PURPOSE: To review the pharmacodynamics, pharmacokinetics, toxicities, and relative clinical activities of cisplatin and carboplatin. Through a search of the MEDLINE database, we identified phase III clinical trials and pharmacologic studies comparing cisplatin and carboplatin published in the English language medical literature from January 1966 to December 1997. RESULTS: Prospective randomized trials comparing cisplatin to carboplatin were identified for ovarian (n = 12), germ cell (n = 4), non–small-cell lung (n = 1), small-cell lung (n = 3), and head and neck (n = 4) cancers. Carboplatin and cisplatin were equally effective in suboptimally debulked ovarian cancer and extensive-stage small-cell lung cancer. One study each showed a trend toward better survival in favor of cisplatin for patients with optimally debulked ovarian and limited-stage small-cell lung cancers. These results were, however, based on subset analyses. In germ cell tumors, carboplatin was inferior because of lower relapse-free surviv...

Review of the Comparative Pharmacology and Clinical Activity of Cisplatin and Carboplatin

Charles F. Kettring prize. Fundamental studies with cisplatin

Cis-diamminedichloroplatinum (II) (c-DDP), a highly effective cytostatic drug, is increasingly used in combination with irradiation both in the laboratory and in patients. This review aims at a critical reassessment of the potential role of this drug as a "radiosensitizer." The opinion about c-DDP being an effective hypoxic cell radiosensitizer in bacteria was substantiated in some studies on mammalian cells in culture but not in others. More powerful mechanisms of radiation enhancement, which are not yet fully explored, may be depletion of endogenous thiols, inhibition of cellular repair processes, and proliferation inhibition. The effects of c-DDP in combination with irradiation in experimental tumors seem to vary between different investigators and between different tumor systems. Occasionally, supra-additive effects have been observed in some animal tumors. This stresses the need for testing this combination treatment in various tumor types, preferentially of human origin. In normal tissues, the effects are, to a large extent, explained by independent cell killing by each agent. A substantial number of clinical pilot studies have shown that the combination treatment is feasible, but the results of ongoing phase III trials will be needed to assess the potential therapeutic benefit of this combined treatment modality.

Combined treatment of radiation and cisdiamminedichloroplatinum (II): a review of experimental and clinical data

We have characterized the accumulation of cisplatin (DDP) into parent and cisplatin-resistant 2008 human ovarian carcinoma cells. Accumulation of DDP at 1 h was a linear function of concentration from 0.25 to 100 microM DDP in both cell types. DDP-resistant cells that were only 3.3-fold resistant had approximately 50% less accumulated platinum at all concentrations examined. Accumulation of 1.0 microM DDP was linear for approximately 3 h and then slowed but did not reach equilibrium at up to 24 h in either cell type. The decreased DDP accumulation in resistant cells did not appear to be due to increased efflux; similar percentages of platinum were available for exodus in parent and resistant cells. Intracellular metabolites of DDP appeared to be decreased by similar amounts in the resistant cells. Native DDP was not driven uphill into cells against a concentration gradient, suggesting that DDP uptake does not involve primary active transport. The metabolic inhibitors, dinitrophenol and NaF, did not decrease DDP accumulation; iodoacetate had a stimulatory effect. Dinitrophenol, however, in combination with NaF or iodoacetate decreased DDP accumulation. A 30-min exposure to 0.2 mM ouabain also decreased DDP accumulation in both parent and resistant cells. A component of DDP accumulation thus appears to be energy dependent. These studies have identified decreased DDP accumulation as an important mechanism of resistance that is expressed early in the acquisition of DDP resistance in human ovarian carcinoma cells.

https://cancerres.aacrjournals.org/content/canres/48/1/68.full.pdf

cis-Diamminedichloroplatinum(II) Accumulation in Sensitive and Resistant Human Ovarian Carcinoma Cells

https://www.ajkd.org/article/S0272-6386(86)80112-3/pdf

Nephrotoxicity Induced by Cancer Chemotherapy With Special Emphasis on Cisplatin Toxicity

Using traditional toxicologic methods, four species were studied for their qualitative and quantitative predictiveness of the toxic effects of cis-dichlorodiammineplatinum(II) in man Of the four species studied, mouse, monkey, rat, and dog, the latter two gave the best overall results Using an in vivo rat model, it was found that except for chloroplatinic acid, eight of the tested analogs were less nephrotoxic than the parent drug, cis-dichlorodiammineplatinum(II) The in vitro renal toxicity screen using flounder tubules showed that of the 26 compounds studied, about half were less toxic than the parent compound This in vitro mini-tox system can be performed about 30 times faster and at one fiftieth the cost of the in vivo model The in vitro studies also provided evidence that the biochemical site of toxicity of platihates is on ATPases The latter studies suggested a basis for unifying the mechanistic interpretation of the toxic actions on such disparate target organs as the kidney, nerve, stomach, and inner ear

Platinate toxicity: past, present, and prospects.

Adsorption of antineoplastic drugs following large-volume ip administration to rats.

Doxorubicin was administered to rats in a simulated "belly bath" protocol. Fifty milliliters of various concentrations of drug solution was administered ip and was allowed to remain in situ for either 4 or 36 hours prior to removal. Animals were analyzed at 2, 14, and 60 days after treatment. Doses ranged from lethal (75 and 150 micrograms/ml for 4 hours; 12 and 24 micrograms/ml for 36 hours) to nontoxic (5 micrograms/ml for 4 hours). The most common lesion in surviving animals was chronic fibrosing peritonitis. Grossly, there were large volumes of peritoneal fluid in animals exposed to low concentrations (12 and 24 micrograms/ml) for 36 hours, but peritoneal adhesions were the most commonly observed finding when higher concentrations (20-150 micrograms/ml) were used for 4 hours. Commonly observed systemic toxic effects (bone marrow, gastrointestinal tract, and heart) were not seen in this study. Vehicle-treated control animals were negative for all histologic lesions and gross observations.

Arnold St

Papers

Platinate toxicity: past, present, and prospects.

Adsorption of antineoplastic drugs following large-volume ip administration to rats.

Local and systemic toxicity resulting from large-volume ip administration of doxorubicin in the rat.