The antitumor activity of
S 16020-2, a new
olivacine derivative, was investigated in vivo and compared with that of
Adriamycin and
elliptinium acetate in a panel of murine (
P388 leukemia, M5076
sarcoma,
Lewis lung carcinoma, and
B16 melanoma) and human (NCI-H460 non-small-cell lung 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 resulting 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 therapeutic index than
Adriamycin: > or = 8 versus 2. A good
therapeutic effect of
S 16020-2 was also observed in three
P388 leukemia sublines displaying the classic multidrug-resistance phenotype, 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 resistant to
adriamycin in vivo.
S 16020-2 was both more active than
Adriamycin 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 active than
Adriamycin. Against the NCI-H460 human
tumor xenograft,
S 16020-2 demonstrated activity superior to that of
Adriamycin (T/C = 20% versus 43% on day 21). Against the MCF7
breast cancer xenograft,
S 16020-2 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 mice at pharmacological dose appeared to be less severe than that of
Adriamycin, particularly in bone-marrow stem cells. These results demonstrate that
S 16020-2 is a highly active
antitumor drug in various experimental
tumor models and is markedly more efficient than
elliptinium acetate. Because of its pharmacological profile, which is globally different from that of
Adriamycin,
S 16020-2 is considered an interesting candidate for clinical trials.