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Preclinical Evaluation of Gemcitabine Combination Regimens for Application in Acute Myeloid Leukemia Ryan H

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Preclinical Evaluation of Gemcitabine Combination Regimens for Application in Acute Myeloid Leukemia Ryan H Cancer Therapy: Preclinical Preclinical Evaluation of Gemcitabine Combination Regimens for Application in Acute Myeloid Leukemia Ryan H. Shanks,1, 2 David A. Rizzieri,2 James L. Flowers,2 O. Michael Colvin, 2 and David J. Adams 2 Abstract The DNA antimetabolite gemcitabine is an anticancer agent with shown preclinical and clinical utility and a low toxicity profile. In this study, we sought to identify and optimize drug partners for binary and tertiary combinations with gemcitabine for use in the treatment of acute myeloge- nous leukemia (AML). Drug interaction was assessed by growth inhibition assay with metabolic end points. The combination index method was used to evaluate combinations of gemcitabine with fludarabine, paclitaxel, chlorambucil, doxorubicin, mitoxantrone, and SN-38 in U937 human AML cells. A three-dimensional method was used to determine the effect of dose ratio and sched- ule on drug interaction. Mechanisms underlying interactions related to cell cycle effects and apo- ptosis were assessed by flow cytometric and caspase-3 and -7 assays, respectively. The most synergistic binary combination was gemcitabine + fludarabine.The most synergistic tertiary com- bination was gemcitabine + fludarabine + paclitaxel, where the interaction was sequence depen- dent with paclitaxel given before gemcitabine + fludarabine, producing a 2-fold increase in synergy. Cell cycle analysis did not reveal a significant G2-M arrest, suggesting that the synergistic effect of paclitaxel in this combination, which produced the greatest caspase activation, might be independent of microtubule stabilization. In contrast, the gemcitabine + fludarabine + mitoxan- trone combination was synergistic and schedule independent. Moreover, few ratios of gemcita- bine + fludarabine to mitoxantrone were antagonistic, which could be important for clinical translation. In conclusion, synergistic interactions with gemcitabine occurred with several drugs, the most promising being gemcitabine + fludarabine, gemcitabine + fludarabine + paclitaxel, and gemcitabine + fludarabine + mitoxantrone. These findings provided a rationale for clinical trials of gemcitabine + fludarabine and gemcitabine + mitoxantrone where responses were observed in heavily pretreated AML patients. Leukemia is one of the 10 leading causes of cancer deaths in potentiation of cytotoxic activity (3). Gemcitabine has proven the United States, and acute myelogenous leukemia (AML) is successful against a wide range of tumor types including lung, responsible for one third of these deaths (1). Whereas several ovarian, head and neck, colon, and blood malignancies (4–7). promising compounds have recently become available, single- Taken together, these characteristics, along with the novel agent therapies have been largely unsuccessful in preventing mechanism of action of gemcitabine and relatively low toxicity relapse (2). When optimized, combination chemotherapy profile, suggest that gemcitabine might be a good candidate regimens can offer increased efficacy, decreased toxicity, dose for combination chemotherapy in the treatment of AML. reductions, and decreased drug resistance. In this preclinical study, we evaluated the interaction of Standard induction chemotherapy consists of cytosine gemcitabine with fludarabine, a DNA antimetabolite; mitox- arabinoside in combination with an anthracycline antibiotic antrone, a topoisomerase II inhibitor; doxorubicin, a top- or anthracenedione (usually daunorubicin, idarubicin, or oisomerase II poison; SN-38 (the active metabolite of mitoxantrone). Gemcitabine (2V,2V-difluorodeoxycytidine) is irinotecan), a topoisomerase I poison; paclitaxel, a microtubule structurally similar to cytosine arabinoside, but creates DNA stabilizing agent; and chlorambucil, an alkylating agent. An damage that is more difficult to repair. In addition, gemcitabine AML cell line (U937) was used to assess growth inhibition. We metabolites inhibit ribonucleotide reductase, leading to self- used the combination effect analysis of Chou and Talalay (8) to identify the most synergistic combinations. Because drug interaction is often dependent on the dosage ratios of the Authors’ Affiliations: 1North Carolina Central University and 2Department of compounds involved, we used the three-dimensional method Medicine, Duke University Medical Center, Durham, North Carolina of Kanzawa et al. (9) to evaluate these combinations across Received 10/18/04; revised 2/22/05; accepted 3/11/05. several concentration ratios. Additionally, as the documented Grant support: Eli Lilly and Company. The costs of publication of this article were defrayed in part by the payment of page mechanism of action of these compounds varies both in the charges. This article must therefore be hereby marked advertisement in accordance target and the stage of the cell cycle in which they act, we also with 18 U.S.C. Section 1734 solely to indicate this fact. evaluated the effect of sequence of administration on the Requests for reprints: David J. Adams, Department of Medicine DUMC2638, interaction of these drugs. We identified two binary combina- Research Drive, Durham, NC27710. P hone: 919-684-4383; Fax: 919-668-3925; E-mail: [email protected]. tions and two tertiary combinations that showed highly F 2005 American Association for Cancer Research. synergistic antitumor activity. www.aacrjournals.org4225 Clin Cancer Res 2005;11(11) June 1, 2005 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2005 American Association for Cancer Research. Cancer Therapy: Preclinical Materials and Methods the manufacturer. This assay measures cellular ATP as a marker for viable cells with a sensitivity of the chemiluminescent end point of 10 Compounds. Gemcitabine (Eli Lilly and Company, Indianapolis, cells per well. Drug response was evaluated as described below. IN), fludarabine (Berlex Laboratories, Richmond, CA), mitoxantrone Growth inhibition assay. Cells were seeded in 96-well microplates (Immunex, Seattle, WA), paclitaxel (Bristol Myers Squibb, Princeton, (Corning, Corning, NY) at a density of 50,000 cells/well and a final NJ), and doxorubicin (Pharmacia, Kalamazoo, MI) were obtained from the Duke University Medical Center Pharmacy and reconstituted according to the instructions of the manufacturer. Stock solutions of 10 mmol/L SN-38 (RTI International, Research Triangle Park, NC) in DMSO and 4 mmol/L chlorambucil (ICN, Aurora, OH) in 4% DMSO and sterile water were prepared and subsequently diluted. Cell culture. U937 cells were obtained from Duke University Shared Cell Culture Resource (Durham, NC) and cultured in RPMI 1640 (Gibco, Grand Island, NY) supplemented with 10% fetal bovine serum (Hyclone, Logan, UT), 1% penicillin/streptomycin, and 0.5% ampho- tericin B (Bristol Meyers Squibb) at 37jC in a humidified atmosphere 5 6 containing 5% CO2. Cell density was maintained at 10 to 10 cells/mL with viability exceeding 90%. Isolation and evaluation of clinical samples. Clinical blood samples were collected from patients diagnosed with AML or chronic myelogenous leukemia after obtaining informed consent under a protocol approved by the Duke University Medical Center Institutional Review Board. Percent blasts ranged from 30% to >80%. The peripheral blood mononuclear cells were isolated by centrifugation in Vacutainer CPT tubes (Becton Dickinson and Company, Franklin Lakes, NJ) at 1,625 Â g for 15 minutes. All centrifugation steps were done at room temperature. Peripheral blood mononuclear cells were harvested and resuspended in growth medium: Iscove’s modified Dulbecco’s medium (Gibco) supplemented with 10% fetal bovine serum (Hyclone), 10% equine serum (Hyclone), 10 ng/mL pixy 321 (Immunex), 0.1 units/mL erythropoietin (Amgen, Thousand Oaks, CA), 25 ng/mL Flt-3 ligand (Immunex), 5 Ag/mL gentamicin (Fujisawa USA, Deerfield, IL), 20 Ag/mL vancomycin (Eli Lilly and Company), and 5 Amol/L hydrocortisone (Sigma, St. Louis, MO). Peripheral blood mononuclear cells were washed thrice with growth medium and collected by centrifugation at 600 Â g for 7 minutes. Initial cell viability was assessed by trypan blue dye exclusion (Trypan Blue, Sigma). Macrophages were depleted by adherence to plastic culture flasks at 37jC for 16 to 21 hours at a concentration of 1 Â 107 to 2 Â 107 cells/mL. Peripheral blood mono- nuclear cells were further purified by density gradient sedimentation at 210 Â g for 30 minutes over Ficoll-Paque PLUS (Pharmacia Biotech, Uppsala, Sweden). The mononuclear cell layer was harvested, washed thrice with growth medium, and stained with trypan blue to determine cell viability. Cells were seeded in 96-well microtiter plates at 250,000 cells/well (with the exception of two patient specimens plated at 50,000 cells/well) in a final volume of 200 AL with viability exceeding 90%. Cells in triplicate wells were exposed to drugs for 48 hours before 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy- phenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. In samples where cells were limited, the ATPLite cytotoxicity assay (Packard Instruments, Downers Grove, IL) was used according to the protocol of Ta b l e 1. Antiproliferative activity of single chemotherapeutic agents against U937 cells in vitro Drug IC50 (nmol/L) Mitoxantrone 3.0 F 0.2 Paclitaxel 3.9 F 0.9 SN-38 6.1 F0.3 Fig. 1. Interaction of gemcitabine and fludarabine in U937 cells. A, composite dose-response curves for antiproliferative activity of gemcitabine (5), fludarabine Gemcitabine 10.4 F 0.8 (o), or the combination (4, at a ratio of gemcitabine/fludarabine
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