Differential in vitro sensitivity of human tumor and normal cells to chemotherapeutic agents and resistance modulators.
The intrinsically Vincristine(Vcr)-resistant human kidney adenocarcinoma cell line ACHN, the human acute lymphoblastic leukemia cell line L0, its more-than-100-fold Vcr-resistant subline LI00, normal human fibroblasts and lymphocytes, also tumor cells from patients with chronic lymphocytic leukemia (CLL), acute myeloblastic leukemia (AML) and solid tumors, were compared for sensitivity to cytotoxic drugs and resistance modulators (RMs). The LI00 cells showed pronounced sensitivity to the RMs verapamil (Ver), cyclosporin A (CsA) and buthionine sulfoximine (BSO) alone as well as to cisplatinum, whereas the L0 and ACHN cells, also slowly growing fibroblasts and non-proliferating lymphocytes, were considerably less sensitive. Compared with AML cells and lymphocytes, CLL cells were more sensitive to Ver and CsA alone. The cytotoxicity of Vcr was significantly increased in the Vcr-resistant ACHN and LI00, but also in sensitive L0 cells by Ver and CsA, with smaller effects on Dox and Vp-16 toxicity. Fibroblasts and lymphocytes were generally resistant to the cytotoxic agents and RM addition had only minor effects. CLL cells were more sensitive to Dox and Vcr as compared with normal lymphocytes, with potentiation of the Vcr effect by Ver and CsA. The Vcr effect in non-proliferating Vcr-resistant cells from a malignant schwannoma was potentiated by Ver and CsA, which had no effect in cells from a kidney adenocarcinoma. We conclude that cytotoxicity of RMs alone is not dependent on the proliferation rate of tumor cells and that potentiation of cytotoxic drugs by RMs may be selective for tumor cells irrespective of their initial level and mode of drug resistance.
Nygren
P
P
Department of Oncology, University Hospital, Uppsala University, Sweden.
Larsson
R
R
D000230:Adenocarcinoma / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019328:Buthionine Sulfoximine; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology; D007700:Kinetics; D007938:Leukemia / Q000097:blood / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009442:Neurilemmoma / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D003524:Cyclosporins; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D014700:Verapamil; D002945:Cisplatin