Chemosensitisation of alkylating agents by pentoxifylline, O6-benzylguanine and ethacrynic acid in haematological malignancies.
The effects of resistance modifiers (RM) on the cytotoxicity of mafosfamide (MAF), bis-chloroethylnitrosourea (BCNU) and dacarbazine (DTIC) were evaluated by the MTT colorimetric assay in isolated lymphocytes and blast cells derived from patients with chronic lymphatic leukaemia (CLL; n = 28) and acute myeloid leukaemia (AML; n = 30), or from healthy donors (n = 19). Pentoxifylline (PTX) has been shown to restore sensitivity to alkylating drugs by interfering with DNA repair. PTX (10 microM) significantly sensitised leukaemic blasts to the cytotoxic effect of MAF. In 8 out of 30 AML samples, sensitisation ratios (SRs; i.e. cytotoxic drug ID50s in the presence or absence of RM) for MAF in the presence of PTX were > 2 ranging up to 4.2. Inhibition of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) by O6-benzylguanine (O6-BG; 50 microM) enhanced the cytotoxicity of DTIC in CLL lymphocytes. SRs > 2 for DTIC in the presence of O6-BG were observed in 7 out of 28 CLL specimens. Sensitisation was generally greater in the more chemo-resistant specimens. Ethacrynic acid (EA; 1 microM), an inhibitor of glutathione-S-transferases (GST), failed to influence the cytotoxicity of alkylating agents in any cell type. Also, all examined RMs did not sensitive leukaemic cells to the cytotoxic effect of BCNU. The data show significant chemosensitisation of leukaemic cells to alkylating agents by PTX and O6-BG, indicating a potential clinical use of these substances as RM in patients.
Müller
M R
MR
Department of Internal Medicine, West German Cancer Centre Essen, University of Essen Medical School.
Thomale
J
J
Lensing
C
C
Rajewsky
M F
MF
Seeber
S
S
D000208:Acute Disease; D000477:Alkylating Agents / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity; D001752:Blast Crisis; D002330:Carmustine / Q000633:toxicity; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000633:toxicity; D003606:Dacarbazine / Q000633:toxicity; D004976:Ethacrynic Acid / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000473:pathology*; D007951:Leukemia, Myeloid / Q000097:blood / Q000473:pathology*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D010431:Pentoxifylline / Q000494:pharmacology*; D012016:Reference Values
D000477:Alkylating Agents; D000970:Antineoplastic Agents; C064976:O(6)-benzylguanine; C048341:mafosfamide; D006147:Guanine; D003606:Dacarbazine; D003520:Cyclophosphamide; D004976:Ethacrynic Acid; D010431:Pentoxifylline; D002330:Carmustine