OBJECTIVE?To brief the pharmacological and clinical studies of oxaliplatin.
METHODS:The advances in the study of oxaliplatin were reviewed.
RESULTS:Oxaliplatin has an anticancer spectrum different from cisplatin and has no cross-resistance with cisplatin. A better result has been obtained in treatment of advanced colorectal cancer with oxaliplatin alone or in combination with 5-fluorouracil and folinic acid with mild ADRs in comparison with cisplatin.
CONCLUSION:Oxaliplatin is a promising anticancer drug in chemotherapy but further studies seem to be needed.
??KEY WORDS?Oxaliplatin; Cisplatin; Colorectal cancer; Phase? clinical trial
??Cisplatin (DDP) came into being, national preparation DDP new derivatives to researchers for many years tried to mitigate its serious renal toxicity. 1981 carboplatin (CBP) to clinical, but its role in bone marrow suppression limits its widespread application. 1,2-second ammonia cyclohexane (Dach) the amino group instead of the DDP, other groups with an anionic residues instead of the chlorine atoms, preparation of a set of Dach derivatives, from which their separation left TRANS compounds Oxaliplatin (oxaliplatin,L-OHP).
??L-OHP is a third generation Platinum compounds, chemical name l-TRANS-cyclohexane second ammonia Oxaliplatin, internationally called Oxaliplatin. Structural formula shown in Figure 1, molecular formula is C8H14N2O4Pt, molecular weight 397.33. It is a white crystalline powder, slightly soluble in water, sparingly soluble in methanol, and insoluble in ethanol and acetone. Injection packing 50,100 mg/bottle respectively. Japan scholar through the United States National Institute of cancer cell lines filter found L-OHP on mouse leukemia L1210 effective, France?s Roger Bellon and Rhone-Poulence firms have completed preliminary studies and phase ? clinical trial of L-OHP, are from Switzerland virtue young Tiger drug companies and France sanofi company continues to develop.
??1 preclinical study
??L-OHP the same pharmacological properties as the other Platinum, to DNA as the target of the site, Platinum Atom with a DNA chain formation of Crosslinking, thus blocking its replication and transcription. Characteristics of L-OHP combination with DDP DNA Dynamics, however there are obvious differences. DDP DNA binding kinetics characteristics of bidirectional, that is, combining fast required 15 min, combining slow needed 4~8 h, and L-OHP is within a 15 min to complete a full combination of DNA. L-OHP same with DDP?s role in the inhibition of RNA synthesis.
??L-OHP in vitro testing for a variety of people, the rat tumor cell lines with antitumor activity, on the human colon, ovarian cancer and melanoma cell line inhibits proliferation, fluorouracil (5-Fu) effective resistance HT29 CaCo2 colon cancer cells. No cross resistance between the L-OHP and DDP, DDP A2780 human ovarian cancer cell lines, HT29 has resistance of colon cancer cell lines are valid. In colon cancer cells HT29 and CaCo2 in vitro, L-OHP and 5-Fu combined synergy and DDP and 5-Fu without this effect. Platinum moles in doses of the same case, the effect of L-OHP on mouse model of DDP and at least the same, also valid for the DDP-resistant tumor cells, such as L1210, LCD (1). Combined with the mouse model study found that L-OHP and cyclophosphamide, 5-Fu, silk Mitomycin, DDP and CBP have synergy. United States National Cancer Institute on DDP and L-OHP activity of anticancer drug screening Center study found that two different tumor resistance spectrum, no cross tolerance with each other, L-OHP can be used to resist or DDP and DDP combination (2,3).
??In mice and rabbits who carried out a study on the pharmacokinetics. Mice after intravenous injection of L-OHP, total plasma clearance can be divided into fast distribution of Platinum (T1/2=2.3 min) and slow (T1/2=49 min). Injection after 24 h, total Platinum distribution within your organization to the spleen, kidney, colon as the highest, very little content in brain tissue. Intravenous injection in rabbits after single-dose DDP or L-OHP, which can be measured to within 60 min of medication free Platinum and ultra-filtration of Platinum, while the latter is to measure after 90min. L-OHP total dissection of the renal clearance rate, rate, plasma protein binding rate is greater than the DDP.
??Toxicology studies in dogs found mild hematologic and gastrointestinal toxicity, maximum doses have mild renal dysfunction, atrial fibrillation appears under the lethal dose (not seen in other animals ? hearts), above toxicity are significantly lower than the DDP (4).
??2 clinical study
??2.1 phase ? clinical trial of L-OHP pharmacokinetics are similar to DDP, described two-compartment model available, rapid distribution phase, eliminate slow, half-life for 24 h. Measured residual Platinum after 3 weeks of medication, final discharge phase is very long. In the human body when intravenous 130 mg/m2 within 2 h, total Platinum plasma peak was 5.1 ? g/ml. At the end of infusion, 50% of the L-OHP and red blood cells, and 50% remained within the plasma. L-OHP 75% in plasma and plasma protein binding. This product is mainly through urine excretion, delivery within 48 h after 45% it is urine discharge, d 11 discharges urine 57%. Fecal excretion rate is very low, only after 11 d (5%).
??In 1984, France and Japan to phase I clinical trials, evaluation of multiple medications, a total of 125 patients to participate in. Incidence of hematological toxicity study found that L-OHP is not high, and a number of mild to moderate. Same with the other Platinum compounds, when L-OHP>45 mg/m2, most of the patients with nausea and vomiting, diarrhea is not common. Correlation between L-OHP Dose-limiting toxicity is dose, cumulative, irreversible peripheral nerve disorders, mainly as insensitive and/or extremities numbness, occur in the pharynx and numbness of the mouth of the less seen, cold symptoms can be induced or aggravated, minorities can also occur in patients with functional impairment. No kidney toxicity was found. All groups without toxic death. Phase ? clinical trial of both the preliminary observation of antitumor activity of L-OHP, of which 1 in patients with colon cancer was some (PR). The recommended dose for phase ? clinical 130~135 mg/m2, short-time infusion, repeated every 3 weeks.
??2.2 phase ? and ? clinical trials since 1957, 5-Fu has been the most effective drug for advanced colorectal, developed a variety of 5-Fu derivatives and strengthening agent, transform delivery, choose a different joint programmes, although this has improved the efficacy of advanced colorectal, but there are still quite a distance. Preclinical studies have shown that L-OHP valid for DDP-resistant colon cancer cell line, L-OHP and 5-Fu in mouse models have synergy, 1 colon cancer patients in a phase I trial is PR, L-OHP focus of phase ? clinical observation on curative effect of L-OHP on advanced colorectal. Histological observation of 139 cases confirmed that a total of advanced colorectal cancer in the group, are in progress after 5-Fu therapy, the use of intravenous infusion of L-OHP130 mg/m2,2 h, the effective rate of 10% (6). Tip L-OHP and 5-Fu no cross resistance.
??Phase ? multicenter clinical study on combination, L-OHP and 5-Fu, formyl tetrahydrofolate calcium (FA) combined a total of 437 cases of patients treated, most of which is the progress of chemotherapy. Results show that the L-OHP combined with 5-Fu and the FA have a synergistic effect, easing rate 31%~53%, where 3.5%~5.8% of complete remission (CR). 86 cases of patients undergoing chemotherapy metastases surgical resection, 52 patients may be cured. De Gramont (7) use L-OHP 100 mg/m2,d 1 static points, 5-Fu1.5~2 g/m2,24 h infusion, and FA 500 mg/m2, use 2 d every 2 weeks, progress in the treatment of 46 cases of 5-Fu+FA after treatment metastatic lesions or secondary June recurrence after treatment, the results get PR of 1 cases of CR and 20 cases, effective rate of 46%. Worth noting is that in 22 of these cases advance after 5-Fu+FA treatment in progress, 10 PR (45%). Lifetime no progress in July, median survival period of 1 July. Show L-OHP on treatment of advanced colorectal cancer effects and synergies and 5-Fu/FA. Garufi (8) L-OHP+5-Fu/FA second-line treatment of advanced colorectal cancer in 12 cases on the 5-Fu/FA resistance of, three-line treatment of 13 cases, evaluators, 24 cases, of which 7 are PR (29.2%) to ease the maturity of 8.5 months, median survival in December. L-OHP join may near reversal on drug resistance of 5-Fu/FA in patients with one-third, has a synergistic effect between L-OHP and 5-Fu and/or regulatory role. Levi (9) from July 1993 8 May ~1994 years in Europe for initial treatment of Metastatic Colorectal tumor Centre 98 cases, L-OHP100 mg/m2 and FA during a week/period increased to 1 200 mg/m2,5-Fu dose 2800~3 400 mg, and in accordance with time to adjust to the drug programme, 64 (65.3%) effective, CR4 cases. 12 (12%) found in postoperative swelling subsides, survival of 86% has more than 1 year. Giacchetti, (10) with above 3 kinds of drug by time adjustment to drug treatment 253 cases cannot resection of transfer sexual large colorectal cancer, which 115 cases advance accept had chemotherapy, 63 cases (which 20 cases for second-line chemotherapy, 36 cases was PR,7 cases was CR, effective rate 68%) chemotherapy across operation treatment, full resection 43 cases (68%), part resection 4 cases (6%), failed to resection 16 cases (25%). 7 patients found no tumor after operation, 20 cases of resection margin no tumor, is expected to survive more than 37 months. This high rate of surgery (63/253,25%) and the removal rate (43/253,16%) further confirmed the programme effective in metastatic colorectal, median survival period of the extension shows the effective value of complete resection after chemotherapy.
??Bertheault c (11) in 1994 in the treatment of 50 cases with advanced colorectal cancer, which previously used 5-Fu+FA,13 cases of initial treatment in 37 cases. Results PR of 2 cases of CR,21 cases, remission rate of 46%.
??3 adverse reactions
??3.1 reversible peripheral sensory nerve disease of nervous system toxicity is Dose-limiting toxicity, mainly to feel abnormal and/or extremities numbness, incidence in alone or in combination as 82%,50% as temporary in nature, constant 19%, dysfunction caused by 12%. Toxicity symptoms usually dose-related. Occurs when the amount of up to 135 mg/m2 rate of 54%,150~175mg/m2 to 80%,200 mg/m2 for 100%. As the courses increase, symptoms will also increase. Other symptoms associated with neurotoxicity, such as the throat feel exception or spasms also occur, but dissipated on its own. Cold can be induced or aggravated nerve toxicity (12).
3.2 Although General digestive system toxicity town preventive treatment has been applied, nausea and vomiting are still quite common (13), the incidence of 64.9%, ? and ? degree of toxicity of 10.7%; diarrhoea incidence of 30.4%, ? and ? degree 4%. Mucositis is 6%.
??3.3 hematological toxicity alone using bone marrow toxicity caused by rare. Hemoglobin decrease of 22.4%, ? and ? degree 1.8%; white blood cells to reduce the incidence of 11%, ? and ? degree 0.4%; neutrophil decrease of 9.4%, ? and ? degree 0.8%; thrombocytopenia of 11.1%, ? and ? degree 1.9%.
??3.4 ototoxicity potential ototoxicity with weak, far greater than the DDP as light (14).
??3.5 other incidence of skin toxicity of 1.6%, heat 3.6%, does not apply in the process of injection syncope is 1%, 26% slightly abnormal liver function, see renal anomalies.
??4 discussion
??40 years, for advanced colorectal cancer 5-Fu is the most effective drug, 5-Fu+FA improve efficiency, but improve not ideal for lifetime; in addition, the 5-Fu Foundation to resist, especially the lack of effective drugs. Third generation Platinum antitumor spectra of different compounds L-OHP and DDP, no cross tolerance with each other, for advanced colorectal, especially on the drug resistance of 5-Fu, L-OHP alone or in combination with 5-Fu are showing encouraging results. In addition, this product has good effect on ovarian cancer, non-Hodgkin?s lymphoma, non-small cell lung, head and neck cancer are also valid, no significant kidney toxicity, negligible ototoxicity, haematological toxicity than light, therefore, worthy of further expansion in clinical research.
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