Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

Abstract

molecularly targeted anticancer therapy with conventional cytotoxic chemotherapy. Such combinations can come about only through rational design of clinical trials, taking into account the pharmacology and clinical development of the drugs involved. It is therefore worthwhile revisiting classical chemotherapy agents, because this renewed knowledge could provide a foundation for future trials.Oxaliplatin is the newest platinum derivative in standard chemotherapy. Here, we review oxaliplatin from the pharmacologic and drug development perspectives, and we comment on possible associations of this drug with molecularly targeted therapy. CHEMICAL AND PHYSICAL PROPERTIES AND BIOTRANSFORMATIONOxaliplatin differs from cisplatin in that the amine groups of cisplatin are replaced by diaminocyclohexane (dach). The molecular weight of oxaliplatin is 397.3. It is slightly soluble in water, less so in methanol, and almost insoluble in ethanol and acetone 1 . Its full chemical name, oxalato(transl-1,2-diaminocyclohexane)platinum, refers to the presence of an oxalate "leaving group" and the dach carrier ligand, which are responsible, at least in part, for its unique properties 2,3 . For example, unlike cisplatin, oxaliplatin in plasma rapidly undergoes non-enzymatic transformation into reactive compounds because of displacement of the oxalate group, a process that complicates its pharmacokinetic profile. Most of the compounds appear to be pharmacologically inactive, but dichloro(dach) platinum complexes enter the cell, where they have cytotoxic properties. MECHANISMS OF ACTIONVarious mechanisms of action are ascribed to oxaliplatin. Like other platinum-based compounds, oxaliplatin exerts its cytotoxic effect mostly through dna damage. Apoptosis of cancer cells can be caused by formation of dna lesions, arrest of dna synthesis, ABSTRACT ObjectiveTo review preclinical and clinical data for oxaliplatin in the current context of molecularly targeted therapy.

The 1,2-Diaminocyclohexane Carrier Ligand in Oxaliplatin Induces p53-Dependent Transcriptional Repression of Factors Involved in Thymidylate Biosynthesis

“…Despite the significant clinical advantages of oxaliplatin in combination with 5-FU-based chemotherapy, the underlying mechanism has not been fully elucidated (12). Downregulation of TS by oxaliplatin has been proposed as one possible mechanism (13).…”

Enhancement of oxaliplatin-induced cell apoptosis and tumor suppression by 3-methyladenine in colon cancer

“…Oxaliplatin (OX), a third generation platinum-based antineoplastic agent, is a commonly used chemotherapeutic agent for the clinical treatment of advanced colon cancer (4). Although the clinical application of OX has resulted in a significant improvement in response rate and progression-free survival in advanced colon cancer (5), ~40% of cases of colon cancer continue to develop resistance (6). Therefore, the development of novel therapeutic strategies is required to overcome the current OX resistance in advanced colon cancer.…”

Platelet Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin

“…Oxaliplatin is one of the most commonly used drugs in hyperthermic intraperitoneal chemotherapy because it has the ability to act at any stage of malignant cell replication (11), its intra-tumoral penetration is optimal (12), and its cytotoxicity is substantially improved by hyperthermia (13). Several phase I dose-escalation studies in PC patients treated with CRS have characterized the HIO pharmacokinetics in both the peritoneum and plasma (14)(15)(16).…”