Platinum Complexes

The parent compound of all platinum-based chemotherapy is cisplatin (Platinol, 66; Figure 14). Rosenberg and co-workers serendipitously discovered the antiproliferative effects of cisplatin in 1965.110 This study demonstrated that cisplatin inhibited cell division, but not growth, of Escherichia coli. Later studies by Rosenberg showed that cisplatin was active in vivo versus Sarcoma 180 and L1210 xenograft mouse models of cancer.111 Cisplatin was approved as an antitumor agent in 1978.112 Cisplatin Mechanism of Action

Cisplatin is activated by intracellular hydrolysis of the chlorides to either hydroxyl or aqua ligands (Figure 15).113 Initially, 66 was assumed to enter the cell via passive diffusion; however, recent investigations have demonstrated that cisplatin enters the cell via a copper transporter.114 The fully activated platinum complex, 68, generates intrastrand purine cross-links in DNA, 65% of which are dGpG (69).115'116 These lesions are recognized by a number of proteins to trigger several cellular processes. The downstream effect is generally cytotoxicity via apoptosis, although cisplatinmediated necrosis has also been documented.117 Clinical Uses of Cisplatin (66)

Cisplatin has found widespread use in a variety of solid tumor types. It is not orally available, and is administered via intravenous infusion. Instead of using body surface area, dosing can be calculated using projected AUC to account for renal function in an effort to help minimize potential side effects.118

Cisplatin has been a particularly effective drug in the treatment of testicular and ovarian cancers. For example, cisplatin is used in combination with bleomycin and etoposide (BEP regimen) for treating testicular cancer, which consists of three cycles, each lasting 3 days. Etoposide is given at a dose of 165 mgm _ 2 day_ 1 for 3 days, bleomycin 50mgm_2 for 1 day, and cisplatin 50 mgm_2 day_ 1 for 2 days yielding ~90% progression-free survival rate after 2 years of completing this therapy.119 Cisplatin Toxicity

There are a number of toxicities associated with cisplatin use. The major dose-limiting toxicity is neuropathy. This may begin as a mild peripheral tingling sensation, but can progress to impairment of fine motor function. While this may gradually improve over time after cessation of therapy, in some cases it can be permanent. The presence of this effect is related to the current dose given, and to the overall cumulative dose. High-dose regimens (>120mgm_2) may cause symptoms from a single treatment, while at more typical levels (50-75mgm_2), symptoms are less likely until a cumulative dose of >300mgm_2 has been achieved.118

Cisplatin's clinical use also results in acute renal toxicity. The mechanism of this toxicity is not yet understood, but several strategies have been developed to help alleviate kidney toxicity. These include delivering the drug over a longer time period, either by increasing the infusion time, or by administering a course of treatment over several days instead of a 1-day treatment.120 The use of hypertonic saline or a nephroprotective agent is also effective.118

One of the most pervasive cisplatin toxicities is emesis, which occurs in >90% of patients that are not treated with a prophylactic antiemetic.121 The onset of emesis can be acute or delayed by >24h. Fortunately, this can often be prevented with antiemetic prophylactic treatment, including use of a 5-hydroxytryptamine-3 (5HT3) antagonist and, more recently, a neurokinin 1 (NK1) antagonist.122

Cisplatin is known to lack bone marrow suppression, thereby enhancing its clinical utility by allowing combinations with other cytotoxics that do have bone marrow suppressive effects. However, this is not true of all platinum complexes, as carboplatin possesses significant hematological toxicity.118 Resistance to Cisplatin

Extensive investigations focused on determining which cellular mechanisms have led to resistance to platinum-based cytotoxics have yielded several possible pathways. As the primary mechanism of action of cisplatin involves damaging DNA, increased levels of DNA repair machinery within the cell can also increase resistance to cisplatin.123 In particular, tumors that are clinically resistant to cisplatin overexpress the DNA-repair gene ERCC1. Tumor cells that are deficient in MMR are also typically resistant to cisplatin.125

About 90% of cisplatin in blood is protein bound, mostly to albumin, and activated cisplatin reacts with many cytosolic nucleophiles other than DNA,117 for example, glutathione and metallothionin.126 The glutathione-cisplatin complex is then actively exported from the cell by the ATP-dependent glutathione S-conjugate pump.127

Treatment with cisplatin also activates several survival pathways, including the ERK and PI3K/Akt pathways. In ovarian cancer cell lines, inhibition of either of these pathways sensitizes resistant cells to cisplatin.128 Other Platinum-Based Cytotoxics

The search for newer analogs of cisplatin has been focused to address the following issues. First, one goal has been to affect tumors that are resistant to cisplatin. Another goal has been the alleviation of some of the more serious side effects of cisplatin. Finally, more recent compounds have sought to achieve oral bioavailability. Indeed, new compounds have been introduced that have addressed all of these issues. There are currently two other platinum compounds marketed in the US: carboplatin (Paraplatin, 70, US approval in 1989; Figure 16) and oxaliplatin (Eloxatin, 71, European approval in 1996, US in 2002; Figure 16).

Carboplatin and oxaliplatin both require activation via intracellular hydrolysis, with retention of the amine ligands. For these compounds, hydrolysis of the dicarboxylate groups is much slower than for the chlorides in cisplatin. The slower hydrolysis comes with a number of differences in vivo, particularly in side effect profiles. The two newer

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