Evaluation of platinum drug toxicity resulting from polyamine catabolism.

Abstract

Polyamines, spermidine (Spd) and Spermine (Spm), are polycations that serve a number of important biological functions. The tissue contents of polyamines are tightly regulated through their cellular import and export, as well as their metabolism (anabolism and catabolism). Polyamine catabolism in mediated via the spermidine/spermine N1-acetyltransferase (SAT1)/acetylpolyamine oxidase (APOX) cascade and oxidation of Spm by spermine oxidase (SMOX). The expression of SAT1 and SMOX increases in injured organs in response to trauma, ischemia/reperfusion, sepsis, and exposure to toxic compounds. Cisplatin is a highly effective chemotherapeutic agent that is used for the treatment of a variety of solid tumors. Its anti-tumor activity is mediated via its ability to form stable DNA adducts that inhibit the growth of actively proliferating cells. However, cisplatin also can lead to severe off-target deleterious effects (e.g., nephrotoxicity and ototoxicity), and because of such adverse effects the use of cisplatin has to be discontinued in many patients. Understanding and decoupling the therapeutic and toxic effects of cisplatin will lead to more effective use of this and other platinum-derived compounds in the treatment of cancer patients. Acute and chronic exposure to cisplatin in mice leads to severe renal tubular injuries and an increase in the expression of SAT1 and SMOX while the ablation of their genes in mice reduces the severity of nephrotoxic injuries caused by cisplatin. Furthermore, neutralization of the toxic by-products of polyamine degradation reduce the severity if cisplatin nephrotoxicity. These observations suggest that interventions targeting the adverse effects of enhanced polyamine catabolism may provide effective therapies by reducing the toxic effects of cisplatin without affecting its anti-neoplastic activity.