Over the last few years, a large number of novel compounds have been identified and characterized. Several of these agents are in the process of entering clinical trials (Table 5). Some of the newest and more interesting agents derived from marine sources have a common mechanism of action, which involves the disruption of microtubular function. The most relevant examples within this category include the halichondrins, spongistatin, curacin, laulimalide and discodermolide . The majority of these compounds bind the vica alkaloids (halicondrins, spongistatin) or the colchicine-binding domain (curacin) inhibiting the polymerization of microtubules. Halichondrin B, a macrocyclic polyether isolated from the sponge Halichondria okadai, was selected for preclinical development by the NCI. Analogs derived from the total synthesis of halichondrin B have shown activity superior to the natural product. One of these, NSC707389, is now being tested in the clinical setting .
Other microtubule interacting agents, such as laulimalide, isolaulimalide, discodermolide and eleutherobin, interact with tubulin in a similar fashion to the taxanes, resulting in the assembly of tubulin and stabilization of the microtubules. In addition, laulimalide and isolaulimalide retained antitumor activity against the P-glycoprotein overexpressing multidrug resistant cell line, suggesting that they are poor substrates for transport by P-glycoprotein [93
Other compounds of marine origin with promising activity include thiocoraline and kahalalide F. Thiocoraline is a novel bioactive depsipeptide isolated from Micromonospora marine, a marine microorganism located in the Mozambique Strait that inhibits RNA synthesis. Thiocoraline demonstrated potent and selective cytotoxic effects against lung and colon cancer cell lines as well as melanoma. Interestingly, this drug exerted preferential antiproliferative effects in colon cancer cell lines with defective p53 systems .
Thiocoraline represents a model of an anticancer agent acquired from marine microorganism and illustrates how the problems of drug supply can be overcome by artificial culture. Kahalalide F (KF) is a dessipeptide isolated from the mollusk Elysia rubefescens from Hawaii. KF induces cytotoxicity and blocks the cell cycle in G1 phase in a p53-independent manner. In vitro, KF displayed activity against solid tumors with an interesting pattern of selectivity in prostate cancer cell lines. In addition, extensive in vivo work demonstrated that the agent had activity in breast and colon cancer. The intracellular target of kahalalide seems to be the lysosomas where the agent interferes with the organization of the organella. These results suggest that cells containing high lysosomal activity, such as prostate cancer cells, would be a suitable tumor type to explore the activity of this agent . In phase I clinical trials of KF evaluating a continuous weekly infusion schedule in patients with advanced solid tumors, the DLT has been early-onset transaminitis. Other reported toxicities have been fatigue, headache, vomiting and pruritus limited to the hands [97, 98]. Hematological toxicities have not been observed. Additional studies of this agent are planned.