Disease relevance of oxaliplatin

• Future directions being evaluated for adjuvant therapy of colon cancer include the use of oral fluorinated pyrimidines, which may replace current intravenous treatments, as well as the incorporation of new agents, such as oxaliplatin and CPT-11, into adjuvant chemotherapy programs [1].
• FDA evaluating oxaliplatin for advanced colorectal cancer treatment [2].
• The extent of hypersensitivity varied among agents, with ratios of inhibitory concentration 50% ranging from 2-fold for oxaliplatin to 14-fold for melphalan, a drug infrequently used in solid tumors [3].
• The action of fludarabine on the removal of oxaliplatin ICLs was explored to investigate the mechanism by which oxaliplatin toxicity was increased by fludarabine [4].
• Fludarabine increases oxaliplatin cytotoxicity in normal and chronic lymphocytic leukemia lymphocytes by suppressing interstrand DNA crosslink removal [4].

Psychiatry related information on oxaliplatin

• The most effective current regimen for adjuvant treatment of surgically resected stage III colon cancer is the FOLFOX regimen of oxaliplatin, 5-FU and LV for 12 weeks, with a proportional risk reduction of 45% compared with approximately 36% for 5-FU/LV regimens [5].

High impact information on oxaliplatin

• CONCLUSIONS: The GSTP1 Ile(105)Val polymorphism is associated in a dose-dependent fashion with increased survival of patients with advanced colorectal cancer receiving 5-FU/oxaliplatin chemotherapy [6].
• Furthermore, with schedule B, the mean dose of oxaliplatin (P less than .001) and its maximum tolerated dose (P = .06) could be increased by 15% over those doses with schedule A [7].
• Unexpectedly, tetraploid cells were more resistant to DNA damaging agents (cisplatin, oxaliplatin and camptothecin) than their diploid counterparts, and this difference disappeared upon inhibition of p53 or knockdown of p53-inducible ribonucleotide reductase [8].
• We postulate that potentiation of oxaliplatin toxicity by fludarabine may be due to the inhibition by fludarabine of the activity of the DNA excision repair pathways activated by oxaliplatin adducts [4].
• Furthermore, strong correlations between the microarray and real-time RT-PCR measurements of average fold changes in gene expression were observed for both the 5-FU (R(2) > or = 0.73) and oxaliplatin gene sets (R(2) > or = 0.63) [9].

Chemical compound and disease context of oxaliplatin

• PURPOSE: To investigate the efficacy and toxicity of oxaliplatin, a diaminocyclohaxane platinum derivative with incomplete cross-resistance to cisplatin in patients with relapsed or cisplatin-refractory germ cell cancer [10].
• XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer [11].
• PURPOSE: To evaluate the efficacy and tolerance of combined irinotecan and oxaliplatin in patients with advanced colorectal cancer pretreated with leucovorin-modulated fluoropyrimidines [12].
• Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: final results of a GERCOR multicenter phase II study [13].
• Randomized multicenter phase II trial of oxaliplatin plus irinotecan versus raltitrexed as first-line treatment in advanced colorectal cancer [14].

Biological context of oxaliplatin

• Analysis of oxaliplatin damage revealed that fludarabine enhanced accumulation of interstrand crosslinks (ICLs) in specific regions of the genome in both populations, but to a lesser extent in normal lymphocytes [4].
• Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors: results of two independent phase I studies with pharmacokinetics [15].
• KRAS(D13) Promotes apoptosis of human colorectal tumor cells by ReovirusT3D and oxaliplatin but not by tumor necrosis factor-related apoptosis-inducing ligand [16].
• In plasma, oxaliplatin was unchanged at 0.5 h, but at 1 h, 30% of the total platinum in plasma was in a peak which had identical retention to that of (trans-1,2-diaminocyclohexane)dichloroplatinum(II), the major biotransformation product of tetraplatin [17].
• Because of the unusual neurosensory toxicity of oxaliplatin, detailed neurologic examination, needle electromyography (EMG), and nerve conduction studies (NCS) were performed before and the day after oxaliplatin in a subset of 13 patients [18].

Anatomical context of oxaliplatin

• Additive interaction of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines results from inhibition of nuclear factor kappaB signaling [19].
• When oxaliplatin was incubated in whole blood (5, 10, and 20 micrograms/ml), the erythrocytes took up 37.1 +/- 2.1% of the total platinum in 2 h (maximum uptake) which was not exchangeable into plasma [17].
• CONCLUSION: Considering the particularly unfavorable prognostic characteristics of this patient population compared with patients from previous trials for new drugs in germ cell cancer, eg, paclitaxel and gemcitabine, a 13% overall response rate and a 19% response rate in the group treated with oxaliplatin 130 mg/m(2) seems to be of interest [10].
• Acute oxaliplatin-induced peripheral nerve hyperexcitability [18].
• Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer [12].

Associations of oxaliplatin with other chemical compounds

• PATIENTS AND METHODS: Patients were treated in a phase I study designed to establish the maximum-tolerated dose of capecitabine given with oxaliplatin [18].
• For N9741, these rates were 3.5% (10 of 289) for IFL, 1.1% (three of 277) for oxaliplatin plus bolus and infusional 5-FU and leucovorin, and 1.1% (three of 275) for oxaliplatin plus irinotecan [20].
• The pharmacokinetics of both raltitrexed and oxaliplatin was assessed at the last three dose levels [21].
• Carboplatin and oxaliplatin treatment led also to stabilization of p53, whereas none of the platinums changed p73 levels [22].
• Chemotherapy was oxaliplatin 80, 100, or 130 mg/m2 2-hour infusion on day 1 followed by L-folinic acid 100 mg/m2/d intravenous bolus, and 5-FU 350 mg/m2/d continuous infusion on days 1 to 5 (FolfoR1) [23].

Gene context of oxaliplatin

• MSH2-/- tumors were significantly less responsive to cisplatin than MSH2+/+ tumors, whereas there was no difference in sensitivity to oxaliplatin [24].
• In oxaliplatin-resistant cells, we noted increased mRNA levels of the nucleotide excision repair gene ERCC1 and ATP-binding cassette transporter breast cancer resistance protein [25].
• CTR1-deficient cells also demonstrated impaired accumulation of the DDP analogs carboplatin, oxaliplatin, and ZD0473 [cis-amminedichloro(2-methylpyridine) platinum (II)] [26].
• In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR [27].
• At a high TS and/or DPD, patients were stratified to receive a combination of oxaliplatin and irinotecan [28].

Analytical, diagnostic and therapeutic context of oxaliplatin

• PURPOSE: The purpose of this study was to establish the feasibility and efficacy of preoperative radiotherapy (RT) with concurrent capecitabine and oxaliplatin (XELOX-RT) in patients with rectal cancer [29].
• Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer [30].
• This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point [31].
• PATIENTS AND METHODS: Patients with a performance status (PS) of < or = 2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks [15].
• CONCLUSION: These data in a heavily pretreated patient population confirm that oxaliplatin is safe when used as a single agent or with a variety of FU-based regimens as salvage therapy in patients with advanced colorectal cancer [32].

References