Antitumour evaluation of dolastatins 10 and 15 and their measurement in plasma by radioimmunoassay

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.

Phase II trials of dolastatin-10 in advanced pancreaticobiliary cancers

“…alkaloids [6]. Dolastatin-10 is a potent inhibitor of cell growth in a variety of solid tumor cell lines, including gastrointestinal cancer cell lines, as well as in several solid tumor xenograft models [5,[7][8][9]. Myelosuppression was dose-limiting in phase I trials [10][11][12].…”

Functional characterization and expression of molluscan detoxification enzymes and transporters involved in dietary allelochemical resistance

“…The distribution of MXRs in tissues involved in absorption, secretion and barrier functions in aquatic invertebrates (Bard 2000) suggests that they may play a role in the prevention of dietary xenobiotic absorption. Several studies have also identified marine natural products from algae, tunicates, sea hares and gorgonians that may be substrates for multixenobiotic resistance proteins (Suganuma et al 1988, Chambers et al 1993, Williams & Jacobs 1993, Aherne et al 1996, Quesada et al 1996, Schroder et al 1998, Tanaka et al 2002, suggesting that the pool of potential substrates in marine ecosystems may be extensive. Given this evidence, the constitutive or inducible expression of MXRs in marine consumers may serve a protective role against a range of allelochemically-rich prey.…”

Phase I and Pharmacokinetic Study of the Dolastatin-15 Analogue Tasidotin (ILX651) Administered Intravenously on Days 1, 3, and 5 Every 3 Weeks in Patients with Advanced Solid Tumors

“…Initial studies showed that this agent binds to tubulin and strongly suppresses microtubule dynamics in a unique manner by suppressing the rate of growth of microtubules more than the rate of shortening thus enhancing the frequency of rescue with little effect on the frequency of catastrophe (32). However, cemadotin is a weak agonist for the angiotensin II type 1 receptor and produced a dose-dependent increase in diastolic blood pressure preclinically (33). Unfortunately, this translated into dose-limiting cardiovascular toxicities in the clinic, including myocardial infarction, peripheral edema, and hypertension (9 -12), all of which were associated with the magnitude of peak blood levels of the parent drug or its metabolites (34).…”