The isolation of new anticancer agents derived from marine sources has been based on the collection of marine macroorganisms, such as algae, sponges, tunicates and bryozoans (Table 1). The progress in scuba-diving techniques and deep-water collection instruments has been pivotal in the collection programs implemented by academic and pharmaceutical groups. While 40 years ago, the collection of marine organisms was limited to those found in intertidal and shallow subtidal environments, the advent of scuba diving has enabled investigators to explore shallow subtidal environments to a depth of 40 m for 15 min with no decompression stops. Depths of up to 200 m are now accessible using closed-circuit computerized mixed gas rebreathers . Deep-water collections can be made by dredging or trawling, and by the use of manned and unmanned submersibles, or remotely operated vehicles (ROVs). Although dredging and trawling are cost-effective methods, they suffer from several disadvantages such as: the limitations on taking photographs; the inability to collect organisms that grow in niches difficult to access; the environmental damage; and the non-selective nature of the sampling. On the other hand, the high cost of ROVs precludes their extensive use in routine collection operations.
The collection of organisms from deep water for pharmacological studies has mainly been performed with the use of manned submersibles. These vehicles can accommodate up to four passengers, operate at depths of 1000 m and are equipped with storage containers and cameras for documentation . Using these techniques, investigators have implemented collection programs in waters from marine regions spanning the whole globe. Although the marine ecosystem is extremely rich and diverse, resources are limited. The exploration of collectable marine organisms is likely to be almost complete within the next 20 years. The collection of wild organisms needs to take into account a detailed assessment of species abundance and distribution in order to avoid their extinction. Re-collection must be considered only for early screening purposes. Identification and development of synthetic or semi-synthetic approaches as the ultimate sources of supply should be the final goal. This area requires governmental supervision and regulation, as well as international cooperation. The appropriate supply methods must be determined carefully prior to considering a marine chemical entity suitable for clinical development .
The expected limitations in the supply of marine macroorganisms, as well as the realization that there is a tremendous biological reserve of marine microorganisms, has resulted in increasing interest in the exploitation of the latter in the search for new chemical entities. Several features make marine microorganisms an attractive source when searching for pharmaceutical compounds. The complex microbiological adaptations needed to grow in the ocean are completely different from those of land-based organisms. Nutrients are scarce and microbial symbiosis is common. Furthermore, competition for resources at the microscopic level is intense. This has resulted in a variety of chemical substances produced by microorganisms for their own defense, a range of compounds that has the potential to be a major source of new drugs .
Although largely still unexplored, the complexities of marine microbial growth and cultivation can be solved. It has been demonstrated that marine bacteria are uniquely adapted to the saline environment. They can be selectively isolated and mass cultured in media that uses natural nutrients and growth factors derived from marine sources. In culture, marine microbes have the potential to provide large quantities of natural products. This approach, however, also has its own caveats, which include the difficulties in isolating and culturing marine microbes, the lack of stable production and the fact that the majority of marine microbes are still unknown . New programs are emerging to exploit marine microorganisms and the results are promising. These studies have demonstrated the capability of marine bacteria to produce compounds not available from terrestrial sources. They also have led to an increase in knowledge of the many bioactive compounds produced by these microorganisms [11, 12].
Another major advance in the study of marine compounds has been the change in the nature of the studies performed with the isolated products. Nowadays, the compounds are systematically tested for relevant biomedical properties including antiproliferative effects. The major screening system is carried out by the National Cancer Institute of the USA. This system looks for selective activity in a panel of 60 human tumor cell lines . Alternative strategies employ a more mechanistic-based approach, with systems designed to screen for substances with inhibitory properties towards specific enzymatic reactions. This type of assay offers specificity and can focus on a number of discrete drug targets. The potentially confounding effects of toxic components are also avoided, permitting the screening of crude extracts from marine organisms . This type of screening can also be adapted to high-throughput screening, which offers the potential to readily screen hundreds of thousands of extracts in parallel against numerous therapeutic targets. Taken together these data show that the study of marine anticancer compounds is yielding not only the discovery and development of new drugs, but also the identification of new molecular targets for therapeutic intervention.