Cisplatin toxic side effects

While carboplatin has the same mechanism of action as cisplatin, it has a much less toxic side-effect profile than cisplatin. The pharmacokinetics of carboplatin are best described by a two-compartment model, with an a half-life of 90 minutes and a terminal half-life of 180 minutes. Carboplatin is eliminated almost entirely by the kidney by glomerular filtration and tubular secretion. Many chemotherapy regimens dose carboplatin based on an area under the curve (AUC), which is referred to... 

Platinum is a relatively rare earth metal usually found with related metals osmium and iridium. While it has a number of industrial applications, its common consumer application is in catalytic converters. This application has actually increased platinum concentrations in roadside dust. The ability of platinum and its derivatives to kill cells or inhibit cell division was discovered in 1965. Platinum-based drugs, such as cisplatin, are used to treat ovarian and testicular cancer, and cancers of the head and neck, as well as others. Unfortunately, the toxic side effects of these agents often limit their usefulness. 

The discovery, ca. 1968, by B. Rosenberg, that the cis isomer has anti-tumor activity stimulated the synthesis and screening of over 2000 different types of complexes with different amines and anionic ligands. Platinum compounds are among the most effective medications for the treatment of advanced cancer PtCl2(NH3)2 ( Cisplatin ) is mainly used for the treatment of testicular and ovarian cancer. One of its drawbacks are the severe toxic side-effects which may be related to the facile hydrolysis of Cl ligands under physiological conditions ... 

There are some serious drawbacks to the use of cis-platin in anticancer therapy. Severe toxicity problems occur, such as failure of the kidneys and bone marrow (nephrotoxicity and hematoxicity), nausea, intractable vomiting (emesis), peripheral neuropathy, deafness (ototoxicity), and seizures. These toxic side effects of cisplatin limit the dose that can be administered to patients typical doses are 100 mg day for up to five consecutive days. The nephrotoxicity can be reduced by hydration and diuresis. 5-HT3-receptor blockers control nausea and emesis. Much effort has been devoted to the development of chemopro-tective agents, which alleviate the side effects on normal tissues without compromising antitumor activity - mainly sulfur-containing agents such as sodium dithiocarbamate (Naddtc), 2-mercaptoethanesulphonate (mesna), and amifos-tine (WR-2721). Amifostine has recently been approved for coadministration with cisplatin, which reduces nephro- and neurotoxicity. ... 

A striking feature of the cellular effects of bismuth compounds in animals (and one shared only by lead) is the production of intranuclear inclusion bodies of up to 5 ixm in diameter (87), for example, in the tubular epithelial cells of the kidney. Electron probe microanalysis shows that these contain both Bi and S, and so could be a complex with a Cys-rich protein such as metallothionein. Bismuth is known to be a potent inducer of renal metallothionein synthesis, and pretreatment of animals with bismuth salts can prevent some of the toxic side effects induced by cisplatin (88). The role of metallothionein in the pharmacology of bismuth remains to be established, but the strong involvement of zinc, also an inducer of metallothionein synthesis, in the metabolism of skin cells, for example, may be related. Like several other elements of Group V, the development of the biological chemistiy of Bi is hampered by the lack of good physical properties, in particular of a well-behaved NMR isotope. 

Nartey N, Cherian MG, Banerjee D (1987) Immunohistochemical localization of metallothionein in human thyroid tumors. Am J Pathol 129 177-182 Pattanaik A, Bachowski G, Laib J, Lemkuil D, Shaw CF III, Petering DH, Hitchcock A, Saryan L (1992) Properties of the reaction of cis-dichlorodiammine-platinum(II) with metallothionein. J Biol Chem 267 16121-16128 Satoh M, Naganuma A, Imura N (1988) Metallothionein induction prevents toxic side effects of cisplatin and adriamycin used in combination. Cancer Chemother Pharmacol 21 176-178... 

The platinum complexes cisplatin, d5-[PtCl2(NH3)2], and its 1,1-cyclo-butanedicarboxylato analogue, [Pt(CBDCA) 113)2] have good clinical utility in the treatment of certain cancers. Initial studies on the antibacterial effects of platinum complexes led to the discovery of their antitumour potential. Toxic side effects may now in general be overcome by suitable clinical manipulation. The early dose-limiting nephrotoxicity is now circumvented routinely and sulfur nucleophiles are particularly effective in obviating this toxicity. 

The use of complexes of cisplatin with modified nucleosides such as acyclovir has also been proposed for antiviral applications [23]. This approach is similar to that described for antitumour responses in Chapter 3. For antiviral effects, the fact that many of the antiviral nucleoside analogues are not very specific must be considered a disadvantage in this approach. Thus, although there is a distinct synergy between say, are-C, and cisplatin in antitumour effects, the therapeutic index of ara-C for a virus is almost unity and thus toxic side effects may not be overcome. The complex d5-[Pt(NH3)2(Guo)2] has also been reported to have antiviral activity [23], and also to have some antitumour activity (Section 3.5) [24]. However, the carrier approach may be more effective in antiviral therapy than in destroying tumour cells. 

Despite the imquestionable success story of cisplatin, limitations remain, including the powerfid toxic side effects. These toxic side effects include gastrointestinal problems such as acute nausea, vomiting, and diarrhea occasional liver dysfunction myelosuppression involving anemia, leukopenia, and thrombocytopenia ... 

As a result of the toxic side effects, intense research to design new derivative Pt compounds has been developed The second-generation platinum drug carboplatin, [Pt(C6H604)(NH3)2], has less toxic side effects than cisplatin and is also more easily used in combination therapy. Its lower reactivity allows a higher dose to be administered (even up to 2000 mg/day). It appears that carboplatin is the reagent of first choice for ovarian cancer treatment, whereas oxaliplatin is known to be most effective in colon cancer treatment... 

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