Comparative Adverse Effect Profiles of Platinum Drugs

Abstract

Since the discovery of the biologically active platinum complexes 30 years ago, 2 agents have become widely established in clinical oncology practice. Both cisplatin and carboplatin are platinum(II) complexes with 2 ammonia groups in the cis- position. However, they differ in their solubility, chemical reactivity, dichloride or alicyclic oxygenated leaving groups, pharmacokinetics and toxicology. Cisplatin causes severe renal tubular damage and reduces glomerular filtration, and requires concurrent saline hydration and mannitol diuresis to eliminate potentially lethal and unacceptable damage to the kidneys. Carboplatin, at conventional doses, causes no decrease in glomerular filtration and only minor transient elevations in urinary enzymes. Cisplatin is the most emetic cancer drug in common use, while nausea and vomiting associated with carboplatin are moderately severe. Serotonin release from enterochromaffin gut mucosal cells and stimulation of serotonin 5-HT3-receptors mediates acute emesis. Selective inhibitors of the 5-HT3-receptor protect against cisplatin- and carboplatin-induced nausea and vomiting. Peripheral neurotoxicity is the most dose-limiting problem associated with cisplatin. Loss of vibration sense, paraesthesia and sensory ataxia comes on after several treatment cycles. Carboplatin, however, is relatively free from peripheral neurotoxicity. Audiometry shows cisplatin-induced ototoxicity in 75 to 100% of patients, which may be associated with tinnitus and hearing loss. Ototoxicity is rare with conventional dose carboplatin therapy. Monitoring hearing with audiograms may identify early signs before significant impairment occurs. Cisplatin causes mild haematological toxicity to all 3 blood lineages. Haematological toxicity is dose-limiting for carboplatin, with thrombocytopenia being a greater problem than leucopenia. Although carboplatin is not toxic to the kidney, renal function markedly affects the severity of carboplatin-induced thrombocytopenia. The major clearance mechanism of cisplatin is irreversible binding in plasma and tissues, while carboplatin is cleared by glomerular filtration. Metabolism of cisplatin to aqua, amino acid and protein species is extensive, whereas carboplatin exists mainly as the free unchanged form. Strong relationships between carboplatin renal clearance, glomerular filtration rate, area under the plasma concentration-time curve (AUC) of filterable platinum and severity of thrombocytopenia have prompted dose adjustment according to renal function. New analogues such as JM216 offer the potential advantages of oral administration and few nonhaematological toxicities. Analogues based on the diaminocyclohexane ligand have encountered problematic neurotoxicity.

The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear

“…The cytotoxic effects of CDDP are due to coordinative bonds between the atom of platinum and DNA and formation intrastrand DNA crosslinks (McKeage, 1995). Apoptotic death of OHCs has emerged as a final common pathway in response to ischaemia, loss of trophic factor support and ototoxins such as aminoglycoside and cisplatin (Huang et al, 2000).…”

The Protective Role of Molsidomine on the Cisplatin-Induced Ototoxicity

“…Hearing loss appears to be bilateral, usually permanent, dose-related, and initially at higher frequencies [2]. Recently it was reported that an increase in hearing thresholds may occur in up to 75-100 % of patients [22]. Many antioxidant agents have been studied to prevent this adverse effect.…”

New developments in cancer treatment with the novel thymidylate synthase inhibitor raltitrexed ('Tomudex')

“…Several thousand platinum complexes have been synthesized over the last 20 years in attempts to develop less toxic, non-cross-resistant or oral analogues, one of which is oxaliplatin (McKeage, 1995).…”