The Analysis Of The Expression Of Asparagine Synthetase And The Efficacy Of Asparaginase-based Chemotherapy Among ENKTL Patients

Part I The efficacy of asparaginase-based chemotherapy among stage ⅠE/ⅡE ENKTL patientsBackgroundExtranodal NK/T-cell lymphoma, nasal type (ENKTL) is a subtype of Non-Hodgkin lymphoma, which is associated with Epstein-Barr Virus (EBV) infection. The characteristic pathology is angiocentricity and angiodestruction on the background of extensive necrosis, with typically CD2+,CD56+,surface CD3-and cytoplasmic CD3(CD3ε)+. Clinically, the primary sites involved are usually nose and nasopharynx, the localized ENKTL can disseminate to gastrointestinal tract, skin and bone marrow. Because of the low incidence, especially in Western countries, standard therapy for localized ENKTL remains to be established. ENKTL cells are quite sensitive to radiotherapy, however, the addition of CHOP or CHOP-like regimens to radiotherapy do not appear to confer any benefit in stage ⅠE/ⅡE ENKTL patients. It’s controversial whether to add CHOP or CHOP-like chemotherapy to radiotherapy. This may result from the P-glycoprotein (P-gp) encoded by multidrug resistance (MDR) gene, which can transport drugs out of cells, thus decreasing the intracellular concentration of drugs. L-asparaginase (L-ASP) is a P-gp independent drug with particular mechanism. It can catalyze the hydrolysis of asparagine to aspartic acid, and the depletion of asparagine results in the inhibition of DNA and protein synthesis of tumor cell and subsequent cell apoptosis. According to previous studies, ASP-based chemotherapy plus radiotherapy is very promising among ENKTL patients.ObjectiveExplore whether the addition of ASP-based chemotherapy to radiotherapy can bring any benefit to stage ⅠE/ⅡE ENKTL patients.MethodsWe retrospectively analyzed100consecutive and non-selected stage ⅠE/ⅡE ENKTL patients from Xiangya Hospital and Affiliated Cancer Hospital of Xiangya School of Medical of Central South University during May2008and may2013. Compared the efficacy between RT group (radiotherapy), RT+CHOP group (CHOP or CHOP-like chemotherapy plus radiotherapy), RT+ASP group (ASP-based chemotherapy plus radiotherapy).ResultsThe results showed that RT group and RT+CHOP group have no difference in both response and survival. The ORR from RT+ASP group (87.6%) is significantly higher than that in RT group (66.6%) and RT+CHOP group (64.5%)(P=0.042,0.015respectively). The1-year progression-free survival (PFS) rate was significantly higher in RT+ASP group (54.1%) than in RT group (28.6%) and RT+CHOP group (22.6%)(P=0.0498,0.0054respectively).ConclusionASP-based chemotherapy plus radiotherapy can improve the treatment results among stage ⅠE/ⅡE ENKTL patients, however, there is no benefit from the addition of CHOP or CHOP-like chemotherapy to radiotherapy. Part II The relationship between asparagine synthetase and asparaginase efficacy among ENKTL patientsBackgroundThe normal cells can synthesize asparagine through asparagine synthetase. However, tumor cells like acute lymphoblastic leukemia and ENKTL express low asparagine synthetase, which makes them have no choice but to rely on the exogenous asparagine. The anti-tumor mechanism of L-ASP is to hydrolyze asparagine in plasma into aspartic acid and ammonia, which results in the inhibition of DNA and protein synthesis of tumor cells. The previous clinical studies showed that the CR rate of the RT+ASP group was only47.9%, and the ORR rate was87.6%, which suggests that some patients were resistant to this regimen. There are reports that support ASNS as a predictor of L-ASP efficacy among ovarian cancer and acute lymphoblastic leukemia.ObjectiveExplore the relationship between the expression of ASNS and the efficacy of ASP-based regimens among stage ⅠE/Ⅱ E ENKTL patients.MethodsWe collected samples from32stage Ⅰ E/ⅡE ENKTL patients and detected the mRNA and protein expression level of ASNS through PCR and western blot, compared the expression of ASNS mRNA and protein between groups with different response, and studied the relationship between the ASNS expression and survival through Spearman Rank Correlation.ResultsThe results showed that the expression of both ASNS mRNA and protein is lower in patients with better reponse than patients with worse reponse. What’s more, the mRNA and protein were both highly negatively correlated with OS and PFS (rs:-0.65,-0.60for mRNA;-0.77,-0.71for protein), and the correlation between protein and asparaginase efficacy was stronger than that between mRNA and asparaginase efficacy. This might because ASNS protein is directly responsible for the synthesis of asparagine.ConclusionThis study indicate that the expression of ASNS, especially the protein expression level, can serve as a predictive marker for the asparaginase efficacy among stage ⅠE/ⅡE ENKTL patients.