ANTITUMOR EVALUATION OF DOLASTATIN-10 AND DOLASTATIN-15 AND THEIR MEASUREMENT IN PLASMA BY RADIOIMMUNOASSAY

Dolastatins 10 and 15 are small peptides isolated from the marine sea hare Dolabella auricularia that have been shown to interact with tubul in. Their growth-inhibitory properties were compared using panels of h uman ovarian and colon-carcinoma cell lines. Both agents were very pot ent inhibitors of cell growth, with dolastatin 10 being an average of 9.1-fold more potent than dolastatin 15 [mean 50% inhibitory concentra tions (IC50 values) 2.3 x 10(-10) and 2.1 x 10(-9) M, respectively; P < 0.05] and more potent than paclitaxel or vinblastine. While neither dolastatin exhibited marked cross-resistance in cisplatin- or etoposid e-resistant cell lines, contrasting effects were observed using an acq uired doxorubicin-resistant (CHldoxR, 100-fold resistant, P-glycoprote in overexpressing) cell line. Resistance was significantly higher to d olastatin 15 (12.7-fold) than to dolastatin 10 (only 3.2-fold; P < 0.0 5) and was reversible in both cases by verapamil. In vivo, using a s.c . advanced-stage human ovarian carcinoma xenograft and equitoxic doses , greater activity was observed with dolastatin 10 (6.1-day growth del ay) versus 0.4 days for dolastatin 15. A radioimmunoassay for dolastat in 10 (limit of detection in mouse plasma 5 ng/ml) was developed. The rabbit antiserum also cross-reacted by 65% with dolastatin 15. Compara tive mouse pharmacokinetics following i.v. administration of 1 mg/kg s howed that both compounds are rapidly eliminated, but with a shorter s econd-phase half-life (t(1/2 beta)) being observed for dolastatin 15 ( being detectable for only up to 4 h postadministration), the t(1/2 bet a) being 3 times longer for dolastatin 10. In addition, areas under th e plasma concentration-time curve (AUG values) were 1.6-fold higher fo r dolastatin 10 (333 versus 208 ng ml(-1) h). Plasma binding of dolast atin 10 exceeded 90%. The highly sensitive RIA will be useful for phar macokinetic studies in conjunction with the planned phase I clinical t rials of these novel, extremely potent, tubulin-binding agents, of whi ch dolastatin 10 appears to possess the more promising preclinical fea tures.