Ongoing and unsaid on oxaliplatin: the hope

Abstract

Summary Oxaliplatin, the first available diaminocyclohexane platinum, has clinical activity in colorectal and ovarian cancers. Its mechanism of action is thought to be similar to that of cisplatin, its main mechanism being the intrastrand DNA adduct between two adjacent guanins or two adjacent guanine and adenine adducts. Ongoing molecular pharmacological studies of the mechanism of action of cisplatin suggest that platinated adducts are recognized by proteins of the mismatch repair system, including the products of the hMLH1 and hMSH2 genes. DNA mismatch repair defects occur in a wide variety of sporadic human cancers, are the main genetic factor in hereditary non-polyposis colon cancer and a frequent de novo or acquired phenomenon in ovarian cancer and other solid tumours. Moreover, they have recently been reported to be a cause of resistance to cisplatin but not to oxaliplatin, as diaminocyclohexane platinum adducts do not appear to be recognized by the mismatch repair complex. These findings explain the oxaliplatin activity in some cisplatin-resistant tumours. In addition, the good safety profile of oxaliplatin makes it a drug of choice for combination therapy, and it has been shown to be synergistic with other cytotoxic agents, including 5-fluorouracil, cisplatin, carboplatin, topotecan, gemcitabine and CPT-11. The results of several ongoing trials are awaited, but available data demonstrate that oxaliplatin is highly effective in the treatment of advanced colorectal and ovarian cancers. Promising early results suggest that it is also efficacious in non-Hodgkin's lymphoma, breast and non-small-cell lung cancers. As a result of its mechanism of action, its favourable safety profile and the differential profile of its antitumoral activity, the full potential of oxaliplatin as an active, versatile antitumoral agent is yet to be fully explored.

Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer

“…Second, increased DNA repair capacity and enhanced tolerance to DNA damage or cytotoxins can lead to cancer cell survival. Changes in the level or activity of hMLH1/hMSH2, ERCC, HIF-1·, or topoisomerases I/II may be involved in these mechanisms (23). Third, abnormalities in signaling proteins such as p53, p21 WAF1 , p27 Kip1 , XIAP, PI3K, caspase-9/3, Akt, JNK1, ERK1/2, and PKC (24)(25)(26) can interfere with intracellular signal transduction pathways at any point, from the primary damage to DNA or microtubules to the eventual death of the cell.…”

Combined modalities of resistance in an oxaliplatin-resistant human gastric cancer cell line with enhanced sensitivity to 5-fluorouracil

“…Although evidence of cross-resistance between CDDP and oxaliplatin exists (Rixe et al, 1996;Safaei and Howell, 2005), oxaliplatin has been frequently shown to be effective against tumours with primary or acquired resistance to CDDP (Cvitkovic, 1998;Misset et al, 2000). Conversely, CDDP is rarely tested in oxaliplatin-resistant cancer cells either in vivo or in vitro.…”

Anticancer Effects of a New Aminosugar-conjugated Platinum Complex Agent Against Cisplatin-resistant Gastric Cancer

“…CDDP is the prototype member of a group of platinum-based antineoplastic agents that also includes CBDCA (11), with L-OHP a new diaminocyclohexane-platinum analogue (12). All of these agents typically form bifunctional intrastrand lesions in cancer cells that bind to and damage genomic doublestranded DNA, thereby inhibiting DNA transcription and blocking the cell cycle to ultimately induce cell death (4).…”

“…ABCB1 gene is the most extensively studied ABC superfamily transporter (19), being implicated in MDR involving CDDP accumulation due to active efflux of drugs (20,21). CDKN2A might also (19), Cl1-Pt1-O1 94.03 (12), N2-Pt1-O1 160.89 (19). enhance CDDP resistance by prolonging the cell cycle at the G 1 -S transition, which allows for DNA repair (22).…”