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Departments of ¹ Medicine and ² Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Lakshmi Pendyala, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263. Phone: 716-845-3287; Fax: 716-845-1659. E-mail: lakshmi.pendyala{at}roswellpark.org

A great deal of experimental evidence connects induction of polyamine catabolism via spermidine/spermine N¹-acetyltransferase (SSAT) to antiproliferative activity and apoptosis. Following our initial observation from gene expression profiling that platinum drugs induce SSAT, we undertook this present study to characterize platinum drug induction of SSAT and other polyamine catabolic enzymes and to examine how these responses might be enhanced with the well-known inducer of SSAT and clinically relevant polyamine analogue, N¹,N¹¹-diethylnorspermine (DENSPM). The results obtained in A2780 ovarian cancer cells by real-time quantitative RT-PCR and Northern blot analysis show that a 2-hour exposure of A2780 cells to platinum drugs induces expression of SSAT, a second SSAT (SSAT-2), spermine oxidase, and polyamine oxidase in a dose-dependent manner. At equitoxic doses, oxaliplatin is more effective than cisplatin in SSAT induction. The most affected enzyme, SSAT, increased 15-fold in mRNA expression and 2-fold in enzyme activity. When combined with DENSPM to further induce SSAT and to enhance conversion of mRNA to activity, oxaliplatin increased SSAT mRNA 50-fold and activity, 210-fold. Polyamine pools declined in rough proportion to levels of SSAT induction. At pharmacologically relevant oxaliplatin exposure times (20 hours) and drug concentrations (5 to 15 µmol/L), these responses were increased even further. Combining low-dose DENSPM with oxaliplatin produced a greater than additive inhibition of cell growth based on the sulforhodamine-B assay. Taken together, the findings confirm potent induction of polyamine catabolic enzymes, such as SSAT by platinum drugs, and demonstrate that these biochemical responses as well as growth inhibition can be potentiated by co-treatment with the polyamine analogue DENSPM. With appropriate in vitro and in vivo optimization, these findings could lead to clinically relevant therapeutic strategies.

Key Words: cisplatin • oxaliplatin • platinum • polyamines • spermidine/spermine N¹-acetyltransferase • N¹,N¹¹-diethylnorspermine

Grant support: CA-22153, CA-76428, and CA-16056.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12/24/03; revised 3/23/04; accepted 5/ 4/04.