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  • Title: Antitumour evaluation of dolastatins 10 and 15 and their measurement in plasma by radioimmunoassay.
    Author: Aherne GW, Hardcastle A, Valenti M, Bryant A, Rogers P, Pettit GR, Srirangam JK, Kelland LR.
    Journal: Cancer Chemother Pharmacol; 1996; 38(3):225-32. PubMed ID: 8646796.
    Abstract:
    Dolastatins 10 and 15 are small peptides isolated from the marine sea hare Dolabella auricularia that have been shown to interact with tubulin. Their growth-inhibitory properties were compared using panels of human ovarian and colon-carcinoma cell lines. Both agents were very potent inhibitors of cell growth, with dolastatin 10 being an average of 9.1-fold more potent than dolastatin 15 [mean 50% inhibitory concentrations (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 etoposide-resistant cell lines, contrasting effects were observed using an acquired doxorubicin-resistant (CH1doxR, 100-fold resistant, P-glycoprotein overexpressing) cell line. Resistance was significantly higher to dolastatin 15 (12.7-fold) than to dolastatin 10 (only 3.2-fold; P < 0.05) 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 delay) versus 0.4 days for dolastatin 15. A radioimmunoassay for dolastatin 10 (limit of detection in mouse plasma 5 ng/ml) was developed. The rabbit antiserum aslo cross-reacted by 65% with dolastatin 15. Comparative mouse pharmacokinetics following i.v. administration of 1 mg/kg showed that both compounds are rapidly eliminated, but with a shorter second-phase half-life (t1/2 beta) being observed for dolastatin 15 (being detectable for only up to 4 h post-administration), the t1/2 beta being 3 times longer for dolastatin 10. In addition, areas under the plasma concentration-time curve (AUC values) were 1.6-fold higher for dolastatin 10 (333 versus 208 ng ml-1 h). Plasma binding of dolastatin 10 exceeded 90%. The highly sensitive RIA will be useful for pharmacokinetic studies in conjunction with the planned phase I clinical trials of these novel, extremely potent, tubulin-binding agents, of which dolastatin 10 appears to possess the more promising preclinical features.
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