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In vivo antitumor activity of S 16020-2, a new olivacine derivative
N Guilbaud1, L Kraus-Berthier, D Saint-Dizier
1Institut de Recherches Servier, Division de Cancérologie Expérimentale, Suresnes, France.
Abstract:
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.
Insights
S 16020-2, a novel olivacine derivative, shows significant antitumor activity against various murine and human tumors, outperforming elliptinium acetate and Adriamycin in several models. This new drug candidate demonstrates a promising therapeutic index and reduced hematological toxicity, warranting clinical trials.
Area of Science:
- Pharmacology and Experimental Therapeutics
- Oncology
- Medicinal Chemistry
Background:
- Development of novel chemotherapeutic agents is crucial for overcoming drug resistance and improving treatment outcomes in cancer.
- Olivacine derivatives have shown potential as antitumor agents, necessitating further investigation into their efficacy and safety profiles.
Purpose of the Study:
- To evaluate the in vivo antitumor activity of S 16020-2, a new olivacine derivative.
- To compare the efficacy and therapeutic index of S 16020-2 against Adriamycin and elliptinium acetate in various preclinical tumor models.
- To assess the activity of S 16020-2 in multidrug-resistant cancer models and evaluate its toxicity profile.
Main Methods:
- In vivo evaluation of S 16020-2 in murine models (P388 leukemia, M5076 sarcoma, Lewis lung carcinoma, B16 melanoma) and human tumor xenografts (NCI-H460, MCF7).
- Comparison of S 16020-2 with Adriamycin and elliptinium acetate using different administration schedules (intermittent vs. single-dose).
- Assessment of S 16020-2 activity against multidrug-resistant cell lines (P388/VCR, P388/VCR-20, P388/MDRC.04, P388/ADR) and evaluation of hematological toxicity in mice.
Main Results:
- S 16020-2 demonstrated significant activity against P388 leukemia, including cures in 60% of mice with an intermittent schedule, showing a superior therapeutic index compared to Adriamycin.
- The drug was effective against multidrug-resistant P388 leukemia sublines but not against P388/ADR.
- S 16020-2 showed superior or comparable activity to Adriamycin in M5076 sarcoma, Lewis lung carcinoma, and NCI-H460 xenografts, with less severe hematological toxicity than Adriamycin.
Conclusions:
- S 16020-2 exhibits potent antitumor activity across a broad spectrum of experimental cancer models, including multidrug-resistant types.
- Its distinct pharmacological profile and favorable toxicity suggest it is a promising candidate for clinical development.
- S 16020-2 represents a significant advancement over elliptinium acetate and offers a potentially valuable alternative to Adriamycin in cancer chemotherapy.