title: 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.
authors.affiliation: CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: G W
authors.initials: GW
authors.lastname: Aherne
authors.forename: A
authors.initials: A
authors.lastname: Hardcastle
authors.forename: M
authors.initials: M
authors.lastname: Valenti
authors.forename: A
authors.initials: A
authors.lastname: Bryant
authors.forename: P
authors.initials: P
authors.lastname: Rogers
authors.forename: G R
authors.initials: GR
authors.lastname: Pettit
authors.forename: J K
authors.initials: JK
authors.lastname: Srirangam
authors.forename: L R
authors.initials: LR
authors.lastname: Kelland
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D003429:Cross Reactions; D047630:Depsipeptides; D018432:Drug Resistance, Multiple / Q000235:genetics; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D011817:Rabbits; D011863:Radioimmunoassay; D011897:Random Allocation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D009842:Oligopeptides; C075610:dolastatin 15; D014700:Verapamil; C064570:dolastatin 10