Toxicity cisplatin compounds

The polymeric nature may inhibit premature drug deactivation. Thus, cisplatin (structure 19.20), the most widely used anticancer drug, is converted into numerous inactive, but more toxic, platinum-containing compounds before it arrives at the targeted cancer cells. Placement of the active platinum-containing moiety into a polymer (structure 19.21) decreases this tendency to hydrolyze into these unwanted cisplatin compounds because of the greater hydrophobic character of the polymeric drug. 

Pt(TV) Prodrugs. Platinum(IV) complexes have been widely studied as potential prodrugs that avoid the limitations of the cisplatin class of anticancer drugs. Indeed, the Pt(IV) compound satraplatin [Pt(cha)Cl2(OAc)2(NH3)] (cha, cyclohexylamine) is currently in clinical trials for treatment of hormone-refractory prostate cancer (Fig. 1) (22). Satraplatin is the first orally bioavailable platinum derivative under active clinical investigation and is particularly attractive because of the convenience of administration, milder toxicity profile, and lack of cross-resistance with cisplatin. These results are promising and support the idea that platinum(IV) complexes offer the opportunity to overcome some of the problems associated with cisplatin and its analogs. 

Novel mechanisms of interest include sensitizing hypoxic tumor cell lines to enhance radiotoxicity. Tirapazamine is a hypoxia-selective compound 1-2-fold greater in magnitude in comparison to mitomycin C or porfiromycin (84). Its mechanism of action results in a one-electron reduction inducing DNA double-strand breaks and cell death under hypoxic conditions. The free radical is oxidized back to the parent compound under aerobic conditions. When combined with the platinum compounds, the cytotoxic effects may be equivalent to that seen with five times the dose of cisplatin without the toxicities that would be encountered if actually administered (85). 

A variety of other compounds have mechanisms of action that involve alkylation. These include procarbazine, dacarbazine, altretamine (hexamethylmelamine), cisplatin, and carboplatin. Dosages and major toxicities are listed in Table 55-2. 

Two of the most important platinum anticancer drugs are cisplatin (2.13) and carboplatin (2.14). Cisplatin is effective against testicular tumours, ovarian carcinoma and some other types of cancer, but relatively inactive against breast and lung cancers it is also a very toxic compound. Side effects include loss of high-frequency hearing, neuropathy and nausea. Kidney damage may also result, but is minimised... 

Most platinum compounds exist as coordination complexes the tetravalent compounds typically are more toxic than the hexavalent ones [10]. Certain neutral platinum complexes exhibit antitumor activity and therefore are used in chemotherapy drugs such as cisplatin. Speeiation is required to distinguish platinum chemotherapy drugs from their metabolites in patients blood and serum samples. 

A substantial body of literature documents the side effects of platinum compounds. The nephrotoxicity of the parent compound cisplatin almost led to its abandonment, until Cvitkovic et al. introduced aggressive hydration, which prevented the development of acute renal failure [2] [3], As noted above, the toxicity of cisplatin was a driving force both in the search for less toxic analogues and for more effective treatments for its side effects, especially nausea and vomiting. 

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