DOLASTATINS

Molecular Weight (Dolastatin 10): 785.092 g/mol
Molecular Formula (Dolastatin 10): C₄₂H₆₈N₆O₆S

Source: Indian Ocean sea hare Dollabella auricularia (MOLLUSCA)
Activity: Tubulin interactive agents
Status: Phase II, Phase I clinical trials

Dolastatin 10 and dolastatin 15 were isolated from the Indian Ocean sea hare Dollabella auricularia. These small linear peptide molecules are promising anti-cancer drugs showing potency against breast and liver cancers, solid tumors and some leukemias. Preclinical research indicated potency in experimental antineoplastic and tubulin assembly systems.

These products had been hypothesized as being microbial products and not actually produced by D. auricularia. The peptides comprising the dolastatins contained an assortment of amino acids that pointed to a probable cynobacterial (blue-green "algae") origin. Later research has shown this to be the case, and both dolastatin 10 and the structurally similar compound Simplostatin 1 have both been isolated from marine cyanobacteria. Rather than being a microbial symbiont, the cyanobacterium that produced dolastatin 10 is a mat-forming species known to be grazed by D. auricularia.

The dolastatins are mitotic inhibitors. They interfere with tubulin formation and thereby disrupt cell division by mitosis. These molecules bind to tubulin at a location known as the vinca/peptide region. This region is the target for several other structurally complex natural products, including the sponge product hemiasterlin.

Phase II clinical trials of dolastatin 10 in patients with indolent lymphoma, Waldenstrom's macroglobulinemia, and chronic lymphocytic leukemia (CLL) have been completed. Performance against solid tumors was lacking, but dolastatin 10 remains a good candidate for combination drug regimes that also include vinca alkaloids or possibly bryostatin 1.

The development of synthetic analogs to the dolastatins has been vigorously pursued. Several such analogs have been successfully synthesized and some of these are now also in the pre-clinical/clinical pipeline. ILX651 and LU103793 are two such compounds. LU103793 has been evaluated in a number of Phase I trials. ILX651 is currently being assessed as a treatment for several tumor types including colorectal, lung, melanoma, renal, and pancreatic cancers.

NCBI PubChem compound summary page (Dolastatin 10) - [ LINK ]

NCBI PubChem compound summary page (Dolastatin 15) - [ LINK ]

NCBI PubMed biomedical literature citations and abstracts - [ LINK ]

References

Amador, M.L., Jimeno, J., Paz-Ares, L., Cortes-Funes, H., and M. Hidalgo. 2003. Progress in the development and acquisition of anticancer agents from marine sources. Annals of Oncology 14:1607-1615.

Kijjoa A and P Sawangwong. 2004. Drugs and cosmetics from the sea (review paper). Mar. Drugs 2004:73-82.

dolastatin 10, dolastatin 15, TZT-1027
http://www.rho-chi-mu-chapter.com/Knipple.htm

Clinical Trial information from ClinicalTrials.gov
http://www.clinicaltrials.gov/ct/gui/show/NCT00005579

American Society of Clinical Oncology: ILX651, a third generation dolastatin
http://www.asco.org/ac/1,1003,_12-002636-00_18-0023-00_19-00103325,00.asp