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.