The Dolastatins

Certain marine animals were known to the ancients for their potent biological constituents and presumed use in primitive medicine. The early periods of recorded history contain references to support these assumptions (1). Illustrative are hieroglyphics on the Egyptian Pharaoh Ti's tomb (approximately 2700 BC) that describe the poisonous puffer fish Tetraodon stellatus. One of the earliest recorded uses of a marine organism in primitive medical practice has been attributed to the Roman, Gaius Plinius Secundus (AD 29–79, Pliny the Elder), who recommended that the sting system of the stingray be ground up and used for treatment of toothache and in obstetrics. One of the first modern pharmacological and chemical studies of potent marine animal constituents involved tetrodotoxin from the poisonous puffer fish (2, 3). About 40 years ago some especially important observations began to be recorded. Illustrative was the fact that extracts from certain sponges and coelenterates were shown to have antibiotic properties (4–8) and that marine invertebrates produce various other potentially medically useful components (9–11). Very importantly, from the viewpoint of anticancer drug discovery, were reports that starfish meal (12–14) and fractions from the peanut worm Bonellia fulginosa (15, 16), certain sea cucumbers, and molluscs [clams (16) and oysters (9, 11)] exhibited antitumor activity against sarcoma-180 and Krebs-2 ascites tumor (10, 17–19).