A novel cytotoxic agent for human carcinoid tumors

Background. Conventional adjuvant therapy for advanced carcinoid tumors rem ains disappointing novel therapeutic agents are needed. We have shown previ ously that inhibiting polyamine biosynthesis with alpha-difluoromethylornit hine (DFMO) slows the growth of carcinoid tumors. However the clinical util ity of DFMO has been limited by its cytostatic property. Synthetic polyamin e 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 antiprolifer ative and cytotoxic agent than DEMO on human carcinoid (BON) cells in vitro . Methods. BON cells were treated with either 5 mmol/L DFMO, 0.5 to 10 mu mol /L BE-4-4-4-4, or vehicle (control). Ornithine decarboxylase activity was d etermined by the rate of (CO2)-C-14 production, and intracellular polyamine levels were determined by chromatography. Cell number and viability were d etermined by Coulter counter and trypan blue exclusion, respectively. Results, 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 incre ase in cell death compared with control or DFMO. Conclusions. BE-4-4-4-4 is cytotoxic and more effective than DEMO in inhibi ting growth of BON cells. Polyamine analogs such as BE-4-4-4-4 may be effec tive adjuvant therapeutic agents for advanced carcinoid tumors.