dolastatin-10 and Pancreatic-Neoplasms

Pancreaticobiliary malignancies respond poorly to conventional chemotherapy, and novel agents are needed. Dolatstatin-10 is a potent antimitotic pentapeptide isolated from the marine mollusk Dolabella auricularia that inhibits microtubule assembly. We conducted 2 parallel phase II trials of dolastatin-10 in patients with advanced hepatobiliary cancers and pancreatic adenocarcinoma.. Eligible patients had histologically-confirmed metastatic pancreatic adenocarcinoma or metastatic, locally advanced or recurrent cancer of the liver, bile duct or gallbladder, and had received no prior chemotherapy for advanced disease. Dolastatin-10 400 microg/m(2) was administered intravenously by bolus every 21 days. Restaging CT scans were obtained every 2 cycles.. Twenty-eight patients (16 hepatobiliary, including 7 hepatomas, 6 cholangiocarcinomas, 2 gallbladder carcinomas, and 12 pancreatic carcinomas) enrolled; 27 were evaluable for response. There were no objective responses. Grade 3/4 neutropenia occurred in 59% of patients and neutropenic fever in 18%. Median and 1-year survival were 5.0 months and 17% for the pancreatic cancer patients, and 3.0 months and 29% for the hepatobiliary patients. Median time to progression was 1.3 months for the pancreatic cancer patients and 1.6 months for the hepatobiliary patients.. Dolastatin-10 is inactive against hepatobiliary and pancreatic carcinomas.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bile Duct Neoplasms; Carcinoma, Hepatocellular; Cholangiocarcinoma; Depsipeptides; Female; Gallbladder Neoplasms; Humans; Liver Neoplasms; Male; Middle Aged; Neutropenia; Oligopeptides; Pancreatic Neoplasms

The potent antitumor agent dolastatin 10 (1) was originally isolated from the sea hare Dolabella auricularia, and we now report its isolation from the marine cyanobacterium Symploca sp. VP642 from Palau. The chemically related analogue symplostatin 1 (2) has been reisolated from Guamanian and Hawaiian varieties of S. hydnoides and its total stereochemistry completed by determining the N,N-dimethylisoleucine unit to be L. Symplostatin 1 (2), like dolastatin 10 (1), is a potent microtubule inhibitor. The antitumor activity of 2 was assessed in vivo against several murine tumors. Symplostatin 1 (2) was effective against a drug-insensitive mammary tumor and a drug-insensitive colon tumor; however, it was only slightly effective against two MDR tumors.

Topics: Animals; Antineoplastic Agents; Aplysia; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Cyanobacteria; Cytotoxins; Depsipeptides; Drug Resistance, Multiple; Female; Fibroblasts; Fluorescent Antibody Technique; Guam; Hawaii; Humans; Magnetic Resonance Spectroscopy; Mammary Neoplasms, Animal; Mice; Molecular Structure; Neoplasms; Oligopeptides; Palau; Pancreatic Neoplasms; Spectrometry, Mass, Fast Atom Bombardment; Spectrophotometry, Ultraviolet; Stereoisomerism; Tumor Cells, Cultured