Cisplatin Scheduling and Dosing Aspects
Klinische en farmacologische aspecten van behandeling met cisplatine
In 1965, during experiments on the effects of electric fields on cell growth and division, Rosenberg and co-workers found that an electric current delivered between platinum electrodes inhibited the proliferation of Escherichia coli bacteria. This inhibitory effect was found to be related to the formation of inorganic platinum complexes. Additional research showed that the cis isomer of dichlorodiammineplatinum II (cisplatin) is an active inhibitor of cell division, whereas the trans isomer had no effect on cell growth processes. The antiproliferative activity of cisplatin has been ascribed predominantly to the binding of cisplatin to the N-7 position of adenine and guanine resulting in DNA-platinum adducts with formation of intrastrand and interstrand cross-links. Cisplatin was introduced into the clinic in the early 1970s, and led to considerable improvement in survival of patients with germ cell and ovarian cancer. In addition, cisplatin demonstrated notable activity against epithelial cancers of the lung, head and neck, esophagus, urine bladder, uterine cervix and endometrium. Unfortunately, nonhematological toxicity associated with cisplatin administration was substantial, renal failure (acute tubular necrosis) being the main dose-limiting side effect. Cisplatin administration schedules with hyperhydration greatly improved treatment tolerability, while administration of cisplatin in hypertonic saline vehicle probably had additional renal protective effects. Severe nausea and vomiting (almost universal at cisplatin doses > 50 mg/m2) became manageable with the introduction of 5HT3 antagonists, especially in combination with dexamethasone. Protective measures against gastrointestinal and renal toxicity enabled treatment with larger individual and cumulative doses of cisplatin resulting in more common and sometimes dose-limiting neurotoxicity and ototoxicity.