Assessment of purging with multidrug resistance (MDR) modulators and VP-16: results of long-term marrow culture.
We studied the effects of two modulators of multidrug resistance (MDR), cyclosporine and verapamil, on the cytotoxicity of etoposide (VP-16) in normal bone marrow cells. VP-16 was toxic to normal bone marrow at concentrations greater than 50 microM, resulting in no granulocyte-macrophage colony-forming units (CFU-GM) in short-term methylcellulose cultures. However, in long-term marrow cultures (LTMC) treatment with VP-16 without the addition of MDR modulators resulted in only a twofold decrease in total cell number at a VP-16 concentration of 50 microM, compared to media alone in the adherent cell layer, and approximately 20% recovery of CFU-GM. The addition of MDR modulators did not result in excessive cytotoxicity, reducing the total CFU-GM by two- to threefold even at the higher VP-16 concentration. Therefore, these modulators in conjunction with VP-16 can be safely used on normal bone marrow cells and may provide an effective method to purge MDR-tumor cells.
Aihara
M
M
Stanford University Medical Center, CA 94305.
Sikic
B I
BI
Blume
K G
KG
Chao
N J
NJ
D001854:Bone Marrow Cells; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003524:Cyclosporins / Q000494:pharmacology*; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology*; D006098:Granulocytes / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D008264:Macrophages / Q000166:cytology; D008747:Methylcellulose; D014700:Verapamil / Q000494:pharmacology*
D003524:Cyclosporins; D005047:Etoposide; D008747:Methylcellulose; D014700:Verapamil