Marine natural products as anticancer drugs T. Luke Simmons, Eric Andrianasolo, Kerry McPhail, Patricia Flatt, and William H. Gerwick College of Pharmacy, Oregon State University, Corvallis, Oregon Abstract The chemical and biological diversity of the marine environment is immeasurable and therefore is an extraor- dinary resource for the discovery of new anticancer drugs. Recent technological and methodologic advances in structure elucidation, organic synthesis, and biological assay have resulted in the isolation and clinical evaluation of various novel anticancer agents. These compounds range in structural class from simple linear peptides, such as dolastatin 10, to complex macrocyclic polyethers, such as halichondrin B; equally as diverse are the molecular modes of action by which these molecules impart their biological activity. This review highlights several marine natural products and their synthetic derivatives that are currently undergoing clinical evaluation as anticancer drugs. [Mol Cancer Ther 2005;4(2):333 – 42] Introduction An exciting ‘‘marine pipeline’’ of new anticancer clinical and preclinical agents has emerged from intense efforts over the past decade to more effectively explore the rich chemical diversity offered by marine life (Table 1). It is not truly known how many species inhabit the world’s oceans; however, it is becoming increasingly clear that the number of microbial species is many times larger than previously estimated, such that total marine species may approach 1 to 2 million. Whereas the oceans are vast and constitute 70% of the world’s surface, the majority of this species diversity is found in the ocean fringe. This slender land-sea interface with its high concentration of species is among the most biodiverse and productive environments on the planet. Deep ocean thermal vent communities represent another highly biodiverse and productive habitat, albeit one of limited extent. By contrast, open ocean waters are generally low in nutrients and have been likened to deserts in terms of biomass and species diversity, although recent evidence suggests the existence of substantial microbial diversity in pelagic waters (1). It can be estimated that <1% of the earth’s surface, the narrow ocean fringe, and the known deep sea vent communities, are home to a majority of the world’s species, and thus constitute the most species rich and biologically productive regions of the world. The intense concentration of species coexisting in these limited extent habitats necessarily makes them highly competitive and complex. Sessile macroscopic organisms such as algae, corals, sponges, and a variety of other invertebrates are in constant battle for suitable attachment space. This competition occurs both in spatial as well as temporal domains. Fish and other motile species are typically both prey and predator, and specialization of feeding habits, body shape, and behavioral characteristics are common adaptations. Nutrient, light, water current, and temperature represent additional growth limiting compo- nents, further fueling competition. As a result of this intense competition, a high percentage of species have evolved chemical means by which to defend against predation, defend against overgrowth by competing species, or conversely, to subdue motile prey species for ingestion (2). These chemical adaptations (3) generally take the form of so-called ‘‘secondary metabolites,’’ and involve such well- known chemical classes as terpenoids, alkaloids, polyke- tides, peptides, shikimic acid derivatives, sugars, steroids, and a multitude of mixed biogenesis metabolites. In addition, and unique to the marine environment, is the relatively common utilization of covalently bound halogen atoms in secondary metabolites, mainly chlorine and bromine, presumably due to their ready availability in seawater. The past decade has seen a dramatic increase in the number of preclinical anticancer lead compounds from diverse marine life enter human clinical trials. This has occurred in part during a period of some retrenchment in the field of natural products in general and may cause some to rethink the wisdom of prematurely departing from this highly productive pursuit (4). Nevertheless, it is useful to consider the evolution of the field of marine natural products drug discovery in this context as it may help to identify future directions which will be even more successful. The earliest efforts in this field derived from the interests of marine biologists and naturalists who found a number of unique toxins that were present in diverse marine life. Cone snails inject incredibly potent peptide toxins (the conotoxins) to immobilize prey fish (5). Lionfish spines carry a lethal protein venom to the unwary (6). Zooanthids from a tide pool in Oahu, HI possess an extraordinarily toxic polyketide, ‘‘palytoxin’’ making them unpalatable to potential predators (7). Microalgae produce Received 9/01/04; revised 11/24/04; accepted 12/03/04. Requests for reprints: William H. Gerwick, Oregon State University, College of Pharmacy Building, 15th and Jefferson Avenue, Corvallis, OR 97331. Phone: 541-737-5801; Fax: 541-737-3999. E-mail: Bill.Gerwick@oregonstate.edu Copyright C 2005 American Association for Cancer Research. Molecular Cancer Therapeutics Minireview 333 Mol Cancer Ther 2005;4(2). February 2005