Intensification of anti-cancer chemo-therapy effect of cyclophosphamid by using a hybrid anti-inflammatory drug – nitrate salt of diclofenac hydroxamic acid

We investigate hybrid non-steroidal anti-inflammatory drugs (NSAIDs), nitrate salt of diclofenac hydroxamic acid (DHA HNO 3), synthesized at the Institute of Problems of Chemical Physics (IPCP), Russian Academy of Sciences. The compound contains a typical anti-inflammatory drug NSAID, an inhibitor of cyclooxygenase (COX) activity, the hydroxaxamic group, an inhibitor of peroxydase (PO) activity, and is a donor of the nitric oxide (NO) formed in the process of HNO 3 reduction. In the present study we suggest to investigate a combined action of cytostatic cyclophosphamid (CP) and DHA HNO 3 on anti-cancer activity. We show that chemosensibilization effect of combined PC and DHA HNO 3, with therapeutic doses of PC, leads to 100 % healing of animals with leukemia P-388. Using ESR technique, we investigate the ESR signal of the active form of cyt P-450 in mouse liver samples after application of DHA HNO 3. We find that application of DHA HNO 3 leads to formation of nitrosyl cyt P-450-NO complexes, resulting in a decrease in the ESR signal of cyt P-450 within the five hours after application. The formation of P-450-NO complexes is related to nitric oxide formation in the process of HNO 3 reduction. We suggest that due to the formation of NO, the prolonged inhibition effect of cyt P-450 results in the enforced chemo-therapeutic activity of CP within the first few hours of application. We conclude that the application of the hybrid nitrate salt of diclofenac hydroxamic acid DHA HNO 3 can lead to the enforced chemo-therapeutic effect of CP and 100 % healing of animals.