[Possibility of overcoming of ACNU resistance in an ACNU-resistant subline of C6 rat glioma].
Membrane-modifying agents such as reserpine, calcium antagonists (nicardipine, verapamil) and calmodulin inhibitor (trifluoperazine) were found to enhance the cytotoxicity of ACNU in vitro and in vivo in ACNU-resistant C 6 (C 6/ACNU) glioma. In in vitro experiments, uptake and retention studies with [14C] ACNU revealed that intracellular uptake and retention of ACNU in C 6 cells were larger than those in C 6/ACNU cells, and that these membrane-modifying agents increased the cellular uptake and retention of ACNU in C 6, especially in C 6/ACNU cells. The amount of ACNU in C 6/ACNU cells reached the same level as that detected in C 6/ACNU cells. When these drugs were added along with ACNU at the concentration of 10 to 20 microM to the culture in vitro, ACNU resistance was completely overcome. In in vivo experiment, reserpine, nicardipine, verapamil and trifluoperazine in doses 250 to 500 micrograms/kg intrathecally administered with 1 mg/kg ACNU 1 day after the tumor inoculation significantly enhanced the chemotherapeutic effect of ACNU in C 6/ACNU bearing (C 6/ACNU-MG) rats. It might be concluded that the mechanism of enhancement of ACNU cytotoxicity presented in in vitro and in vivo is explained by the enhanced accumulation of ACNU by these membrane-modifying agents in C 6, especially in ACNU-resistant (C 6/ACNU) cells, and, furthermore, that combination chemotherapy with ACNU and such membrane interacting drugs as reserpine, calcium antagonists (nicardipine, verapamil) and calmodulin inhibitor (trifluoperazine) could lead to the capability of overcoming resistance to ACNU in glioma.
Yoshida
T
T
Shimizu
K
K
Ushio
Y
Y
Mogami
H
H
Sakamoto
Y
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D002478:Cells, Cultured; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009529:Nicardipine / Q000494:pharmacology; D015376:Nimustine; D009607:Nitrosourea Compounds / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012110:Reserpine / Q000494:pharmacology; D014268:Trifluoperazine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D015376:Nimustine; D014268:Trifluoperazine; D012110:Reserpine; D014700:Verapamil; D009529:Nicardipine