Effect of dose, schedule, and route of administration on the in vivo toxicity and antitumor activity of two activated sulfhydryl derivatives of cyclophosphamide.

Two cyclophosphamide (CP) derivatives, 4-S-(hexane-6-ol)-sulfidocyclophosphamide (C-1) and 4-S-(propionic acid)-sulfidocyclophosphamide (C-2), that hydrolyze spontaneously under physiological conditions to 4-hydroxycyclophosphamide, are compared to CP for antitumor activity in male C57BL/6 x DBA/2 F1 mice with ascites L1210 leukemia or solid Lewis lung carcinoma. When C-1 or C-2 is administered i.p. as a single injection at 10% lethal dose (approximately LD10) to mice bearing L1210 (1 x 10(5) cells i.p.), early treatment produces a 5- to 6-log tumor cell kill and results in substantial numbers of long-term survivors (greater than or equal to 30 days). Such antitumor activity is comparable to that of CP treatment. However, i.p. administration of either sulfido derivative produces liver atrophy and fibrosis of hepatic capsular structures. Hepatotoxicity is eliminated if single-dose C-2 (less than or equal to LD10) is administered i.v.; however, when administered by this route, C-2 results in only a 1-log cell kill of i.v. implanted leukemic cells as compared to the 4-log tumor cell kill obtained with CP given i.v. In addition to hepatotoxicity, C-2 causes an acute and dose-limiting toxicity in mice, manifested by severe muscular spasms and cessation of breathing. In the treatment of advanced L1210, C-2 shows no therapeutic advantage over CP. When mice bearing s.c. Lewis lung carcinoma receive early i.p. treatment with CP, C-1, or C-2, each drug results in long-term tumor-free survivors. However, CP (< LD10) consistently cures all mice, whereas C-1 or C-2 (approximately LD10) produces only 10 to 30% tumor-free survivors. These data suggest that, in the L1210 and Lewis lung tumor systems studied, the two activated CP derivatives offer no therapeutic advantage over CP. In addition, two forms of toxicity occur with these derivatives that do not occur with CP.