TRTH-11. EFFICACY OF ASPARAGINASE ERWINIA CHRYSANTHEMI WITH OR WITHOUT TEMOZOLOMIDE AGAINST GLIOMA CELLS AND INTRACRANIAL MOUSE MEDULLOBLASTOMA

摘要

>BACKGROUND: Anti-metabolites are less myelosuppressive than DNA-damaging drugs used for brain tumors, and can be tested for efficacy and less overlapping toxicity if combined. We studied if anti-leukemia agent Erwinaze (which depletes asparagine and glutamine) has antitumor effect with or without temozolomide (TMZ) against brain tumors. >METHODS: Erwinaze, TMZ, and their combinations were tested against malignant glioma and medulloblastoma cells, neurospheres, and against SMO/SMO mouse model (typically succumbing from spontaneous medulloblastoma). MTT cell viability assays were used for dose-response curves. Mice survival and weight loss were used as efficacy and toxicity surrogates, respectively. >RESULTS: Erwinaze monotherapy showed dose-dependent cytotoxicity against 4 tested cell lines with range of IC50s 0.1->10 IU/ml. Erwinaze at <1 IU/ml concentrations synergized with TMZ against cells with 1.5–4 fold decrease of TMZ IC50s (range 100-1000uM). Glutamine supplementation at 1 and 10 mmol/L concentrations counteracted Erwinaze cytotoxicity in dose-dependent manner. Neurospheres treated with Erwinaze also showed dose-dependent reduction (IC50s: 0.1–3 IU/ml). Four groups of 7 week-old SMO/SMO mice were treated with 3 cycles of 10 IP injections of DMSO (control), TMZ, Erwinaze, and combination (n=30, 6 in control and 8 in each of treatment groups). Preliminary analysis 17 weeks after initiation of therapy shows trends towards 35% survival advantage of mice receiving Erwinaze (with or without TMZ), compared to those that didn’t (p=0.08). Temozolomide alone didn’t improve survival of SMO/SMO mice (5/8 succumbed), and resulted in 10% less weight compared to other groups. Immunohistochemistry of brains and complete statistical analyses are pending. >CONCLUSION: Erwinaze is effective against brain tumor cells in vitro and may enhance cytotoxicity of TMZ. Erwinaze may improve survival of SMO/SMO mice used with or without TMZ per preliminary data. The Erwinaze effect maybe due to glutamine depletion behind blood-brain barrier. Non-increased toxicity, as measured by weight, justifies further testing of conceptually similar combinations.