thioguanine-anhydrous and Leukemia-P388

In order to support planning of clinical trials of trimetrexate (CI-898) in combination chemotherapy regimens, several studies were carried out to determine the potential for therapeutic synergy between CI-898 and several clinically proven agents including doxorubicin, cytoxan, FUra, 6-thioguanine (6-TG), vincristine, methotrexate, and cisplatin. F1 hybrid mice bearing either early or advanced stage P388 leukemia were treated with either the single agents or with various combination regimens and observed for lifespan. These studies demonstrated a high degree of therapeutic synergism between CI-898 and doxorubicin, cytoxan, and 6-TG. Combinations of CI-898 with FUra, vincristine, and cisplatin also produced enhanced tumor cell kill, although the results were less dramatic than those mentioned above. The host toxicities of CI-898 and methotrexate were synergistic and appeared to negate any potential therapeutic benefit of the combination. The synergistic effect of the doxorubicin, vincristine, and cytoxan combinations may have been due to a lack of overlapping host toxicities, but the synergy observed with 6-TG was obtained in spite of synergistic host toxicity.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Doxorubicin; Drug Synergism; Fluorouracil; Leukemia P388; Leukemia, Experimental; Mice; Quinazolines; Thioguanine; Trimetrexate; Vincristine

Tiazofurin is a synthetic "C" nucleoside analogue with a promising spectrum of experimental antitumor activity and a relatively novel mechanism of action. Previous work in our laboratories had revealed indications of collateral sensitivity and therapeutic synergism for selected murine tumor models treated with tiazofurin alone or in combination with an antimetabolite or an alkylating agent. Elucidation by others of biochemical indicators of tiazofurin activity provided the rationale for extending our studies to include the tiazofurin combinations reported here. Young, adult, female, BALB/c X DBA/2 F1 mice bearing body burdens of about 4 X 10(7) cells at the start of treatment were used. Cells were implanted either i.p. or s.c. Tiazofurin plus cisplatin or the 5'-palmitate of 1-beta-D-arabinofuranosylcytosine (ara-C) was evaluated against the parent P388/O leukemia line. Tiazofurin plus 6-thioguanine was evaluated against the ara-C-resistant P388. All drug treatments were i.p. injections given daily for 9 days. The experimental design permitted comparison of optimal nontoxic single-agent and two-drug combination regimens on the basis of the estimated log10 change in tumor cell burden at the end of treatment. Concurrent untreated control mice bearing tumor burdens ranging from approximately one to 10(7) cells permitted estimates of cells surviving treatment. Optimal treatment with each of these combinations afforded tumor burden reductions that were greater by 1 to 7 orders of magnitude than the effects of the respective single agents. Optimal single-agent and combination dosages (mg per kg per dose) were as follows: tiazofurin, 500; cisplatin, 2.0; the 5'-palmitate of ara-C, 25; 6-thioguanine, 0.8; tiazofurin, 330 plus cisplatin, 0.58; tiazofurin, 220 plus the 5'-palmitate of ara-C, 20; tiazofurin, 100 plus 6-thioguanine, 0.8. The observed therapeutic synergism of these drugs with tiazofurin in animal models suggests the possibility that treatment with tiazofurin combinations may yield clinical results superior to those obtained with the single agents alone. Therapeutic synergism can be most readily maximized when biochemical markers of drug action are available to provide appropriate clinical-laboratory correlations. Extension of these approaches to the use of tiazofurin, for which biochemical markers and experimental combination chemotherapy leads are now available, would support the rational clinical development of tiazofurin combinations.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Cisplatin; Cytarabine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Female; Leukemia P388; Leukemia, Experimental; Mice; Phosphonoacetic Acid; Ribavirin; Ribonucleosides; Thioguanine

Wild-type cells and thymidine kinase-deficient clones from two mouse lymphoma cell lines, P388 and L5178Y, were compared for sensitivity to killing by the mutagens, ultraviolet irradiation (UV), ethyl methane sulfonate (EMS), and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Two out of three thymidine kinase-deficient P388 clones showed significantly enhanced sensitivity to killing by all three mutagens. This increased sensitivity to killing was also reflected in increased mutagenesis by the three mutagens. In the L5178Y cell line, wild-type cells showed little difference to two thymidine kinase-deficient clones in terms of mutagen sensitivity. This indicates that thymidine kinase may be significant for DNA repair processes in P388 but not in L5178Y cells. Unscheduled DNA synthesis (UDS) experiments were carried out on P388 and L5178Y wild-type cells and wild-type Friend leukemia cells (which are mutagen-sensitive when deficient in thymidine kinase). The UDS experiments showed the L5178Y cells were low in excision repair abilities relative to the P388 cells and the Friend cell clone. This indicates that the increased mutagen sensitivity in thymidine kinase-deficient P388 and clone 707 Friend cells may be due to thymidine kinase playing an indirect role in DNA excision repair, a process which is of little significance in the L5178Y cell line.

Topics: Animals; Cell Line; Cell Survival; Clone Cells; DNA Repair; DNA, Neoplasm; Drug Resistance; Leukemia L5178; Leukemia P388; Leukemia, Experimental; Mice; Mutagens; Mutation; Thioguanine; Thymidine Kinase; Ultraviolet Rays

Combination chemotherapy using the water-soluble nitrosourea MCNU with various anti-cancer agents was studied using L1210 leukemia and P388 leukemia. In titration experiments MCNU showed remarkable antitumor effects at doses from 5 mg/kg to 80 mg/kg, producing numbers of 60-day survivors with L1210 leukemia. In L1210 leukemia, respective combinations of MCNU with the antimetabolites, MTX, 6-MP, 6-TG, MCNU, 5-FU and Cyclo-C showed enhanced antitumor effects. MCNU combined with each of ADR, MMC and CPM also showed marked anti-tumor effects with 60-day survivors. In P388 leukemia MCNU combined with each of ADR, MMC, VDS and CPM produced strong anti-tumor effects with numbers of 60-day survivors. In the results of these combinations, especially the combinations of MCNU + 5-FU in L1210 leukemia and MCNU + CPM in both L1210 and P388 leukemia, a significant increase in mean survival time was achieved. These combinations also produced many 60-day survivors which were considered to be due to the synergistic antitumor effects of the combined drugs.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Doxorubicin; Female; Fluorouracil; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Mercaptopurine; Methotrexate; Mice; Mice, Inbred DBA; Mitomycin; Mitomycins; Nitrosourea Compounds; Thioguanine

While the combination of L1210 murine leukemia cell vaccine (L1210 vaccine) with 6-mercaptopurine (6-MP) or 6-thioguanine produces a therapeutic response greater than that induced by either of these agents alone, its combination with cyclophosphamide, N4-behenoyl-1-beta-D-arabinofuranosylcytosine, or 5-fluorouracil does not produce such a response. The administration of cyclophosphamide, N4-behenoyl-1-beta-D-arabinofuranosylcytosine, or 5-fluorouracil alone resulted in a response as great as, or greater than, that induced by 6-MP alone. This and the finding that the 6-MP-induced response was more pronounced upon its delayed rather than its early administration indicate that 6-MP-induced reduction of the tumor burden does not explain this augmentation. The combination of 6-MP and L1210 vaccine was not effective in mice bearing 6-MP-resistant L1210 leukemia; however, an augmented response occurred when the tumor burden was reduced by N4-behenoyl-1-beta-D-arabinofuranosylcytosine, indicating that reduction of the tumor burden by 6-MP was only partially associated with augmentation of the therapeutic response. Augmentation was associated with vaccine-induced antitumor immunity because it was induced by the combination of 6-MP and concanavalin A-bound, but not concanavalin A-free L1210 vaccine. This augmentation was dependent on the timing of the L1210 vaccine administration. The combination was not effective in mice bearing P388 leukemia, indicating the tumor specificity of the augmentation. These results show that 6-MP not only reduced the tumor burden but also potentiated the vaccine-dependent antitumor immunity, resulting in the induction of an augmented therapeutic response.

Topics: Animals; Concanavalin A; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Immunotherapy; Leukemia; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Male; Mercaptopurine; Mice; Thioguanine