The Basal And Clinical Study In The Chemotherapy Regimen Of Cisplatin-based Chemotherapeutic Agents With Toremifene For NSCLC

Objective Triphenylethylene toremifene(TOR) is a new anti-oestrogenreceptor drug. Some researchers have found that high-dose TOR can reinfOrcesensitivity of tUmor cells to chemotherapy drugs and thus enhance thecytotoxicity of cisplatin. This stUdy aims at evaluating the activity of TORand its synergistic effect with cisplatin on human lung adenocarcinoma cellline A549. In order to demonstrate the mechanism, we measured the plasmaconcentration of TOR in all our subjiects to determine the optimal dosage,observe possible toxicities and to evaluate the curative effect expected so as toprovide a new theraPeutic mode fOr the cIinical management of lung cancerMethods 1. The cytotoxic effects of cisplatin combined with TOR onhuman lung cancer cell line A549 were measured by a tetrazolium-basedvolorimetric assay (Mn assay).The cell cycle was analyzed by the flowcytometer technology. Expression levels of P2l and P53 were determined byWestern blot in order to find out possible mechanism. 2. Twenty NSCLCpatients who never received treatment previously were randomized into 2equal grouPs: one grouP was treated by NP chemotheraPy rigemen[c ispl atin(DDP )+v inere lb in(N'VB )] al on e, the oth er group was tre ate d byNP+TOR scheme. Serum levels of TOR were measured usinghigh-porformance liquid chromatography (HPLC). Drug toxicity andresponse rate were evaluated by a criterion formulated by WHO.3. Anothertwenty patients who were resistent to platinum-based chemotherapeutic agents were treated by cisplatin-based chemotherapy comibined with TOR (480mg/d or 360mg/d). Serum levels of TOR were measured by HPLC. Toxicity and response rate were also evaluated. Results 1. TOR can inhibit the growth of A549 cell, and at serum levels of 5 u M it can significantly enchance cytotoxicity of cisplatin. Compared with DDP only group, S-G2 phase cells treated with DDP+TOR 'decreased significantly.Gl phase cells stagnated. The cell expression of P21 was increased,but that of P53 was not. 2. In the ten NSCLC patients who were on NP+TOR chemotherapy regimen, the response rate was 50%, however, in the patients treated by NP regimen alone, the response rate was 40%.There was no statistically significant difference. 3. The twenty patients who were resistant to platinum and with mean plasma concentration of TOR of >5 y M.,were evaluated for their response rate as follows: (PR+CR) 15%.Toxicity was well tolerated. Conclusion TOR(>5 U M) combined with cisplatin shows significant synergistic anti-tumor effect on A549 cells. The results also indicate that targeted TOR serum levels can be achieved clinically with 360mg oral daily dose in combination with cisplatin and are well tolerated. The mechanism of its action may be related to the change of phase which occurs during cell cycle,and which is blocked by cisplatin, and could be associated with P21 induction and may involve a P53-independent pathway. So in conclusion, it can be said that high-dose(360mg, dl-7) toremifene plus DDP is feasible, active and well-tolerated in NSCLC patients.