AGENTS DERIVED FROM MARINE ORGANISMS
Marine organisms have survived for up to 700 million years through natural selection and the release of potent chemicals that offer protection in a hostile milieu without the need for bioactivation. It follows that there is extraordinary potential among these toxic chemicals for anti-tumour specificity. Over the past 10-15 years, a wide range of potent chemicals with different cellular targets has been isolated. Many have been evaluated in clinical trials, and some are listed briefly here.
Bryostatin 1 is the prototype of a novel class of structurally related compounds isolated from the marine bryo-zoan Bugula neritina. It is a macrocyclic lactone, which exhibits many biological effects mediated through modulation of protein kinase C, a family of enzymes crucial in cellular signalling pathways controlling proliferation and differentiation. It has demonstrated broad-spectrum pre-clinical anti-tumour activity, and has also been shown to induce differentiation, enhance the immune response and inhibit the production of members of the matrix metallo-proteinase family thought to be essential for angiogenesis. Dolastatin 10 was isolated from a herbivorous mollusc in the Indian Ocean, and acts by halting microtubule assembly. Exceptional potency has been described in pre-clinical models, and it is rapidly and extensively metabolized, with high protein binding.
Ecteinascidin 743 (ET-743; Yondelis) was isolated from a Caribbean tunicate in 1990 and forms covalent adducts with DNA in the minor groove, with sequence specificity. In addition, effects on the microtubular spindle are postulated, and down-regulation of transcription factors. A broad spectrum of pre-clinical anti-cancer activity has been demonstrated, in addition to a lack of cross-resistance with other agents, including anthracyclines, taxoids and platinum. Target organs for toxicity are the liver and bone marrow. This agent has been evaluated extensively in clinical trials, with activity in soft-tissue sarcoma.16*
Aplidine is a potent cyclic depsipeptide isolated from a Mediterranean marine tunicate, Aplidium albicans. The mechanism of action is not completely understood, but studies are in progress to identify the potentially unique target involved in its anti-tumour activity.
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