Effect of thalidomide on gastrointestinal toxic effects of irinotecan

Govindarajan, Rangaswamy; Heaton, Keith M.; Broadwater, J. R.; Zeitlin, Andrew; Lang, Nicholas P.; Hauer‐Jensen, Martin

doi:10.1016/s0140-6736(00)02586-1

Cited by 76 publications

(36 citation statements)

References 3 publications

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“…For some the direct target is the intestinal mucosa, controlling the absorption of electrolytes and water (glutamine, acetorphan and octeotride) or modulating the immune/inflammatory reactions (budesonide, thalidomide, Celecoxib, and JBT 3002 lipopeptide; refs. [28][29][30][31][32][33][34]. Other drugs reduce the endoluminal concentration of active SN-38 by blocking the intestinal carboxylesterase using alkalinization of intestinal lumen, baicaline, or, more significantly, antibiotics (12, 35 -39).…”

Section: Discussionmentioning

confidence: 99%

Intestinal microflora and digestive toxicity of irinotecan in mice.

Brandi

Dabard

Raibaud

et al. 2006

Clinical Cancer Research

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Purpose: Delayed diarrhea is the most important side effect of irinotecan. The aim of this study was to investigate the role of intestinal microflora on the induction of systemic and intestinal toxicity and diarrhea, studying germ-free and holoxenic mice i.p. injected with irinotecan. Experimental Design: To evaluate the lethal dose, starting with 100 mg/kg/4 d, we treated the holoxenic mice with100, 80, and 60 mg/kg/4 d and germ-free mice with 60, 80,100, and150 mg/ kg/4 d. We recorded the percentage of dead animals, diarrhea, and the epithelial damage to the jejunum, ileum, cecum, and colon at optical and scanning electron microscopy. Results: Germ-free mice were more resistant to irinotecan than the holoxenic group. The lethal dose was between 60 and 80 mg of irinotecan for holoxenic mice and z150 mg for the germ-free. The intestinal damage score was higher in holoxenic than germ-free mice at 100 mg and equally diffuse in the small and large bowel. The damage in germ-free mice was less severe (8 of 40 samples) prevailing in the ileum. The differences were significant for all sites (jejunum, P < 0.001; ileum, P = 0.012; cecum, P = 0.001; colon, P < 0.001). No damage was found in germ-free mice at 60 mg. Diarrhea was present in all 100 and 80 mg holoxenic mice and in 19 of 20 cases at 60 mg whereas it was absent in 60 mg or sporadic in 80 and 100 mg germ-free mice. Conclusions: The intestinal microflora plays a key role in the intestinal toxicity of irinotecan.

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Section: Discussionmentioning

confidence: 99%

Intestinal microflora and digestive toxicity of irinotecan in mice.

Brandi

Dabard

Raibaud

et al. 2006

Clinical Cancer Research

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“…Thalidomide has been used in combination with palliative chemotherapy regimens using irinotecan (CPT-11) in colorectal cancer patients. Apart from its ability to ameliorate irinotecan induced side effects, especially nausea and diarrhoea, 162 thalidomide is undergoing clinical testing 163 164 due to its antiangiogenic effects on colorectal carcinoma in preclinical models. 165 Angiogenesis is tightly dependent on the viability of involved endothelial cells.…”

Section: Antiangiogenic Therapymentioning

confidence: 99%

Antiangiogenic therapy in human gastrointestinal malignancies

Heidemann

Binion

Domschke

et al. 2006

Gut

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SUMMARYAngiogenesis is a crucial process involved in numerous physiological and pathophysiological settings. During the past three decades, the field of tumour associated angiogenesis has been the focus of a plethora of basic research projects and clinical studies. Tumour associated neovessels satisfying the increased demand of oxygen and nutrients in malignant tumours are now emerging as specific targets for novel antineoplastic agents. This article discusses the present data on antiangiogenic treatment of human gastrointestinal malignancies, including gastric, pancreatic, and colorectal adenocarcinoma, and outlines potential future perspectives, such as development of surrogate markers of angiogenesis. PROCESS OF TUMOUR ANGIOGENESIS cAngiogenesis, the formation of new vessels from existing capillary beds, represents a central mechanism involved in many physiological and pathophysiological conditions, including embryonal development, wound healing, and chronic inflammation.1 In malignant tumours, angiogenesis represents a prerequisite for tumour growth, as the high metabolism of tumour cells requires large amounts of oxygen and nutrients. Without angiogenesis, the growth of malignant tumours is limited to 1-2 mm in diameter, which corresponds to the maximum distance oxygen can diffuse.2 3 Tumour vascularisation represents a conditio sine qua non for exponential tumour growth. Studies have indicated that the mitotic index of tumour cells decreases with increasing distance from the supplying microvessel.1 3 4 Primary tumours as well as their metastases are dependent on tumour associated microvessels to establish an independent blood supply. Enhanced vascularity allows tumours not only to expand in size but also facilitates haematogenous spreading by a higher probability of tumour angioinvasion. Once deposited in a distant organ, tumour metastases are dependent on building their own microvasculature.6 For this reason, disruption of angiogenesis pathways provides a therapeutic perspective in the treatment of primary malignant human tumours as well as their metastases.The concept that metastases are solely dependent on newly formed blood vessels in order to grow is opposed by observations made by Vermeulen and colleagues.7 According to their findings, approximately one third of hepatic colon cancer metastases studied (n = 28) do not induce new vessels but rather use and preserve the existing abundant vascularisation of the liver parenchyma. This pattern, called ''replacement pattern'', differs from the so-called ''desmoplastic'' and ''pushing''-type of metastasis. In all three patterns of metastasis, overall vessel density was not significantly different. However, a much lower endothelial cell proliferation was encountered in the replacement-type of metastasis. These findings suggest that not counting vessels, but rather evaluating endothelial cell (EC) proliferation, might be the appropriate way for assessing angiogenesis, depending on the type of metastasis.

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“…Severe diarrhea is the most important toxicity observed in this study, and new strategies to decrease its incidence are needed. Preliminary results of Govindarajan et al (24,25) indicate a reduced incidence of gastrointestinal toxic effects of irinotecan by the concomitant use of thalidomide, and we are conducting a clinical and pharmacokinetic trial to confirm these findings. The optimization of such combinations requires careful evaluation in future trials.…”

Section: Discussionmentioning

confidence: 67%