Optimized anti–tumor effects of anthracyclines plus Vinca alkaloids using a novel, mechanism-based application schedule

Ehrhardt, Harald; Schrembs, David; Moritz, Christian P.; Wachter, Franziska; Haldar, Subrata; Graubner, Ulrike; Nathrath, Michaela; Jeremias, Irmela

doi:10.1182/blood-2010-02-269811

Cited by 23 publications

(54 citation statements)

References 31 publications

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“…For instance, in one extensively studied example, the anthracycline doxorubicin antagonized activity of the vinca alkaloid vincristine in 83% (15/18) of hematopoietic cell lines tested. This antagonism was reproduced in vivo in a xenograft model and was also observed in 34% (12/35) of childhood leukemia cells simultaneously treated with both drugs ex vivo [35]. Moreover, combination activity was shown to be sequence dependent: if cells are exposed to the anthracycline first, antagonism is observed, but if exposure to vinca alkaloid precedes anthracycline, the combination result is beneficial.…”

Section: Discussionmentioning

confidence: 76%

“…For example, low concentrations of cytarabine or topotecan have little effect on proliferation as single agents, but can dramatically antagonize eribulin activity under combination conditions. Indeed, this is not without precedent: antagonism has been observed for a variety of cancer drug combinations in preclinical studies, prompting follow up analyses to investigate both the mechanisms of the synergies as well as the effects of drug combination sequencing [28][29][30][31][32][33][34][35]. For instance, in one extensively studied example, the anthracycline doxorubicin antagonized activity of the vinca alkaloid vincristine in 83% (15/18) of hematopoietic cell lines tested.…”

Section: Discussionmentioning

confidence: 99%

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Identification of Combinatorial Drugs that Synergistically Kill both Eribulin-Sensitive and Eribulin-Insensitive Tumor Cells

Toshimitsu¹

2015

Glob J Cancer Ther

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Eribulin sensitivity was examined in a panel of twenty-five human cancer cell lines representing a variety of tumor types, with a preponderance of breast and lung cancer cell lines. As expected, the cell lines vary in sensitivity to eribulin at clinically relevant concentrations. To identify combination drugs capable of increasing anticancer effects in patients already responsive to eribulin, as well as inducing de novo anticancer effects in non-responders, we performed a combinatorial high throughput screen to identify drugs that combine with eribulin to selectively kill tumor cells. Among other observations, we found that inhibitors of ErbB1/ErbB2 (lapatinib, BIBW-2992, erlotinib), MEK (E6201, trametinib), PI3K (BKM-120), mTOR (AZD 8055, everolimus), PI3K/mTOR (BEZ 235), and a BCL2 family antagonist (ABT-263) show combinatorial activity with eribulin. In addition, antagonistic pairings with other agents, such as a topoisomerase I inhibitor (topotecan hydrochloride), an HSP-90 inhibitor (17-DMAG), and gemcitabine and cytarabine, were identified. In summary, the preclinical studies described here have identified several combination drugs that have the potential to either augment or antagonize eribulin's anticancer activity. Further elucidation of the mechanisms responsible for such interactions may be important for identifying valuable therapeutic partners for eribulin.of care. Chemotherapeutic drugs are often most effective when given in combination, in particular when synergistic killing is achieved without additive toxicity. To date, potential combination therapies for eribulin have been explored with only a limited number of anticancer agents. We therefore have performed an in vitro study of eribulin combined with 34 anticancer agents in 25 different tumor cell lines of various types, through use of a combination high throughput screening (cHTS) platform. Our goals were to identify drugs that might be paired with eribulin to increase clinical efficacy in metastatic breast cancer, to identify drugs that convert eribulin non-responders to responders, and to identify new therapeutic indications for eribulin utilization. Several compelling synergy effects with approved and emerging drugs were observed. The preclinical data provides insights about future clinical development strategies.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Identification of Combinatorial Drugs that Synergistically Kill both Eribulin-Sensitive and Eribulin-Insensitive Tumor Cells

Toshimitsu¹

2015

Glob J Cancer Ther

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“…3, 5, 22 We had recently demonstrated p53 functionality in the JURKAT cells used here, which showed p53-dependent upregulation of ,for example, caspase-8 upon stimulation with methotrexate. 23, 24, 25, 26 BA is known to induce apoptosis independently from p53 in several cell systems. 11, 12 Interestingly and in contrast to other cancer cells, cell death induction by doxo alone did not depend on the presence of p53 in JURKAT cells (Supplementary Figures S4A and B), although p53 was activated after stimulation with doxo (Figure 5a).…”

Section: Resultsmentioning

confidence: 99%

NOXA as critical mediator for drug combinations in polychemotherapy

et al. 2012

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During polychemotherapy, cytotoxic drugs are given in combinations to enhance their anti-tumor effectiveness. For most drug combinations, underlying signaling mechanisms responsible for positive drug–drug interactions remain elusive. Here, we prove a decisive role for the Bcl-2 family member NOXA to mediate cell death by certain drug combinations, even if drugs were combined which acted independently from NOXA, when given alone. In proof-of-principle studies, betulinic acid, doxorubicin and vincristine induced cell death in a p53- and NOXA-independent pathway involving mitochondrial pore formation, release of cytochrome c and caspase activation. In contrast, when betulinic acid was combined with either doxorubicine or vincristine, cell death signaling changed considerably; the drug combinations clearly depended on both p53 and NOXA. Similarly and of high clinical relevance, in patient-derived childhood acute leukemia samples the drug combinations, but not the single drugs depended on p53 and NOXA, as shown by RNA interference studies in patient-derived cells. Our data emphasize that NOXA represents an important target molecule for combinations of drugs that alone do not target NOXA. NOXA might have a special role in regulating apoptosis sensitivity in the complex interplay of polychemotherapy. Deciphering the differences in signaling of single drugs and drug combinations might enable designing highly effective novel polychemotherapy regimens.

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“…1 I mportantly, multivariate analysis revealed that patients with persistence of 18F-fluorodeoxyglucose (FDG) uptake 3 months after ASCT had significantly worse progression-free survival (PFS) and overall survival (OS). The prognostic impact of this parameter was stronger than that of cytogenetic abnormalities.…”

Section: Philippe Moreau University Hospital Nantesmentioning

confidence: 99%

“…1 These findings challenge us to take a fresh look at how drugs are combined when treating patients with hematologic malignancies.…”

mentioning

confidence: 99%

It's all in the timing

Bendall

2011

Blood

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Optimized anti–tumor effects of anthracyclines plus Vinca alkaloids using a novel, mechanism-based application schedule

Abstract: Application of anthracyclines and

Cited by 23 publications

References 31 publications

Identification of Combinatorial Drugs that Synergistically Kill both Eribulin-Sensitive and Eribulin-Insensitive Tumor Cells

Identification of Combinatorial Drugs that Synergistically Kill both Eribulin-Sensitive and Eribulin-Insensitive Tumor Cells

NOXA as critical mediator for drug combinations in polychemotherapy

It's all in the timing

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