IN-VIVO ANTITUMOR-ACTIVITY OF S-16020-2, A NEW OLIVACINE DERIVATIVE

The antitumor activity of S 16020-2, a new olivacine derivative, was i nvestigated in vivo and compared with that of Adriamycin and elliptini um acetate in a panel of murine (P388 leukemia, M5076 sarcoma, Lewis l ung carcinoma, and B16 melanoma) and human (NCI-H460 non-small-cell lu ng and MCF7 breast carcinomas) tumor models. S 16020-2 given i.v. was active against P388 leukemia implanted i.p., s.c., or intracerebrally. The therapeutic effect of an intermittent schedule (administration on days 1, 5, 9) was superior to that of single-dose treatment, allowing the i.v. administration of high total doses of S 16020-2 and resultin g in the cure of 60% of mice in the i.p. P388 model. In this model, S 16020-2 was more active than elliptinium acetate and showed a better t herapeutic index than Adriamycin: greater than or equal to 8 versus 2. A good therapeutic effect of S 16020-2 was also observed in three P38 8 leukemia sublines displaying the classic multidrug-resistance phenot ype, namely, P388/VCR, P388/VCR-20, and P388/MDRC.04, the latter being totally insensitive to vincristine and Adriamycin. However, S 16020-2 was not active against the P388/ADR leukemia, a model highly resistan t to adriamycin in vivo. S 16020-2 was both more active than Adriamyci n and curative in the M5076 sarcoma and Lewis lung carcinoma implanted s.c. In the B16 melanoma implanted i.p. or s.c., S 16020-2 was less a ctive than Adriamycin. Against the NCI-H460 human tumor xenograft, S 1 6020-2 demonstrated activity superior to that of Adriamycin (T/C = 20% versus 43% on day 21). Against the MCF7 breast cancer xenograft, S 16 020-2 was active, but less so than Adriamycin (T/C = 23% versus 9% on day 21), whereas elliptinium acetate was marginally active (T/C = 49% on day 24). The hematological toxicity of S 16020-2 given to B6D2F1 mi ce at pharmacological dose appeared to be less severe than that of Adr iamycin, particularly in bone-marrow stem cells. These results demonst rate that S 16020-2 is a highly active antitumor drug in various exper imental tumor models and is markedly more efficient than elliptinium a cetate; Because of its pharmacological profile, which is globally diff erent from that of Adriamycin, S 16020-2 is considered an interesting candidate for clinical trials.