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

Shanks, Ryan H.; Rizzieri, David A.; Flowers, James L.; Colvin, O. Michael; Adams, David J.

doi:10.1158/1078-0432.ccr-04-2106

Cited by 24 publications

(20 citation statements)

References 22 publications

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“…Finally, we used cell types (ovarian and pancreatic cancer) that are known to be responsive to topo I poisons and gemcitabine. Consistent with our results, antagonism has also been reported when U937 human leukemia cells are simultaneously exposed to gemcitabine and SN-38 (Shanks et al, 2005), although the mechanism of this antagonism was not examined. Several experiments were performed to assess the mechanism of antagonism observed in the present study.…”

Section: Discussionsupporting

confidence: 91%

Overcoming S-Phase Checkpoint-Mediated Resistance: Sequence-Dependent Synergy of Gemcitabine and 7-Ethyl-10-hydroxycamptothecin (SN-38) in Human Carcinoma Cell Lines

et al. 2008

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Although agents that inhibit DNA synthesis are widely used in the treatment of cancer, the optimal method for combining such agents and the mechanism of their synergy is poorly understood. The present study examined the effects of combining gemcitabine (2Ј,2Ј-difluoro 2Ј-deoxycytidine) and 7-ethyl-10-hydroxycamptothecin (SN-38; the active metabolite of irinotecan), two S-phaseselective agents that individually have broad antitumor activity, in human cancer cells in vitro. Colony-forming assays revealed that simultaneous treatment of Ovcar-5 ovarian cancer cells or BxPC-3 pancreatic cancer cells with gemcitabine and SN-38 resulted in antagonistic effects. In contrast, sequential treatment with these two agents in either order resulted in synergistic antiproliferative effects, although the mechanism of synergy varied with the sequence. In particular, SN-38 arrested cells in S phase, enhanced the accumulation of gemcitabine metabolites, and diminished checkpoint kinase 1, thereby sensitizing cells in the SN-38 3 gemcitabine sequence. Gemcitabine treatment followed by removal allowed prolonged progression through S phase, contributing to synergy of the gemcitabine 3 SN-38 sequence. These results collectively suggest that S-phase-selective agents might exhibit more cytotoxicity when administered sequentially rather than simultaneously.Gemcitabine (2Ј,2Ј-difluoro 2Ј-deoxycytidine), a pyrimidinebased antimetabolite, is active against cancers of the pancreas, lung, breast, and ovary as well as some lymphomas (Ryan et al., 2006). According to current understanding, this agent is taken into target cells mainly by the equilibrative nucleoside transporter hENT1 (Damaraju et al., 2003) and sequentially phosphorylated to the 5Ј-mono-, di-, and triphosphate derivatives Ryan et al., 2006). The antiproliferative and cytotoxic effects of gemcitabine have been attributed to two major factors, the ability of gemcitabine diphosphate to inhibit ribonucleotide reductase, thereby depleting deoxyribonucleotide triphosphates required for DNA synthesis, and incorporation of gemcitabine into DNA, in which it stalls advancing replication forks one base pair beyond the site of incorporation Ryan et al., 2006). In addition, it has been suggested that upon incorporation into DNA gemcitabine acts as a topo I poison, stabilizing covalent DNA-topo I complexes that then contribute to DNA damage and cytotoxicity (Pourquier et al., 2002).Over the past decade, there has been considerable interest in combining gemcitabine with a variety of agents that have different mechanisms of action, including doxorubicin, cisplatin, paclitaxel, docetaxel, capecitabine, vinorelbine, or ionizing radiation. Particularly pertinent to the present study have been previous attempts to combine gemcitabine with irinotecan, a semisynthetic derivative of camptothecin that is approved for the treatment of colorectal cancer and also is active against pancreatic cancer, non-small-cell lung cancer, and breast cancer (Sparreboom and Zamboni, 2006). Irinotecan is a prodru...

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Section: Discussionsupporting

confidence: 91%

Overcoming S-Phase Checkpoint-Mediated Resistance: Sequence-Dependent Synergy of Gemcitabine and 7-Ethyl-10-hydroxycamptothecin (SN-38) in Human Carcinoma Cell Lines

et al. 2008

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“…Synergism, additive effects, or antagonism was assessed using the Chou-Talalay method (42,60) and Calcusyn software (Biosoft). The extent of apoptosis in drug-treated samples was quantified as a percentage of Annexin V -positive cells over the total cell population; apoptosis in DMSO-treated controls was negligible.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinase Inhibitors Sensitize Tumor Cells to Nutlin-Induced Apoptosis: a Potent Drug Combination

Cheok

Dey

Lane

2007

Molecular Cancer Research

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Current chemotherapy focuses on the use of genotoxic drugs that may induce general DNA damage in cancer cells but also high levels of toxicity in normal tissues. Nongenotoxic activation of p53 by targeting specific molecular pathways therefore provides an attractive therapeutic strategy in cancers with wild-type p53. Here, we explored the antitumor potential of cyclin-dependent kinase (CDK) inhibitors in combination with a small molecule inhibitor of p53-murine double minute 2 (MDM2) interaction. We show that low doses of CDK inhibitors roscovitine and DRB synergize with the MDM2 antagonist nutlin-3a in the induction of p53 activity and promote p53-dependent apoptosis in a dose-and timedependent manner. Statistical measurement of the combination effects shows that the drug combination is additive on the reduction of cell viability and synergistic on inducing apoptosis, a critical end point of cytotoxic drugs. The degree of apoptosis observed 24 to 48 h after drug treatment correlated with the accumulation of p53 protein and concomitant induction of proapoptotic proteins Puma and PIG3. The antiproliferative and cytotoxic effects of this drug combination are validated in a range of tumor-derived cells including melanoma, colon carcinoma, breast adenocarcinoma, and hepatocarcinoma cells. Furthermore, this drug combination does not induce phosphorylation of Ser 15 on p53 and does not induce genotoxic stress in the cell. Given that many cytotoxic drugs rely on their ability to induce apoptosis via DNA damage -mediated activation of p53, the data presented here may provide a new therapeutic approach for the use of CDK inhibitors and MDM2 antagonists in combinatorial drug therapy.

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“…5–7 Preclinical studies have suggested a synergism between gemcitabine and fludarabine. 8 For these reasons, we evaluated the addition of gemcitabine (G) to our standard fludarabine (F) - melphalan 140 mg/m 2 (M140) reduced-intensity conditioning regimen (FM140) 9 in patients with relapsed and refractory HL undergoing allo-SCT. Initial results of this study were presented previously.…”

Section: Introductionmentioning

confidence: 99%

Gemcitabine, Fludarabine, and Melphalan for Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation for Relapsed and Refractory Hodgkin Lymphoma

Anderlini

Saliba

Ledesma

et al. 2016

Biology of Blood and Marrow Transplantation

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Forty patients with Hodgkin lymphoma underwent an allogeneic stem cell transplant with the gemcitabine-fludarabine-melphalan reduced-intensity conditioning regimen. The median age was 31 years (range 20–63). Thirty-one (77%) had undergone a prior autologous stem cell transplant, and the median time to progression after the transplant was six months (1–68). Disease status at transplant was complete remission/complete remission, undetermined (n=23; 57%), partial remission (n=14; 35%), and other (n=3; 7%). Twenty-six patients (65%) received brentuximab vedotin prior to allotransplant. The overall complete response rate prior to allotransplant was 65% in brentuximab-treated patients vs. 42% in brentuximab-naïve patients (p=0.15). At the latest follow-up (October 2015), thirty-one patients are alive. The median follow-up is 41 months (5–87). Transplant-related mortality at three years is 17%. Pulmonary, skin toxicities and nausea were seen in 13 (33%), 11 (28%), and 37 (93%) patients, respectively. At three years, estimates for overall and progression-free survival are 75% (95% CI: 57–86) and 54% (95% CI: 36–70). Overall incidence for disease progression is 28% (95% CI 16–50). We feel that the gemcitabine-fludarabine-melphalan regimen allows moderate dose-intensification with acceptable morbidity and mortality. The inclusion of gemcitabine affected nausea, pulmonary and likely skin toxicity. Exposure to brentuximab vedotin allowed more patients to reach allogeneic stem cell transplant in complete remission. With over 50% of patients progression-free at 3 years, allogeneic stem cell transplant with reduced-intensity conditioning remains an effective and relevant treatment option for Hodgkin lymphoma in the brentuximab vedotin era.

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

Cited by 24 publications

References 22 publications

Overcoming S-Phase Checkpoint-Mediated Resistance: Sequence-Dependent Synergy of Gemcitabine and 7-Ethyl-10-hydroxycamptothecin (SN-38) in Human Carcinoma Cell Lines

Overcoming S-Phase Checkpoint-Mediated Resistance: Sequence-Dependent Synergy of Gemcitabine and 7-Ethyl-10-hydroxycamptothecin (SN-38) in Human Carcinoma Cell Lines

Cyclin-Dependent Kinase Inhibitors Sensitize Tumor Cells to Nutlin-Induced Apoptosis: a Potent Drug Combination

Gemcitabine, Fludarabine, and Melphalan for Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation for Relapsed and Refractory Hodgkin Lymphoma

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