Small intestinal mucosal toxicity of cis-platinum – comparison of toxicity with platinum analogues and dexamethasone

Abstract

Summary Cis-platinum causes profound gastrointestinal symptoms in patients and these may persist for many days after drug administration. Gut mucosal toxicity may be a factor in the pathogenesis of such prolonged nausea, vomiting and anorexia. The effects of cis-platinum on mouse ileal mucosal architecture, villus epithelial cell influx and disaccharidase activity are described in comparison with dhe effects of two platinum analogues, CBDCA and CHIP. In addition the effect of dexamethasone, a useful drug in the palliation of cis-platinum-induced emesis, in combination with cis-platinum is described.Cis-platinum, CBDCA and CHIP cause profound reduction in crypt cell production rate (CCPR) and thus villus epithelial cell influx within hours of administration leading to villus stunting and diminished function. CBDCA showed the least profound effect with early rebound in CCPR by day 3. Cis-platinum and CHIP were roughly equitoxic to ileal crypts with rebound in CCPR being delayed until day 7. Similarly, CBDCA caused least reduction in disaccharidase activity with cis-platinum and CHIP being equitoxic. The addition of dexamethasone had no protective effect on the effects of cis-platinum on murine ileal mucosa and mice given the combination chronically had no weight gaii over 18 weeks, their weight paralleling those receiving cisplatinum alone.The platinate compounds have differing degrees of intestinal mucosal toxicity but no direct inference can be drawn in respect to the clinical situation where CBDCA causes less gastrointestinal symptomatology than CHIP but where both cause less than cis-platinum. Dexamethasone does not act by mucosal protection to provide its useful effects in prolonged cis-platinum-induced gastrointestinal symptoms.

Acute Gastroduodenal Mucosal Injury after Cisplatin plus Etoposide Chemotherapy

“…This sequence is mainly referred to the changes ob served in bowel epithelium, and several studies con firmed the development of proximal jejunum mucosal damage on specimens taken from 2 to 9 days after antiblastic treatment [20,21]. Small intestinal mucosal toxicity induced by cisplatin was observed in mice between days 3 and 7 after administration of the drug [9]. Considering that the total renewal time of gastric, duodenal and jejunal epithelium is similar [19], and that cytosine-arabinoside-induced gastric mucosal alterations follow the same above-mentioned evolu tionary sequence [18], we decided to rely on this time course to fix the well-timed day for evaluating the gastroduodenal changes in our patients.…”

“…Indeed, chemotherapy-in duced nausea and vomiting are due mainly to central mechanisms [6,7], and the role of the gastrointestinal mucosal injury is uncertain and unproven [9]. Con sequently.…”

“…The toxicity of this combination therapy is mainly due to the major side effects of cisplatin, name ly nephro-, oto-, myelo-and gastrointestinal toxicity [1]; also, etoposide can provoke myelosuppression of modest degree and short duration [2,3], and oro pharyngeal mucositis was observed after administra tion of very high doses of the drug [4], One of the major drawbacks for patients receiving PE is vomiting, which is considered to be due mainly to cisplatin, although etoposide may induce moderate nausea and vomiting in some cases [4], The term 'gas trointestinal toxicity' is commonly used to point out the highly emetogenic power of cisplatin, but nausea and vomiting seem to be due chiefly to the effects of the drug on the chemotactic trigger zone [5][6][7]; peri pheral mechanisms are also suspected [8], but the correlation between vomiting and gastrointestinal mucosal toxicity is unproven [9], In this study, we evaluated endoscopically the PEinduced injury on stomach and first tract of duodenum and its possible correlation with the onset of nausea and vomiting.…”

Association ofCASP3polymorphism with hematologic toxicity in patients with advanced non‐small‐cell lung carcinoma treated with platinum‐based chemotherapy

“…Platinum causes the apoptosis of small intestinal crypt-like cells, ileal mucosal architecture, and villus epithelial cell influx, leading to prolonged nausea, vomiting, and anorexia. (36) Binding of TNF to TNFR1 induces the recruitment of the signaling proteins, further initiating apoptosis. (6)(7)(8)(9)(10) The TNFa rs1800629 was located 308 nucleotides upstream of the translation initiation site in the TNFa promoter.…”

Action of Cyclooxygenase Inhibitors and a Leukotriene Biosynthesis Inhibitor on Cisplatin-Induced Acute and Delayed Emesis in the Ferret

“…Cisplatin and other chemotherapeutic drugs are reported to increase COX-2 mRNA levels in the gastric mucosa with concurrent permeability changes and structural damage (26,27). In our studies, the selective COX-2 inhibitor DFU had an action to transiently antagonize the delayed phase of emesis, although this was not dose-related when measured over 8 -16-h periods, and the other COX-2 inhibitor, L-745,337, had no action.…”