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Development of difluoromethylornithine as a chemoprevention agent for the management of colon cancer
Author(s) -
Meyskens Frank L.,
Gerner Eugene W.
Publication year - 1995
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.240590816
Subject(s) - putrescine , spermidine , spermine , ornithine decarboxylase , polyamine , colorectal cancer , medicine , pharmacology , cancer research , endocrinology , chemistry , biochemistry , cancer , enzyme
Experimental studies have demonstrated that carcinogenesis is a multistep process in which inappropriate proliferation of cells is a critical‐determinant. Polymines support sustained growth and are highly regulated in all cells. The rate limiting enzyme for this pathway is ornithine decarboxylase (ODC), an enzyme that exhibits rapid turnover, and converts the amino acid ornithine to putrescine, which in turn is converted to the longer chain amines spermidine and spermine. In animal models of colon carcinogenesis, inhibition of ODC by difluoromethylornithine (DFMO), an enzyme‐activated irreversible inhibitor, reduces the number and size of colon adenomas and carcinomas. DFMO was first in‐effective when used clinically to treat acute leukemia or melanoma and caused clinically significant but reversible ototoxicity. Subsequently, we performed a series of analyses demonstrating that hearing loss was rare below a total cumulative dose of 150 gm/m 2 and increased with total cumulative dose of DFMO. The hearing loss was reversible with rapid reversion to baseline hearing. We and others have conducted Phase IIa trials to determine the lowest dose at which DFMO can decrease colon mucosa polyamine content, and found that an oral dose as low as 0.25 gm/m 2 per day (perhaps lower) decreases colon tissue putrescine content and lowers the spermidine/spermine ratio. We are currently conducting a long‐term randomized Phase IIb trial which serially measures the long‐term effect of several low doses (and placebo) of DFMO on sustaining polyamine depletion in colon mucosa, as well as carefully monitoring hearing by audiometry and other sophisticated tests. The eventual goal of these studies is to conduct a randomized Phase III trial of DFMO in preventing polyps development (as a surrogate for colon cancer) in patients with prior polyps, and second cancers in patients with resected low‐stage colon cancers.