Abstract: The activities of three cytochrome Р450 families involved in metabolic transformation of cyclophosphamide (CP) (CYP2B and CYP2C responsible for metabolic activation of CP and СYP3A responsible for inactivation of CP) have been investigated in lymphosarcoma and liver microsomes of tumor-bearing CBA mice. Two strains of mouse lymphosarcoma distinguished by their sensitivity to cytostatic action of CP were used in this study for implantation in mice femur muscle. There was certain relationship between CP resistance of lymphosarcoma and tumor P450s activity. CYP2В, CYP2C and CYP3А activities in the CP sensitive tumor were comparable to those in liver, and CYP2В, CYP2C were induced by phenobarbital and dexamethasone. CYP2В and CYP2C in the CP resistant tumor were inactive and only slightly induced by dexamethasone. CYP3А activity was lower than in LS tumor and unchanged during drug treatment.
Implantation of LS and RLS tumor in mice caused different effects on P450 activities. LS insigniticantly influenced liver CYP2В, CYP2C and CYP3А activities and their inducibility by phenobarbital and dexamethasone was similar to that obtained in liver of mice without tumor. At the same time, CYP2В and CYP2C activity in liver of RLS-bearing mice were essentially reduced, the activity CYP3А remained unchanged, and inducibility of CYP2B, CYP2C and CYP3A by phenobarbital and dexamethasone was similar to that in liver of mice without tumor. These results prove the role of cytochromes Р450 activating CP in formation drug resistant phenotype of mice lymphosarcoma and suggest possibility of overcoming of this resistance using cytochrome P450 inducers.
Reference: Grishanova A.Y., Kaledin V.I., Zueva T.V., Nehoroshkova E.K., Nikolin V.P., Lyakhovich V.V., CYP2B, CYP2C and CYP3A activity and inducibility in tissue of sensitive and resistance to cyclophosphamide tumors and liver of tumor-bearing mice, Biomeditsinskaya khimiya, 2003, vol: