxol and tiazofurin in human ovarian carcino~a cells. Taxol (2 to 25 nM) stopped cell growth in 4 to 25~ of the OVCAR-5 cells. Tiazofurin (5 to 15 ~M) inhibited cell growth in 25 to 67~ of the cells. The two drugs were synergis~ic in the concentrations tested as shown by the C.I. of 0.40 to .90. The most effective combination, however, included 25 nM taxol with 15 ~M tiazofurin, (1:600 ratio), which inhibited 84% of cell growth Table III summarizes the synergistic activity of taxol and tiazofurin in pancreatic cancer cells. Taxol (0.4 to 10 nM) ~;
stopped proliferation in 2 to 68~ of the PANC-l cells.
Tiazofurin in concentrations of 0.1 through 10 ~M inhibited ..

4 to 83~ of cell proliferation. In the various combinations .;
tested, synergism was observed against PANC-l cells. In the best "~
combination, 10 nM taxol and 10 ~M tiazofurin yielded 96~
inhibition of cell proliferation. A 10-fold increase (1 to 10 ~M) in tiazofurin concentration yielded little anti-proliferative advantage. Hence, with respect to PA~C-1 cells, the combination of 10 nM taxol and 1 ~M tiazofurin, (1:100 ratio), was the most effective combination tested.

Table IV summarizes the synergistic activity of taxol and tiazofurin in human lung cancer cells. Taxol ~0.4 to 10 nM) resulted in 12 to 42~ inhibition of H-125 cell proliferation. -~
Tiazofurin ~0.1 to 10 ~M~ inhibited growth of 21 to 75~ of the cells. The two drugs were synergistic in the concentrations tested with best results obtained with 10 nM taxol and 10 ~M
tiazofurin ~1:1000 ratio), yielding 89% inhibition of cell proliferation. A 5-fold increase in taxol concentration to 10 nM .
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in the presence of 10 ~M tiazofurin improved results, with 89%
inhibition of cell proliferation.

With respect to the synergistic action of taxol and tiazofurin in rat hepatoma 3924A cells, taxol ~2 to 25 nM) inhibited 7 to 18~ of cells and tiazofurin (1 to 10 ~M) inhibited .
15 to 62~ of cells. In all combinations tested, taxol and tiazofurin were synergistic (not shown). The best combination appeared to be 25 nM taxol and 10 ~M tiazofurin (1:400 ratio) :
which provided 81~ inhibition of cell proliferation.
,' ' Thus, a method of treating neoplastic cells with a `;
combination of taxol and tiazofurin has been disclosed. While specific embodiments and applications of this invention have been shown and described, it would be apparent to those skilled in the art that many more modifications are possible without departing from the inventive concepts herein. The invention, therefore, is not to be restricted except ~n the spirit of the appended claims.
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TA~LE I
Effect of t~tol and u Iofurin on 1C", irt culrurc . , .
Doublirlg IC: ,UM
t~me Ccll Line Origin l iistolo,y h T3~01 TLa2ofurin OVCAR-5Humao Ov i~n carcinom~ ~50.05 ~.i (ad~nor~reinoma) PANC-IHuman Pancrc~dc c3rcinoma ;~i0.0O 2.;
I~pi~h~lo;d carcinoma) H-~5 lluman Lung earcinoma 27 0.0 - (ade nosqu~mous carHnoma) 3974~ Rat H~p~tom3 lj 0.0-t 6.9 (hepatoccllular carcinoma) -T~
Svn~r?stic ~ion of ~a~ol and ~i orurin in hum3n OVCA~.; c-!ls Ta tol ~r~3 of urir Fa C.l.
1~ _ _ o ca -- ' ' U.O'5 -- 0.~5 ---- 10 O,J5 -- 1i 0.67 :f - 10 0~ 0 5 0 010 10 0.61 0.5i 0 010 15 0 71 0.90 O O)i 5 0.6-~ 0i0 O O~i 10 0.79 0. t9 0 0~5 15 0.~ OJ7 ,:
~bbrevi31ions and ev~lua~ion are as oullined in .~,lal~-ials and ~Iethods.
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TABI~ lll Svner~istic ~ion of ta~ol 3nd dazofurin irt human P.~C-I cells _ Tl~ol rta~orurin Fl c. I .
~M ) ( ,llM ) o.ooo~ _ o.11 û.CO~ _ O.63 0.010 0 1 0 0~
-- . 0.6j ---- 10 0.~; --o oo~ 0.1 00.09; 0 ~3 O.OOO t 0.00~ 10 O.~o 0.83 ^~ 0.~ O.BO
0.010 u.~ o r,~ 0.~7 t 0.95 0 56 0.10 0.010 10 Abbr~iations and cvalua~ion arc as ou~cthods.

T~BI IV
Svncrgislic aclion of ta~ol and tiazolurin in human lun, carcjnornt H-:75 cclls TJ.tolTia~ofurin (,llM) .(~IM) F~ Cl.
O 001~ -- . 0.17 o:oo7 _ 0.11 0.01~) 0 1 0_5 ~ lO 0_9 ~ l 0 315 0 ;' 0 002 10 ~; l9 0.010 ' o.76 o~O
', ,~l~b~ io~s and ~v~lu~lion r- as -~lincd ~ j~1a~ 1s nd r lelh-ds

Claims

1. Use of a combination of taxol and tiazofurin for treating neoplastic cells in a patient.

2. The use of claim 1 further comprising the use of allopurinol.

3. Use of a first pharmaceutical composition containing at least one of 5.beta.20-epoxy-1,2.alpha.,4,7.beta., 10.beta., 13.alpha.-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine and a pharmaceutically acceptable salt thereof;
and a second pharmaceutical composition containing at least one of 2-.beta.-D-ribofuranosylthiazole-4-carboxamide and a pharmaceutically acceptable salt thereof for treating neoplastic disease in a patient.

4. The use of claim 3 in which the first pharmaceutical composition is in a form administrable in an approximately 31 day cycle and in a form in which a patient can receive a dosage of between about 110 mg/m2 and about 250 mg/m2 during a single day, followed by about 31 days of rest.

5. The use of claim 3 in which the second pharmaceutical composition is in a form administrable in an approximately 31 day cycle, and in a form in which a patient can receive a dosage of between about 1800 mg/m2 and about 4,000 mg/m2 per day over a period of about two to ten days, followed by about 21 days of rest.

6. The use of claim 3 further comprising the use of allopurinol to attain plasma hypoxanthine serum levels of about 40-80 micromolar.

7. Use of a therapeutically effective dosage of a first pharmaceutical composition containing at least one of 5.beta.20-epoxy-1,2.alpha.,4,7.beta., 10.beta.,13.alpha.-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine and a pharmaceutically acceptable salt thereof, said first composition being in a form administrable at the rate of between approximately 110 mg/m2 to approximately 250 mg/m2 in an approximately three hour infusion; and a therapeutically effective dosage of a second pharmaceutical composition containing at least one of 2-.beta.-D-ribofuranosylthiazole-4-carboxamide and a pharmaceutically acceptable salt thereof, said second composition being in a form administrable by infusion pump over approximately one hour at a dose of 4,400 mg/m2 per day for approximately two days, to treat neoplastic growth in a patient.

8. The use of claim 7, further comprising the use of approximately 100 mg doses of allopurinol.

9. The use of claim 7 wherein the dosage of said first composition is reduced to a minimum of about 110 mg/m2 in response to severe anemia.

10. The use of claim 7 wherein the dosage of said second composition is reduced to a minimum of about 1800 mg/m2 in response to severe leucopenia.

11. The use of claim 7 wherein said first composition is administrable in cyclical manner, in which each of said three hour infusions is followed by approximately 31 days of rest.

12. The use of claim 7 wherein said second composition is administrable in an approximately 31 day cycle, in which the patient receives up to about ten consecutive days of said administration of said second composition followed by about 21 days of rest.

13. The use of claim 7 wherein both of said first and second compositions are administrable in a cycle having a period of approximately 31 days.

14. The use of claim 13 wherein said first composition is administrable in the evening and said second composition is administrable in the morning on the first day of each of said cycles.

15. A commercial package comprising a pharmaceutically

16 effective amount of taxol and tiazofurin together with instructions for use thereof for treating neoplastic cells in a patient.

16. A commercial package according to claim 15 wherein the proportions of taxol to tiazofurin are such that they mutually enhance anti-neoplastic activity.

17. A commercial package according to claim 15 further comprising allopurinol.

18. A commercial package comprising a first pharmaceutical composition containing at least one of 5.beta.20-epoxy-1,2.alpha.,4,7.beta., 10.beta., 13.alpha.-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine and a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition containing at least one of 2-.beta.-D-ribofuranosylthiazole-4-carboxamide and a pharmaceutically acceptable salt thereof together with instructions for use thereof for treating neoplastic disease in a patient.

19. A commercial package according to claim 18 in which the first pharmaceutical composition is in a form administrable in an approximately 31 day cycle and in a form in which a patient can receive a dosage of between about 110 mg/m2 and about 250 mg/m2 during a single day, followed by about 31 days of rest.

20. A commercial package according to claim 18 in which the second pharmaceutical composition is in a form administrable in an approximately 31 day cycle and in a form in which a patient can receive a dosage of between about 1800 mg/m2 and about 4 000 mg/m2 per day over a period of about two to ten days followed by about

21 days of rest.

21. A commercial package according to claim 18 further comprising sufficient allopurinol to attain plasma hypoxanthine serum levels of about 40-80 micromolar in a patient.

22. A commercial package comprising a therapeutically effective dosage of a first pharmaceutical composition containing at least one of 5.beta.20-epoxy-1,2.alpha.,4,7.beta., 10.beta.,13.alpha.-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine and a pharmaceutically acceptable salt thereof, said first composition being in a form administrable at the rate of between approximately 110 mg/m2 to approximately 250 mg/m2 in an approximately three hour infusion; and a therapeutically effective dosage of a second pharmaceutical composition containing at least one of 2-.beta.-D-ribofuranosylthiazole-4-carboxamide and a pharmaceutically acceptable salt thereof, said second composition being in a form administrable by infusion pump over approximately one hour at a dose of 4,400 mg/m2 per day for approximately two days.

23. A commercial package according to claim 22 further comprising at least one approximately 100 mg dose of allopurinol.

24. A commercial package according to claim 22 wherein the dosage of the first composition is in a form administrable at about 110 mg/m2.

25. A commercial package according to claim 22 wherein the dosage of the second composition is in a form administrable at about 1800 mg/m2.

26. A commercial package according to claim 22 wherein the first composition is in a form administrable in a cyclical manner.

27. A commercial package according to claim 15 wherein said taxol and said tiazofurin are each in a form whereby said taxol and said tiazofurin are separately administrable.

28. A kit for treating neoplastic cells comprising at least two separate containers, a first container containing a pharmaceutically effective amount of taxol and a second container containing a pharmaceutically effective amount of tiazofurin.