Biomarkers of chemotherapy-induced diarrhoea: a clinical study of intestinal microbiome alterations, inflammation and circulating matrix metalloproteinases

Stringer, Andrea M.; Al‐Dasooqi, Noor; Bowen, Joanne M.; Tan, Thean Hsiang; Radzuan, Maryam; Logan, Richard M.; Mayo, Bronwen J.; Keefe, Dorothy; Gibson, Rachel J.

doi:10.1007/s00520-013-1741-7

Cited by 114 publications

(94 citation statements)

References 41 publications

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“…We have previously shown that MMPs are upregulated in the gut in a number of preclinical models of chemotherapy-induced GI toxicity [5, 6]. We have also confirmed these findings in a clinical cohort, with upregulated MMP concentrations in the serum of patients treated with standard dose chemotherapy for breast and colorectal cancer [7]. These findings are of clinical importance as MMP inhibitors have been investigated for their anti-tumor activity, both alone and in combination with chemotherapy [8, 9], with data suggesting they may be a valid adjunct to traditional cancer care.…”

Section: Introductionsupporting

confidence: 75%

“…Its affinity for MMP-9 and MMP-12 also holds therapeutic potential as these have both been implicated in the pathobiology of GI toxicity. This is particularly the case for MMP-9, which has been shown to increase in the gut following preclinical irinotecan [6, 12], as well as systemically in patients undergoing standard dose chemotherapy [7]. In the case of cancer progression, a number of MMPs have been implicated in cancer progression, invasion, and metastasis, including MMP-2, 9, 11, 12, and 14 [13, 14], with altered expression/activity in the tumor microenvironment, as well as MMP polymorphisms linked with increased susceptibility to various malignancies [15, 16].…”

Section: Introductionmentioning

confidence: 99%

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Selective MMP Inhibition, Using AZD3342, to Reduce Gastrointestinal Toxicity and Enhance Chemoefficacy in a Rat Model

et al. 2018

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Background: The common cytotoxic mechanisms that underpin chemoefficacy and toxicity have hampered efforts to deliver effective supportive care interventions, particularly for gastrointestinal (GI) toxicity. Matrix metalloproteinases (MMPs) have been implicated in both tumor growth and GI toxicity, and as such MMP inhibitors present as a novel therapeutic avenue to simultaneously enhance treatment efficacy and reduce toxicity. Objectives: The aim of this study was to determine the efficacy of an MMP-9/12 inhibitor, AZD3342, on tumor growth and GI toxicity in a rat model. Methods: Female tumor-bearing Dark Agouti rats (n = 90) were divided into 4 groups: vehicle control; methotrexate (MTX); AZD3342, and MTX + AZD3342. Tumors were measured daily (for 5 days) using digital calipers. GI toxicity was assessed using well-established clinical markers (diarrhea/weight loss), histopathological analysis, and functional assessment of intestinal barrier permeability. Results: AZD3342 delayed the onset of severe diarrhea by 1 day (vs. MTX) but was unable to improve the overall severity of diarrhea. No changes were detected in tissue morphology or intestinal barrier function. AZD3342 alone suppressed tumor growth (p = 0.003 vs. vehicle) but did not enhance the efficacy of MTX. Conclusions: This study showed partial efficacy of AZD3342 in reducing tumor growth and delaying the onset of severe diarrhea caused by MTX in rats. We suggest further studies be undertaken targeting appropriate scheduling of AZD3342 as well as investigating different cytotoxic therapies that strongly activate MMP signaling.

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Section: Introductionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Selective MMP Inhibition, Using AZD3342, to Reduce Gastrointestinal Toxicity and Enhance Chemoefficacy in a Rat Model

et al. 2018

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“…The gut microbiota is critical in regulating the severity of gut toxicity, with increased levels of LPSproducing, gram-negative bacteria correlating with diarrhoea severity (5,30). Comparable levels of major phylogenies (fermicutes, bacteroidetes) were seen in WT and BALB/c-Tlr4 -/-billy mice at baseline.…”

Section: Discussionmentioning

confidence: 99%

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

Wardill

Gibson

Sebille

et al. 2016

Molecular Cancer Therapeutics

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124

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Strong epidemiological data indicate that chemotherapy-induced gut toxicity and pain occur in parallel, indicating common underlying mechanisms. We have recently outlined evidence suggesting that TLR4 signaling may contribute to both side effects. We therefore aimed to determine if genetic deletion of TLR4 improves chemotherapy-induced gut toxicity and pain. Forty-two female wild-type (WT) and 42 Tlr4 null (−/−) BALB/c mice weighing between 18 and 25 g (10–13 weeks) received a single 270 mg/kg (i.p.) dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. Bacterial sequencing was conducted on cecal samples of control animals to determine the gut microbiome profile. Gut toxicity was assessed using validated clinical and histopathologic markers, permeability assays, and inflammatory markers. Chemotherapy-induced pain was assessed using the validated rodent facial grimace criteria, as well as immunologic markers of glial activation in the lumbar spinal cord. TLR4 deletion attenuated irinotecan-induced gut toxicity, with improvements in weight loss (P = 0.0003) and diarrhea (P < 0.0001). Crypt apoptosis was significantly decreased in BALB/c-Tlr4−/−billy mice (P < 0.0001), correlating with lower mucosal injury scores (P < 0.005). Intestinal permeability to FITC-dextran (4 kDa) and LPS translocation was greater in WT mice than in BALB/c-Tlr4−/−billy (P = 0.01 and P < 0.0001, respectively). GFAP staining in the lumbar spinal cord, indicative of astrocytic activation, was increased at 6 and 72 hours in WT mice compared with BALB/c-Tlr4−/−billy mice (P = 0.008, P = 0.01). These data indicate that TLR4 is uniquely positioned to mediate irinotecan-induced gut toxicity and pain, highlighting the possibility of a targetable gut/CNS axis for improved toxicity outcomes. Mol Cancer Ther; 15(6); 1376–86. ©2016 AACR.

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“…Cytotoxic chemotherapy may also change the gut microbiota in both humans (17) and animal models (18). In cancer patients, microbiota changes have been correlated with gut toxicity (19) and, in some experimental rat models, alleviation of chemotherapy-induced symptoms is observed after administration of probiotics (20)(21)(22). Under germ-free conditions in mice, the response to chemotherapy is either reduced (23) or increased (24).…”

Section: Introductionmentioning

confidence: 98%

Bovine Colostrum Modulates Myeloablative Chemotherapy–Induced Gut Toxicity in Piglets

Pontoppidan

Shen

Cilieborg

et al. 2015

The Journal of Nutrition

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Biomarkers of chemotherapy-induced diarrhoea: a clinical study of intestinal microbiome alterations, inflammation and circulating matrix metalloproteinases

Cited by 114 publications

References 41 publications

Selective MMP Inhibition, Using AZD3342, to Reduce Gastrointestinal Toxicity and Enhance Chemoefficacy in a Rat Model

Selective MMP Inhibition, Using AZD3342, to Reduce Gastrointestinal Toxicity and Enhance Chemoefficacy in a Rat Model

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

Bovine Colostrum Modulates Myeloablative Chemotherapy–Induced Gut Toxicity in Piglets

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