Oral RDP58 allows CPT-11 dose intensification for enhanced tumor response by decreasing gastrointestinal toxicity.
Cancer patients undergoing triple therapy (CPT-11, 5-fluorouracil, and leucovorin) often present with severe delayed diarrhea as a result of chemotherapy-induced gastrointestinal (GI) toxicity and inflammation. RDP58 is a novel, anti-inflammatory, D-amino acid decapeptide that inhibits the production of tumor necrosis factor alpha, IFN-gamma, and interleukin 12, and has been shown to effectively inhibit clinical symptoms and intestinal inflammation in several rodent models of chemically induced colitis, nonhuman primates with spontaneous colitis, and humans with mild to moderate ulcerative colitis. We evaluated RDP58 as a potential protective agent in chemotherapy-induced GI inflammation. Oral administration of RDP58 significantly decreased the incidence of diarrhea and improved the survival rates of mice treated with toxic doses of CPT-11 or 5-fluorouracil. Histological analysis showed that RDP58 significantly reduced the destruction of the intestinal mucosa by inhibiting local overproduction of tumor necrosis factor alpha, IFN-gamma, and interleukin 12 in vivo. Furthermore, RDP58 administration allowed the maximum tolerated dose of CPT-11 to be doubled in tumor-bearing mice resulting in significantly enhanced primary tumor responses and prolongation of time to relapse without a concomitant increase in GI toxicity. Our results suggest that RDP58 may have clinical utility in cancer therapy by preventing treatment-associated GI toxicity and potentially increasing the effectiveness of chemotherapy.
Zhao
Jingsong
J
Department of Discovery Research, SangStat Medical Corporation, Fremont, California 94555, USA. jingsongzhao@sbcglobal.net
Huang
Lingyan
L
Belmar
Nicole
N
Buelow
Roland
R
Fong
Timothy
T
D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000633:toxicity; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004064:Digestive System / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015395:Histocompatibility Antigens Class I; D007413:Intestinal Mucosa / Q000378:metabolism; D000077146:Irinotecan; D007583:Jejunum / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D010455:Peptides; C092373:allotrap; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin