Xeloda Related Study On Its Clinical Application

【Background and objective】The incidence of breast cancer is raising year by year. According toprediction made be NCI, there will be 180,510 new cases, while 40,910 willdie of it. Meanwhile, great progress has been made about breast cancertherapy, and a comprehensive therapy model has been developed, which hasgreatly raised the 5-year and 10-year survival. Chemotherapy plays a quiteimportant role in fighting with breast cancer, and new chemotherapy drugshave been developed in the past few years. 5-Fu is a kind of traditionalchemotherapy drug treating cancer including breast cancer. It is veryuseful and can be used combining with other chemotherapy drugs. Howevermany kinds of side effects have been observed, for examplediarrhea, baldness, mucositis and so on. These side effects are believed tobe caused by FdUMP, which is a derivative of 5-Fu. Xeloda(Capecitabine) isa drug developed from 5-Fu, but it is activated specially into 5-Fu intissues(especially in cancer tissues) with TPase. Therefore the incidenceof side effects have been greatly decreased. Both Capecitabine and 5-Fuare finally degraded by DPDase, which is the enzyme limiting the wholemetabolic route. DPDase is coded by the gene named DPYD. If there is certainmutation in the gene, the activity of DPDase will be more or less defected.This topic is aimed to further investigate the relationship among theexpression levels of Thymidine Phosphorylase(TPase)/DihydropyrimidineDehydrogenase(DPDase) in breast cancer tissue and normal breast tissuebeside cancer, concentration of Xeloda/5-Fu in vivo and DPYD polymorphismin population of breast cancer patients of Han nationality in Chinaaccording to the patients'clinical appearance, drugconcentration, enzyme activity and relative base sequence. With thepurpose to direct clinical drug selection based on gene and enzyme status. 【Subjects and method】Being of Han nationality, all the subjects come from NorthernChina. For the first part of enzyme activity, it included 2 parts:Xelodagroup involving 26 breast cancer individuals with Xeloda administeredbefore operation, and control group involving 28 breast cancer individualswithout Xeloda administered before operation. For the second part of drugconcentration, 26 individuals are involving to detect the 5-Fu/Xelodaconcentration in plasma and tissue. For the third part, 96 individuals areinvolving to investigate the gene status of DPYD so as to correlate itwith the clinical appearance.After blood and tissue sample were obtained, the enzyme activity wasmeasured with ELISA, and the drug concentration was detected withHPLC. After DNA was extracted, the DPYD*5 and DPYD*9 were sequenced with377 sequencer.【Results】1. TPase is highly expressed in breast cancer tissue (353.649±202.766ng/mg protein),and is expressed at relatively low level (41.803±34.235ng/mg protein) in normal breast tissue beside tumor. There is asignificant correlation between them (F=127.94＞F_0.01(1,50))=7.17, P＜0.01).There is no significant correlation between the Xeloda group andcontrol group for breast cancer and normal breast tissue each.2. DPDase is expressed at the level of 220.017±124.698ng/mg proteinin breast cancer tissue, and at the level of 272.130±333.036ng/mg proteinin normal breast tissue. No significant between the two groups (F=1.16＜F_0.05(1,50)=4.03,P＞0.05).3. The concentration of 5-Fu is 0.4085±0.4361ug/mg(tissue) in breastcancer tissue, and is 0.2521±0.3233ug/mg(tissue) in normal breasttissue. 4. The concentration of Capecitabine is 0.3252±0.2347ug/mg(tissue)in breast cancer tissue, and is 0.2883±0.2006ug/mg(tissue) in normalbreast tissue.5. For DPYD*5, the status of 1627 site(A1627G) is:7G, 31R, 45A, 11N; ForDPYD*9, the status of 84 site(T84C) is: 74T, 18Y, 1N, 1C.【Conclusion】1. Breast cancer patients with B blood group is apt to experienceadverse effect if administered Xeloda. Patients withER(-)/PR(-)/CerbB-2(-) is inclined to suffer from adverse effect.2. TPase is highly expressed in breast cancer tissue, and is expressedrelatively low in normal breast tissue beside tumor. Xeloda dosen't havedefinitive affect on TPase concentration in tissue.3. DPDase is expressed at similar level in breast cancer and normalbreast tissues. And Xeloda dosen't have definitive affect on DPDaseconcentration in tissue.4. At the level of P=0.05, about 5-Fu there is no significantcorrelation between breast cancer and normal breast tissue;while at thelevel of P=0.10, there is significant correlation between them, and thissignificance is caused by TPase.5. About the distribution of Capecitabine there is no significantcorrelaton between breast cancer and normal breast tissue.6. To certain extent, the mutation in the DPYD gene can explain why thereis great difference among individuals about drug concertration and sideeffects. However further research work is warranted in the future.