Nitric oxide donor increases the efficiency of cytostatic therapy and retards the development of drug resistance.
The potentiality to increase the chemotherapeutic effectiveness of some cytostatics in low, subtherapeutic doses in combination with nitric oxide (NO) donor has been shown. This type of combined therapy results in significant increase in life span and number of survivors among mice bearing leukemias P388 and L-1210. A similar effect was observed for intracerebral leukemia P388 transplantation. In this case the life span of mice treated with cyclophosphamide and NO donor increased by three times in comparison to therapy with cyclophosphamide alone. The coinjection of nitric oxide donor and cytostatics improved the antimetastatic activity of the cytostatics: the index of melanoma B16 metastasis inhibition at the cyclophosphamide monotherapy is 50%; on addition of NO donor the index is over 80%. Comparative studies of NO donor (organic nitrate) and a similar compound in which ONO(2) moieties were replaced by OH groups demonstrated that the presence of NO(2) is required for adjuvant activity of compounds and confirmed that nitric oxide modifies the antitumor effects of cytostatics. It is shown also that nitric oxide donor retards the development of drug resistance to cyclophosphamide.
Konovalova
N P
NP
Institute of Problems of Chemical Physics, Russian Academy of Sciences, 142432 Chernogolovka, Moscow Region, Russia. ninap@icp.ac.ru
Goncharova
S A
SA
Volkova
L M
LM
Rajewskaya
T A
TA
Eremenko
L T
LT
Korolev
A M
AM
D000008:Abdominal Neoplasms / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004988:Ethers, Cyclic / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
C479364:3,3-bis(nitroxymethyl)oxetane; D000970:Antineoplastic Agents; D004988:Ethers, Cyclic; D020030:Nitric Oxide Donors; D004317:Doxorubicin; D003520:Cyclophosphamide; C479363:3,3-bis(hydroxymethyl)oxetane; D002945:Cisplatin