Covalent Binding of Platinum to Kidney Subcellular Fractions from Guinea Pig Strains Sensitive or Resistant to Cisplatin Toxicity

Abstract

Since the introduction of platinum-containing anticancer drugs in the early 1970’s scientists have attempted to find a mechanisnm by which the drug causes its toxic effects. Theories involving enzyme inhibition (1,2), DNA interaction (3) and immunomodulation (4) all have been proposed but each has limitations and shortcomings. In the past few years numerous drugs and chemicals have been found to exert their toxic effects through an irreversible binding to tissue components. Thus such disparate chemicals as bromobenzene, acetaminophin, and 4-ipomeanol all act through covalent binding to tissue proteins. Cisplatin, through its highly electrophilic chlorine centers has the potential to interact with tissue by such a mechanism and the prolonged biological half life of platinum in animals and humans, and the known binding of platinum to plasma proteins support this theoretical concept. It has recently been established that two strains of guinea pigs used widely in hearing research have an obvious difference in their response to cisplatinum. One strain (pigmented) is highly sensitive to cisplatin toxicity and the other strain (albino) is much more resistant to cisplatin toxic effects.