Platinum oxaliplatin

Oxaliplatin belongs to the group of diaminocyclohex-ane platinum complexes that can overcome platinum resistance. Its place in the primary and adjuvant treatment of colon cancets is being defined. It is prominently neurotoxic. 

Other subgroups of alkylating agents are the nitrosoureas (examples carmustine, BCNU lomustine, CCNXJ) and the triazenes (example dacarbazine, DTIC). Platinum derivatives (cisplatin, carboplatin, oxaliplatin) have an action that is analogous to that of alkylating agents (formation of crosslinks) and therefore are appended to this class, as well. 

Oxaliplatin Similar to other platinum analogs Dose-limiting... 

Oxaliplatin (Eloxatin ) is similar to other platinum analogs (e.g., cisplatin) in that it binds to the N-7 position of guanine, which results in cross-linking of DNA and double-stranded DNA breaks.26,40 Oxaliplatin differs from cisplatin in that the DNA damage induced by oxaliplatin may not be as easily recognized by DNA repair genes often seen in colorectal cancer. Oxaliplatin, in combination with 5-FU-based regimens, is indicated for the first- and second-line treatment of metastatic colon cancer, as well as the adjuvant treatment of colon cancer. 

The main uses for platinum are as a catalyst in the catalytic converter and in fuel cells. And of course platinum, a very expensive metal, is used in jewellery. However, certain platinum-containing compounds are chemotherapeutic agents, examples being cisplatin, carboplatin and oxaliplatin. This explains the synthetic interest in platinum compounds. 

Oxaliplatin has a mechanism similar to that of cisplatin but, unlike other platinums, is associated with minimal renal toxicity, hematologic toxicity, and nausea and vomiting. 

The second criteria, a different activity spectrum, is met by oxaliplatin (Figure 1.9A), the l isomer of [oxalatol f ra/rv-1,2-diaminocyclohexane)platinum (II)], oxaliplatin, [Pt(II)(oxalato)(DACH)]. This platinum agent is used for secondary treatment of metastatic colorectal cancer.77 Oxaliplatin, like carboplatin, has a kinetically slower leaving group, and is also less nephrotoxic than cisDDP. The limiting toxicity of oxaliplatin is peripheral sensory neuropathy, also seen with cisDDP. The neuropathy affects the extremities and increases in incidence and... 

Figure 7.9 Other platinum-containing anticancer agents evaluated in clinical trials. (A) Oxaliplatin, Pt(II) (B) ZD0473, Pt(II) (C) iproplatin, Pt(IV) (D) ormaplatin, Pt(IV).

In 1965 Rosenberg et al. (8, 9) accidentally discovered the antiproliferative effect of cis-diammine platinum complexes, which led to the first clinical trials of cis-[PtCl2(NH3)2] 1 in 1971 and resulted in the clinical use of cisplatin worldwide. Cisplatin and carboplatin 2 are the most widely used anticancer drugs, and two other analogs, nedaplatin 3 and oxaliplatin 4 (chiral centers indicated), have recently been approved for clinical use in Japan and France, respectively. 

Chemotherapeutic agents that have significant cancer response when combined with hyperthermia (up to 43°C) include doxorubicin, melphalan, mitomycin C (MMC), mitoxantrone, gemcitabine, etoposide, and especially the platinum-based agents carboplatin and oxaliplatin (Mohamed et al., 2003 Sugarbaker et al., 2005). Agents that do not work well with hyperthermia include irinotecan, paclitaxel, docetaxel, 5-fluorouracil, and floxuridine (Mohamed et al., 2003 Sugarbaker et al., 2005). 

Oxaliplatin (trans-L-diaminocyclohexane oxalate platinum II) was selected for development based on preclinical antitumor activity in murine leukemia lines and in colon cancer models (151,152). The clinical development of oxaliplatin has been primarily in colorectal cancer alone and in combination with 5-fluorouracil. 

Oxaliplatin is a novel platinum compound that has shown promising activity in colorectal cancers. It has been associated with up to 60% response rates when used as front-line therapy, and 25-50% response rates in relapsed or refractory colorectal cancer. It is currently being evaluated in a Phase I study with 5-FU and radiation in patients with locally advanced esophageal cancer (NCI T99-0061). 

Oxaliplatin is a newer platinum-based agent. It is most frequently administered in combination with fluorouracil and leucovorin for the treatment of colorectal cancer. Oxaliplatin has less ototoxicity and nephrotoxicity than cisplatin and carboplatin. 

Stordal B, Peters G, Davey R. Similar ehromosomal changes in cisplatin- and oxaliplatin-resistant sublines of the H69 SCLC eell line are not associated with platinum resistance. Genes Chromosomes Cancer 2006 45 1094-1105. 

Reconstitution of full-length BRCAl into mouse embryonic fibroblast cells with a disrupted BRCAl led to an increase in resistance to several DNA damaging agents, including the platinum compounds carboplatin and oxaliplatin, the topoisomerase 1 drugs irinotecan and topotecan, and the topoisomerase 11 drugs doxorubicin and etoposide (61). 

ICP-MS has been employed, as discussed in Section 9.5, for the determination of platinum originating from cisplatin, carboplatin and oxaliplatin in human plasma ultrafiltrate. The method developed was successfully used to support pharmacokinetic studies in cancer patients treated with cisplatin, carboplatin or oxaliplatin.5 Counterfeit products on the drug market, which have important implications for pharmaceutical companies and human health, can be clarified by mass spectrometric isotope ratio measurements. For example, precise and accurate sulfur isotope measurements (a 54S) by MC-ICP-MS, were employed to study the isotope variation of pharmaceuticals and to detect to the origin of counterfeits by Clough el al.6... 

Heavy metal compounds used to treat cancer include cisplatin, carboplatin, and oxaliplatin (see Table 36-6). These drugs, which contain platinum, are also known as platinum coordination complexes.10,27 Heavy metal drugs act like the alkylating agents that is, they form strong cross-links between and within DNA strands,... 

Oxaliplatin is a third generation diaminocyclohexane platinum analog. Its mechanism of action is identical to that of cisplatin and carboplatin. However, it is not cross-resistant to cancer cells that are resistant to cisplatin or carboplatin on the basis of mismatch repair defects. This agent was recently approved for use as second-line therapy in metastatic colorectal cancer following treatment with the combination of fluorouracil-leucovorin and irinotecan, and it is now widely used as first-line therapy of this disease as well. Neurotoxicity is dose-limiting and characterized by a peripheral sensory neuropathy, often triggered or worsened upon exposure to cold. While this neurotoxicity is cumulative, it tends to be reversible—in contrast to cisplatin-induced neurotoxicity. 

More recently, however, a DACH compound oxaliplatin [DACH-(ox-alato)platinum(II)] t[SP-4-2-(l Ak/ra/ulHl -cyclohcxancdiamine-Ak/V l-tethanedioato - OjO lplatinumUI)) has been successfully developed in France (Fig.) [15-17], The spectrum of DNA adducts formed by oxaliplatin are the same as that observed with cisplatin and carboplatin [18], The... 

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