Local bacteria affect the efficacy of chemotherapeutic drugs

Lehouritis, Panos; Cummins, Joanne; Stanton, Michael; Murphy, C.; McCarthy, Florence O.; Reid, Gregor; Urbaniak, Camilla; Byrne, William L.; Tangney, Mark

doi:10.1038/srep14554

Cited by 219 publications

(221 citation statements)

References 52 publications

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“…This experiment revealed that conditioned medium from M. hyorhinis -infected HDFs metabolizes gemcitabine into its deaminated inactive metabolite 2′,2′-difluorodeoxyuridine (7) as has been previously reported (8, 9) (Fig. 1C and fig.…”

supporting

confidence: 82%

Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine

Geller

Barzily-Rokni

Danino

et al. 2017

Science

1,183

1,148

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Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2′,2′-difluorodeoxycytidine) into its inactive form, 2′,2′-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDDL), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intra-tumor Gammaproteobacteria, dependent on bacterial CDDL expression, and abrogated by co-treatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intra-tumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.

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supporting

confidence: 82%

Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine

Geller

Barzily-Rokni

Danino

et al. 2017

Science

1,183

1,148

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“…A recent survey of in situ bacterial effects on frequently used chemotherapeutics suggests profound influence of distinct bacteria speciesonthe antitumor effect of these drugs. 117 Lehouritis et al found that after preincubation with nonpathogenic gram-negative E. coli Nissle 1917 or gram-positive Listeria welshimeri Serovar 6B SLCC5334, 10 of 30 chemotherapeutic drugs (eg, gemcitabine, cladribine, daunorubicin, and so forth) showed reduced cancer cell killing efficacy, whereas 6 drugs (eg, fludarabine phosphate, CB1954, and so forth) showed increased cancer cell killing efficacy in vitro. 117 High-performance liquid chromatography–mass spectrometry studies showed that these effects are often bacteria specific, likely because of the unique biotransforming activities associated with each bacterial species/strain.…”

Section: Microbiota and Cancer Therapy Efficacymentioning

confidence: 99%

“…117 Lehouritis et al found that after preincubation with nonpathogenic gram-negative E. coli Nissle 1917 or gram-positive Listeria welshimeri Serovar 6B SLCC5334, 10 of 30 chemotherapeutic drugs (eg, gemcitabine, cladribine, daunorubicin, and so forth) showed reduced cancer cell killing efficacy, whereas 6 drugs (eg, fludarabine phosphate, CB1954, and so forth) showed increased cancer cell killing efficacy in vitro. 117 High-performance liquid chromatography–mass spectrometry studies showed that these effects are often bacteria specific, likely because of the unique biotransforming activities associated with each bacterial species/strain. 117 The in vitro bacteria-specific effect on drug cytotoxicity can be replicated in vivo using a xenograft mouse tumor (CT26 colon carcinoma) model.…”

Section: Microbiota and Cancer Therapy Efficacymentioning

confidence: 99%

“…117 High-performance liquid chromatography–mass spectrometry studies showed that these effects are often bacteria specific, likely because of the unique biotransforming activities associated with each bacterial species/strain. 117 The in vitro bacteria-specific effect on drug cytotoxicity can be replicated in vivo using a xenograft mouse tumor (CT26 colon carcinoma) model. 117 Thus, bacteria could directly metabolize chemotherapeutic drugs to affect their efficacy.…”

Section: Microbiota and Cancer Therapy Efficacymentioning

confidence: 99%

“…117 The in vitro bacteria-specific effect on drug cytotoxicity can be replicated in vivo using a xenograft mouse tumor (CT26 colon carcinoma) model. 117 Thus, bacteria could directly metabolize chemotherapeutic drugs to affect their efficacy. Understanding the microbial pathways involved could help to improve cancer therapy outcomes.…”

Section: Microbiota and Cancer Therapy Efficacymentioning

confidence: 99%

See 2 more Smart Citations

Microbiota as a mediator of cancer progression and therapy

Pope

Tomkovich

Yang

et al. 2017

Translational Research

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Complex and intricate circuitries regulate cellular proliferation, survival, and growth, and alterations of this network through genetic and epigenetic events result in aberrant cellular behaviors, often leading to carcinogenesis. Although specific germline mutations have been recognized as cancer inducers, the vast majority of neoplastic changes in humans occur through environmental exposure, lifestyle, and diet. An emerging concept in cancer biology implicates the microbiota as a powerful environmental factor modulating the carcinogenic process. For example, the intestinal microbiota influences cancer development or therapeutic responses through specific activities (immune responses, metabolites, microbial structures, and toxins). The numerous effects of microbiota on carcinogenesis, ranging from promoting, preventing, or even influencing therapeutic outcomes, highlight the complex relationship between the biota and the host. In this review, we discuss the latest findings on this complex microbial interaction with the host and highlight potential mechanisms by which the microbiota mediates such a wide impact on carcinogenesis.

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Association of Antibiotic Receipt With Survival Among Patients With Metastatic Pancreatic Ductal Adenocarcinoma Receiving Chemotherapy

Fulop

Zylberberg

et al. 2023

JAMA Netw Open

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ImportanceThe prognosis for patients with metastatic pancreatic ductal adenocarcinoma (PDAC) is dismal, due in part to chemoresistance. Bacteria-mediated mechanisms of chemoresistance suggest a potential role for antibiotics in modulating response to chemotherapy.ObjectiveTo evaluate whether use of peritreatment antibiotics is associated with survival among patients with metastatic PDAC treated with first-line gemcitabine or fluorouracil chemotherapy.Design, Setting, and ParticipantsUsing the population-based Surveillance, Epidemiology, and End Results–Medicare linked database, this retrospective cohort study analyzed data for patients diagnosed with PDAC between January 1, 2007, and December 31, 2017. Data analysis was conducted between September 1, 2021, and January 15, 2023. The population-based sample included 3850 patients with primary metastatic PDAC treated with first-line gemcitabine or fluorouracil chemotherapy. Patients who received antibiotics were matched based on propensity scores to patients who did not receive antibiotics.ExposuresReceipt of 5 or more days of oral antibiotics or 1 injectable antibiotic in the month before or after beginning first-line chemotherapy.Main Outcomes and MeasuresOverall survival and cancer-specific survival. The end of follow-up was December 31, 2019, for overall survival and December 31, 2018, for cancer-specific survival.ResultsOf the 3850 patients treated with first-line gemcitabine (3150 [81.8%]) or fluorouracil (700 [18.2%]), 2178 (56.6%) received antibiotics. The mean (SD) age at diagnosis was 74.2 (5.8) years and patients were predominantly women (2102 [54.6%]), White (3396 [88.2%]), and from metropolitan areas (3393 [88.1%]) in the northeastern or western US (2952 [76.7%]). In total, 1672 propensity-matched pairs were analyzed. Antibiotic receipt was associated with an 11% improvement in overall survival (hazard ratio [HR], 0.89; 95% CI, 0.83-0.96; P = .003) and a 16% improvement in cancer-specific survival (HR, 0.84; 95% CI, 0.77-0.92; P &lt; .001) among patients treated with gemcitabine. In contrast, there was no association between antibiotic receipt and overall survival (HR, 1.08; 95% CI, 0.90-1.29; P = .41) or cancer-specific survival (HR, 1.12; 95% CI, 0.90-1.36; P = .29) among patients treated with fluorouracil. In a subgroup of gemcitabine-treated patients who received antibiotics, nonpenicillin β-lactams were associated with an 11% survival benefit (HR, 0.89; 95% CI, 0.81-0.97; P = .01).Conclusions and RelevanceIn this cohort study, receipt of perichemotherapy antibiotics was associated with improved survival among patients treated with gemcitabine, but not fluorouracil, suggesting that antibiotics may modulate bacteria-mediated gemcitabine resistance and have the potential to improve PDAC outcomes.

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Local bacteria affect the efficacy of chemotherapeutic drugs

Cited by 219 publications

References 52 publications

Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine

Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine

Microbiota as a mediator of cancer progression and therapy

Association of Antibiotic Receipt With Survival Among Patients With Metastatic Pancreatic Ductal Adenocarcinoma Receiving Chemotherapy

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