Enzyme regulation as an approach to interference with polyamine biosynthesis--an alternative to enzyme inhibition.

The progress reviewed here would seem to validate the regulatory approach to interference with polyamine biosynthesis as an antiproliferative strategy. To our knowledge, this is the first example, among anticancer drugs, of pharmacological intervention of a biochemical pathway based strictly on regulatory control. Several features of polyamine biology naturally favor this approach and may account for its relative success. These include (a) the nature of the regulatory mechanisms themselves, (b) the exquisite sensitivity of the pathway to regulatory control, (c) the rapid turnover of ODC and AdoMetDC, (d) the different structural specificity of ODC and AdoMetDC regulation versus growth-dependent functions, and (e) the direct dependence of growth on sustained polyamine biosynthesis. As such, the regulatory approach to interference with polyamine biosynthesis offers several advantages over the use of specific enzyme inhibitors (Table 10). Of these, perhaps, the more significant are the facts that more than one enzyme can be simultaneously and specifically suppressed and that compensatory mechanisms, which otherwise counter the effects of enzyme inhibitors (11), are not invoked. We are encouraged by the concurrence of in vitro mechanistic findings with the predictions of the hypothesis for the regulatory approach and by the in vitro and in vivo growth inhibitory effects of the analogs against murine leukemia. One disadvantage of the regulatory analogs, such as BESm, has been that, as with specific polyamine inhibitors such as DFMO, analog-induced polyamine depletion results in cytostatic growth inhibition. While this response may help to minimize host toxicities, it clearly compromises antitumor activity. An intriguing exception to this generality has recently been found among human lung carcinoma cell lines. Previously, Luk et al. (93, 94) and others (95) reported that, among a spectrum of human lung carcinoma lines, small cell carcinoma was exquisitely sensitive to the ODC inhibitor, DFMO. Not only did these cells display a cessation of growth but also an inability to survive during DFMO-induced polyamine depletion. Studies extending these findings to long term maintenance therapy in human small cell lung carcinoma implants in athymic mice revealed sustained growth inhibition of the tumor for longer than one year (96). Casero et al. (97) now find that human large cell carcinoma, which is otherwise refractory to chemotherapeutic intervention, displays a cytotoxic response in vitro to polyamine depletion induced by BES or BESm but not by DFMO.(ABSTRACT TRUNCATED AT 400 WORDS)