Optimization of Erlotinib Plus Sulindac Dosing Regimens for Intestinal Cancer Prevention in an Apc-Mutant Model of Familial Adenomatous Polyposis (FAP)
| Autor: | Omer F. Yavuz, Powel H. Brown, Wan Mohaiza Dashwood, Praveen Rajendran, Michelle I. Savage, Roderick H. Dashwood, Ahmet M. Ulusan, Shizuko Sei, Trace A. Gustafson, Eduardo Vilar, Altaf Mohammed, Sabeeta Kapoor |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Cancer Research medicine.medical_treatment Gastroenterology 0302 clinical medicine Sulindac Antineoplastic Combined Chemotherapy Protocols Colectomy Cancer Colo-Rectal Cancer medicine.anatomical_structure Oncology Adenomatous Polyposis Coli 030220 oncology & carcinogenesis 6.1 Pharmaceuticals Toxicity Colonic Neoplasms Erlotinib Drug medicine.drug medicine.medical_specialty Genes APC Clinical Sciences Oncology and Carcinogenesis Colonic Polyps Article Familial adenomatous polyposis Dose-Response Relationship 03 medical and health sciences Erlotinib Hydrochloride Therapeutic index Internal medicine Intestinal Neoplasms medicine Animals Oncology & Carcinogenesis Dose-Response Relationship Drug business.industry Animal Prevention Evaluation of treatments and therapeutic interventions medicine.disease digestive system diseases Small intestine Colon polyps Rats APC Disease Models Animal 030104 developmental biology Genes Disease Models Mutation business Digestive Diseases |
| Zdroj: | Cancer prevention research (Philadelphia, Pa.), vol 14, iss 3 Cancer Prev Res (Phila) |
| Popis: | A clinical trial in patients with familial adenomatous polyposis (FAP) demonstrated that sulindac plus erlotinib (SUL+ERL) had good efficacy in the duodenum and colon, but toxicity issues raised concerns for long-term prevention. We performed a biomarker study in the polyposis in rat colon (Pirc) model, observing phosphorylated Erk inhibition in colon polyps for up to 10 days after discontinuing ERL+SUL administration. In a follow-up study lasting 16 weeks, significant reduction of colon and small intestine (SI) tumor burden was detected, especially in rats given 250 ppm SUL in the diet plus once-a-week intragastric dosing of ERL at 21 or 42 mg/kg body weight (BW). A long-term study further demonstrated antitumor efficacy in the colon and SI at 52 weeks, when 250 ppm SUL was combined with once-a-week intragastric administration of ERL at 10, 21, or 42 mg/kg BW. Tumor-associated matrix metalloproteinase-7 (Mmp7), tumor necrosis factor (Tnf), and early growth response 1 (Egr1) were decreased at 16 weeks by ERL+SUL, and this was sustained in the long-term study for Mmp7 and Tnf. Based on the collective results, the optimal dose combination of ERL 10 mg/kg BW plus 250 ppm SUL lacked toxicity, inhibited molecular biomarkers, and exhibited effective antitumor activity. We conclude that switching from continuous to once-per-week ERL, given at one-quarter of the current therapeutic dose, will exert good efficacy with standard-of-care SUL against adenomatous polyps in the colon and SI, with clinical relevance for patients with FAP before or after colectomy. Prevention Relevance: This investigation concludes that switching from continuous to once-per-week erlotinib, given at one-quarter of the current therapeutic dose, will exert good efficacy with standard-of-care sulindac against adenomatous polyps in the colon and small intestine, with clinical relevance for patients with FAP before or after colectomy. |
| Databáze: | OpenAIRE |
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