Figure 18 Active species from satraplatin.

compounds are not considered to be nephrotoxic, whereas this toxicity can be severe with cisplatin.118 Carboplatin is also less neurotoxic than cisplatin and oxaliplatin.

One negative aspect of carboplatin is that it demonstrates pronounced bone marrow suppression, in contrast to cisplatin and oxaliplatin. This toxicity can be controlled to some extent by dosing based on projected AUC, which accounts for renal function. Clinically, typical treatment programs include carboplatin at an AUC of 4-7 (mgmL) min.129 Although both carboplatin and paclitaxel suppress bone marrow, the combination of carboplatin with paclitaxel results in significantly lower hematological toxicity than either agent alone, through a currently unknown mechanism.130

Cisplatin and carboplatin form similar DNA cross-links, and are effective against similar tumors. They are also cross-resistant with each other; thus, they are affected by the same resistance mechanisms. Oxaliplatin can circumvent some forms of cisplatin resistance, particularly when mediated by cellular mismatch repair mechanisms.131 Indeed, a key component in MMR has been shown to be twofold selective to bind to cisplatin over oxaliplatin modified DNA.132

A common factor among cisplatin, carboplatin, and oxaliplatin is that they are all square planar Pt(II) complexes. All lack oral bioavailability, and are thus dosed by intravenous infusion. An important quality of life consideration for the patient has been the development of orally active platinum-based therapeutics. The use of an octahedral Pt(IV) complex has provided several orally active candidates for clinical trials. One member of this class that has reached phase III trials is satraplatin 72 (JM216, BMS-182751; Figure 17).133

Satraplatin must be reduced and hydrated in vivo to the active platinum (II) species 74, via the intermediacy of 73 (Figure 18). The use of the cyclohexylamine ligand does confer some activity to tumors that are resistant to cisplatin. Satraplatin-DNA adducts are not recognized by mismatch repair proteins.134 In addition, satraplatin also has different transport properties from cisplatin, and in vitro experiments suggest that it can overcome cisplatin resistance caused by reduced platinum transport.135

Satraplatin has shown some promise in a phase II trial against small-cell lung cancer.136 The regimen of treatment in this trial was an oral dose of 120 mgm_ 2 day_ 1 for 5 consecutive days, with a course given every 3 weeks.

Unfortunately, the drug suffers from nonlinear pharmacokinetics due to saturable absorption.137 However, for this trial the dosing level of 72 was within the range of linear absorption. Satraplatin showed a response rate of 38%, which was similar to cisplatin. The major dose-limiting toxicity associated with satraplatin is myelosuppression.

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