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- Title
Reversal of cytosine arabinoside (ara-C) resistance by the synergistic combination of 6-thioguanine plus ara-C plus PEG-asparaginase (TGAP) in human leukemia lines lacking or expressing p53 protein.
- Authors
Fu, Cecilia H.; Martin-Aragon, Sagrario; Weinberg, Kenneth I.; Ardi, Veronica C.; Danenberg, Peter V.; Avramis, Vassilios I.; Fu, C H; Martin-Aragon, S; Weinberg, K I; Ardi, V C; Danenberg, P V; Avramis, V I
- Abstract
<bold>Background: </bold>Sequence-specific combinations of purine analogs, such as fludarabine or 6-mercaptopurine (6-MP), administered prior to cytosine arabinoside (ara-C) have been shown to abrogate ara-C resistance in human leukemia cells in vitro and in patients with relapsed acute myeloid or lymphoblastic leukemias. The two-drug combination of 6-MP plus ara-C results in greater cytotoxicity than that achieved with either ara-C or 6-MP alone. Further preclinical investigations have shown that the addition of PEG-asparaginase (PEG-ASNase) to the combination of 6-MP plus ara-C (6-MP + ara-C + PEG-ASNase) results in 15.6-fold synergism over that achieved with the two-drug regimen. This is due to increased DNA damage leading to apoptotic cell death.<bold>Purpose: </bold>Since the intravenous preparation of 6-MP is no longer available and since oral 6-thioguanine (6-TG) provides higher levels of intracellular thioguanine nucleotides than an isotoxic dose of oral 6-MP, we investigated the potential drug synergism of 6-TG plus ara-C plus PEG-ASNase (TGAP) in myeloid (HL60/S, HL60/SN3, U937) and lymphoblastic (CEM/0, CEM/ ara-C/B, CEM/ara-C/I, MOLT-4) leukemia cell lines. The CEM clones, MOLT-4 and HL60/SN3 cell lines expressed functional or measurable p53 protein, while the other cell lines did not.<bold>Methods: </bold>The MTT and trypan blue dye exclusion assays were used to determine drug cytotoxicity. In addition, cellular apoptosis and cellular p53, p21/waf-1 and bcl-2 protein concentrations were determined by FACS analysis and ELISA assays.<bold>Results: </bold>Sequential exposure to 6-TG (24 h) plus ara-C (24 h) plus PEG-ASNase (24 h) produced 1.3- to 18.3-fold drug synergism over the two-drug combination of 6-TG plus ara-C. The molecular mechanism of synergism was due to the fact that the three-drug combination was capable of downregulating bcl-2 oncoprotein levels in these cell lines even when p53 was absent.<bold>Conclusion: </bold>These studies strongly demonstrate that the TGAP regimen is highly synergistic in p53-null and p53-expressing leukemia cell lines. We conclude that this combination regimen is collaterally sensitive with ara-C and further evaluation in an investigational phase I trial in relapsed leukemia patients is warranted.
- Subjects
CELL culture; LEUKEMIA; CANCER; NUCLEIC acids; CELL death; LYMPHOBLASTIC leukemia; LYMPHOCYTIC leukemia; DNA damage; CANCER chemotherapy; ANTINEOPLASTIC agents; APOPTOSIS; ASPARAGINASE; COMPARATIVE studies; DRUG resistance in cancer cells; DRUG synergism; CLINICAL drug trials; RESEARCH methodology; MEDICAL cooperation; POLYETHYLENE glycol; PROTEINS; PURINES; RESEARCH; RESEARCH funding; EVALUATION research; MYELOID leukemia; CYTARABINE; CANCER cell culture; PHARMACODYNAMICS
- Publication
Cancer Chemotherapy & Pharmacology, 2001, Vol 48, Issue 2, p123
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s002800100289