Gemcitabine and Oxaliplatin in Patients With Metastatic Breast Cancer Resistant to or Pretreated With Both Anthracyclines and Taxanes

Airoldi, Mario; Cattel, Luigi; Passera, Roberto; Pedani, Fulvia; Delprino, Laura; Micari, C

doi:10.1097/01.coc.0000231363.95334.ee

Cited by 15 publications

(19 citation statements)

References 20 publications

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“…Carboplatin (10 mg/mL) was generously supplied from the UC Davis Comprehensive Cancer Center pharmacy and oxaliplatin (5 mg/mL) was purchased from Sanofi-Aventis. 14 C-labeled carboplatin (specific activity of 54 mCi/mmol) and 14 C-labeled oxaliplatin (specific activity of 58 mCi/mmol) were purchased from Moravek Biochemicals. Radiolabeled drugs were combined with unlabeled drugs to reduce the amount of radiocarbon used.…”

Section: ■ Experimental Proceduresmentioning

confidence: 99%

“…Though oxaliplatin is not currently approved for the treatment of breast cancer, it has been shown to be clinically efficacious as a single agent or in combination regimens in breast cancer patients. In metastatic breast cancer patients, oxaliplatin alone had an overall response rate of 21% and in combination therapies had a range of overall response rates from 6.7 to 59% with a median of 31.2%. − In locally advanced breast cancer patients, the overall response rate was even higher at 69% …”

Section: Introductionmentioning

confidence: 99%

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Correlation of Platinum Cytotoxicity to Drug-DNA Adduct Levels in a Breast Cancer Cell Line Panel

Wang

Scharadin

Zimmermann

et al. 2018

Chem. Res. Toxicol.

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Platinum drugs, including carboplatin and oxaliplatin, are commonly used chemotherapy drugs that kill cancer cells by forming toxic drug-DNA adducts. These drugs have a proven, but modest, efficacy against several aggressive subtypes of breast cancer but also cause several side effects that can lead to the cessation of treatment. There is a clinical need to identify patients who will respond to platinum drugs in order to better inform clinical decision making. Diagnostic microdosing involves dosing patients or patient samples with subtherapeutic doses of radiolabeled platinum followed by measurement of platinum-DNA adducts in blood or tumor tissue and may be used to predict patient response. We exposed a panel of six breast cancer cell lines to 14C-labeled carboplatin or oxaliplatin at therapeutic and microdose (1% therapeutic dose) concentrations for a range of exposure lengths and isolated DNA from the cells. The DNA was converted to graphite, and measurement of radiocarbon due to platinum-DNA adduction was quantified via accelerator mass spectrometry (AMS). We observed a linear correlation in adduct levels between the microdose and therapeutic dose, and the level of platinum-DNA adducts corresponded to cell line drug sensitivity for both carboplatin and oxaliplatin. These results showed a clear separation in adduct levels between the sensitive and resistant groups of cell lines that could not be fully explained or predicted by changes in DNA repair rates or mutations in DNA repair genes. Further, we were able to quantitate oxaliplatin-DNA adducts in the blood and tumor tissue of a metastatic breast cancer patient. Together, these data support the use of diagnostic microdosing for predicting patient sensitivity to platinum. Future studies will be aimed at replicating this data in a clinical feasibility trial.

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Section: ■ Experimental Proceduresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Correlation of Platinum Cytotoxicity to Drug-DNA Adduct Levels in a Breast Cancer Cell Line Panel

Wang

Scharadin

Zimmermann

et al. 2018

Chem. Res. Toxicol.

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“…Gemcitabine shows anticancer activity against a variety of solid tumors, including non-small-cell lung (11), pancreatic (12), bladder (13), and breast cancers (14). Gemcitabine is converted intracellularly to the active metabolites difluorodeoxycytidine di-and triphosphates (dFdCDP and dFdCTP).…”

Section: Introductionmentioning

confidence: 99%

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

Zhang

Cai

Zhu

et al. 2011

Molecular Cancer Therapeutics

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The Bcl-2 antagonist ABT-737 targets Bcl-2/Bcl-xL, but not Mcl-1, which may confer resistance to this agent in various cancers with high levels of Mcl-1. Here, we showed that the combination of gemcitabine and ABT-737 exhibited synergistic cytotoxicity and induced significant apoptosis in multiple cancer types, including lung, renal, bladder, and prostate cancers. The enhanced apoptosis induced by gemcitabine plus ABT-737 was accompanied by the greater extent of mitochondrial depolarization, caspases-3 activation, and PARP cleavage in 95-D and 5637 cell lines. Importantly, in ABT-737-resistant cancer cells, the interaction between USP9X and Mcl-1, which was increased by ABT-737 treatment, could be disrupted by gemcitabine, thus resulting in enhanced ubiquitination and the subsequent degradation of Mcl-1 and ultimately in the synergism of these two drugs. Moreover, the increased anticancer efficacy of gemcitabine combined with ABT-737 was further validated in a human lung cancer 95-D xenograft model in nude mice. Taken together, our data first showed the synergistic anticancer capabilities achieved by combining gemcitabine and ABT-737 and, second, opened new opportunities to use antiapoptotic Bcl-2 family members, which drive tumor cell resistance in current anticancer therapies, therapeutically. Mol Cancer Ther; 10(7); 1264-75. Ó2011 AACR.

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“…La gemcitabine est l'une des molécules clé dans le traitement des cancers du sein métastatiques du fait de sa bonne tolérance, elle peut être utilisée en association avec différents produits [9]. Dans trois études publiées dans la littérature, l'association gemcitabine et oxaliplatine chez des patients ayant un cancer du sein métastatique prétraités avec des anthracyclines et des taxanes a donné une réponse complète ou partielle dans 7,5 à 25 % des cas et une stabilisation dans 27,5 à 40 %, les effets secondaires comportaient surtout neutropénie, thrombopénie, neuropathie périphérique et asthénie [10][11][12]. Les métastases nasosinusienne du cancer du sein sont exceptionnelles mais possibles, ce diagnostic devrait être évoqué devant toute manifestation nasosinusienne chez un patient ayant des antécédents de cancer du sein, ce qui permettrait de poser un diagnostic précoce et d'éviter dans la mesure du possible les complications locorégionales telles que la cécité.…”

Section: Discussionunclassified

Métastase nasosinusienne d’un cancer du sein chez un homme

et al. 2010

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Gemcitabine and Oxaliplatin in Patients With Metastatic Breast Cancer Resistant to or Pretreated With Both Anthracyclines and Taxanes

Abstract: The combination gemcitabine plus oxaliplatin has moderate activity in anthracycline and taxanes resistant/relapsed heavily treated patients, mild toxicity and no administration sequence-dependent pharmacokinetic interactions.

Cited by 15 publications

References 20 publications

Correlation of Platinum Cytotoxicity to Drug-DNA Adduct Levels in a Breast Cancer Cell Line Panel

Correlation of Platinum Cytotoxicity to Drug-DNA Adduct Levels in a Breast Cancer Cell Line Panel

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

Métastase nasosinusienne d’un cancer du sein chez un homme

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