Therapeutic Synergism of Tiazofurin and Selected Antitumor Drugs against Sensitive and Resistant P388 Leukemia in Mice1

Tiazofurin is a synthetic "( " nucleoside analogue with a promising spectrum of experimental antitumor activity and a relatively novel mech anism of action. Previous work in our laboratories had revealed indica tions 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 bio chemical indicators of tiazofurin activity provided the rationale for ex tending our studies to include the tiazofurin combinations reported here. Young, adult, female, BALB/c x DBA/2 !•', mice bearing body burdens of about 4 x IO7 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 l-/3-r>-arabinofuranosylcytosine (ara-C) was evaluated against the par ent P388/0 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 logio change in tumor cell burden at the end of treatment. Concurrent untreated control mice bearing tumor burdens ranging from approximately one to IO7cells 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 singleagent and combination dosages (mg per kg per dose) were as follows: tiazofurin, 500; cisplatin, 2.0; the 5'-palmitate of ara-C, 25; 6-thioguan ine, 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 combina tions 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 appro priate 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.