Aphidicolin markedly increases the in vitro sensitivity to ara-C of blast cells from patients with AML.
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.
Sargent
J M
JM
Pembury Hospital, Kent, United Kingdom.
Elgie
A W
AW
Williamson
C J
CJ
Taylor
C G
CG
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
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D003561:Cytarabine; D016590:Aphidicolin; D005047:Etoposide