title: Aphidicolin markedly increases the in vitro sensitivity to ara-C of blast cells from patients with AML.
abstract: Drug resistant cells often have an increased capacity to repair their DNA after damage by cytotoxic agents. Aphidicolin can inhibit this DNA repair. We describe a study of the effect of aphidicolin to modulate the sensitivity to cytotoxic drugs of blast cells from 13 patients with AML, 11 with de novo disease on presentation and 2 secondary to MDS. Three patients had relapsed following previous therapy and samples were received from 1 patient both on presentation and relapse. Blast cells were exposed to anthracyclines, antimetabolites or etoposide +/- aphidicolin (15 microM) for 48 hours. The MTT assay was used to measure cell survival and the LC50 (concentration of drug required for 50% cell kill) was calculated. Overall, there was a significant increase in sensitivity to ara-C on co-incubation with aphidicolin in 12/14 samples (p = 0.007). The median increase in sensitivity was 3.88-fold (range 1.26- to 80-fold). Interestingly, when patients were grouped according to in vitro sensitivity to ara-C, cells from resistant patients demonstrated the greatest increase in sensitivity (median 14-fold compared to 2-fold for the sensitive group, p = 0.02). Despite the documented evidence for altered DNA repair as a mechanism of resistance to the topoisomerase II inhibitors, we found no significant increase in sensitivity to daunorubicin, doxorubicin or etoposide on co-incubation with aphidicolin. Nevertheless, we believe the unparalleled modulation of ara-C warrants further investigation.
authors.affiliation: Pembury Hospital, Kent, United Kingdom.
authors.forename: J M
authors.initials: JM
authors.lastname: Sargent
authors.forename: A W
authors.initials: AW
authors.lastname: Elgie
authors.forename: C J
authors.initials: CJ
authors.lastname: Williamson
authors.forename: C G
authors.initials: CG
authors.lastname: Taylor
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity*; D016590:Aphidicolin / Q000494:pharmacology*; D001752:Blast Crisis / Q000473:pathology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects*; D003561:Cytarabine / Q000633:toxicity*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005047:Etoposide / Q000633:toxicity; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D003561:Cytarabine; D016590:Aphidicolin; D005047:Etoposide