Effects of Dietary N-(4-Hydroxyphenyl)retinamide on N-Nitrosomethylbenzylamine Metabolism and Esophageal Tumorigenesis in the Fischer 344 Rat

Abstract

Dietary 4-HPR enhances tumorigenesis in response to NMBA in the rat esophagus by increasing tumor initiation events. Dietary 4-HPR may exert paradoxical effects at some sites, such as the aerodigestive tract, by modulating the bioactivation of carcinogens in target tissues.

A Phase I Clinical and Pharmacokinetic Study of Fenretinide Combined with Paclitaxel and Cisplatin for Refractory Solid Tumors

“…It is difficult to determine the meaning of this pattern of response, however, given the extensive preclinical data regarding retinoids in tobacco related malignancies including lung cancer and head and neck squamous carcinomas, it would be reasonable to take this regimen into more extensive clinical studies in these populations of patients. Caution must be exercised in this population of patients given the recent report showing enhanced N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in male Fischer 344 rats who also received dietary fenretinide [28]. This paradoxical effect is unexplained and certainly gives pause to the consideration of utilizing this agent as a chemopreventive.…”

Fenretinide: a prototype cancer prevention drug

“…Although fenretinide as a single agent (0.75 -1.5 mmol/kg diet or greater) has been consistently shown to inhibit tumour Buccal pouch Hamster DMBA NE [130] Colon (adenoma) Rat DMH + [131] Colon (adenoma) Rat AOM + [55,115,132,133] Colon (carcinoma) Rat AOM NE [115] Colon (adenoma) Rat MNU NE [131] Oesophagus Rat MBN NE (-) [56] Lung (carcinoma) Hamster DEN + [54] Lung (carcinoma) Hamster DEN NE [54] Lung (carcinoma) Hamster B(a)P NE [134] Lung (carcinoma) Mouse/Inhalation B(a)P NE [52] Lung (carcinoma) Mouse NNK NE (-) [53] Lymphatic system (lymphoma) Mouse None + [135,136] Mammary gland Mouse None + [137] Mammary gland Rat DMBA + [44,138] Mammary gland Rat DMBA NE (-) [57] Mammary gland Mouse DMBA NE [139] Mammary gland Rat MNU + [16,43,140,143] Mammary gland Rat MNU NE [57,144] Ovary Rat BOP On test…”

“…Mixed results have been noted for single-agent fenretinide prevention in various models of prostate [46][47][48], bladder [49,50], lung, oesophagus [51][52][53][54] and colon carcinogenesis [55] with some studies showing little or no effect. Indeed, in a few experimental systems, using high dosages or alternative routes of delivery, fenretinide potentiation of tumour formation has been observed [53,56,57]. There have been several possible explanations proposed for the tumour-enhancing effect of fenretinide in certain experimental settings.…”

“…These include the differential response shown by a number of retinoids, including fenretinide, when administered during the initiation versus the promotion phase of carcinogen administration [53,57]. In the rat N-methylbenzylnitrosamine-induced oesophageal cancer model, fenretinide was shown to increase metabolic activation of the carcinogen by cytochrome P450 induction, thereby increasing the number of tumour-promoting adducts in oesophageal tissue DNA [56]. Prior to the first clinical studies, subchronic and chronic mouse, rat and dog toxicity assays of fenretinide confirmed that the drug was well-tolerated compared to other retinoids [58].…”