A novel cytotoxic agent for human carcinoid tumors.

Abstract

Conventional adjuvant therapy for advanced carcinoid tumors remains disappointing; novel therapeutic agents are needed. We have shown previously that inhibiting polyamine biosynthesis with alpha-difluoromethylornithine (DFMO) slows the growth of carcinoid tumors. However, the clinical utility of DFMO has been limited by its cytostatic property. Synthetic polyamine analogs such as 1,19-bis(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4) appear to be cytotoxic against several human tumors. The purpose of our study was to determine whether BE-4-4-4-4 is a more effective antiproliferative and cytotoxic agent than DFMO on human carcinoid (BON) cells in vitro. BON cells were treated with either 5 mmol/L DFMO, 0.5 to 10 mumol/L BE-4-4-4-4, or vehicle (control). Ornithine decarboxylase activity was determined by the rate of 14CO2 production, and intracellular polyamine levels were determined by chromatography. Cell number and viability were determined by Coulter counter and trypan blue exclusion, respectively. BE-4-4-4-4 inhibited ornithine decarboxylase activity and depleted all 3 polyamines. BE-4-4-4-4 decreased cell numbers by 81% compared with control and 27% compared with DFMO. BE-4-4-4-4 also induced a 2-fold increase in cell death compared with control or DFMO. BE-4-4-4-4 is cytotoxic and more effective than DFMO in inhibiting growth of BON cells. Polyamine analogs such as BE-4-4-4-4 may be effective adjuvant therapeutic agents for advanced carcinoid tumors.