The adipocytokines are biologically active polypeptides that are produced either exclusively or substantially by the adipocytes, and act by endocrine, paracrine, and autocrine mechanisms. Most have been associated with obesity, hyperinsulinaemia, type 2 diabetes, and chronic vascular disease; in addition, six adipocytokines--vascular endothelial growth factor, hepatocyte growth factor, leptin, tumour necrosis factor-alpha, heparin-binding epidermal growth factor-like growth factor, and interleukin-6--promote angiogenesis while one, adiponectin, is inhibitory. Obesity and insulin resistance have both been identified as risk factors for breast cancer and are associated with late-stage disease and poor prognosis. Angiogenesis is essential for breast cancer development and progression, and so it is plausible that obesity-related increases in adipocytokine production and a reduction in adiponectin may adversely affect breast cancer outcome by their angiogenesis-related activities. There is also experimental evidence that some adipocytokines can act directly on breast cancer cells to stimulate their proliferation and invasive capacity. Thus, adipocytokines may provide a biological mechanism by which obesity and insulin resistance are causally associated with breast cancer risk and poor prognosis. Both experimental and clinical studies are needed to develop this concept, and particularly in oestrogen-independent breast cancers where preventive and therapeutic options are limited.

Background & Aims-Non-steroidal anti-inflammatory drugs (NSAIDs) are effective cancer chemopreventive agents. However, chronic administration of NSAIDs is associated with significant side effects, mainly gastrointestinal. Given these limitations, we synthesized phospho-sulindac (P-S; OXT-328), a novel sulindac derivative.

The insulin resistance-colon cancer hypothesis, stating that insulin resistance may be associated with the development of colorectal cancer, represents a significant advance in colon cancer, as it emphasizes the potential for this cancer to become a modifiable disease. The fact that the incidence of insulin resistance has been increasing in the United States and much of the rest of the Western world where colon cancer remains the second leading cause of cancer death makes the exploration of the interrelationship of these conditions a subject of high priority. Here, we review the salient features of insulin resistance, defined as impaired biological response to the action of insulin. Recent epidemiological studies, evaluating potential associations between colon cancer risk and diabetes mellitus, dietary intake and metabolic factors, and IGF levels in several clinical settings, provide strong support of the insulin resistance-colon cancer hypothesis (without establishing causality). Mechanistically, insulin resistance has been associated with hyperinsulinemia, increased levels of growth factors including IGF-1, and alterations in NF-kappaB and peroxisome proliferator-activated receptor signaling, which may promote colon cancer through their effects on colonocyte kinetics. It is a reasonable expectation that in the not too distant future, critical interventions to the already mapped molecular sequence of events, which link two apparently disparate entities, combined with lifestyle changes could abrogate the development of colon cancer.

Previously, we demonstrated that life-long methionine restriction (MR) in rats increases life span and inhibits aging-related disease processes. The present study examines the effects of MR on the formation of preneoplastic aberrant crypt foci (ACF) in the colon of azoxymethane (AOM)-treated rats. Six-week-old male F344 rats were placed on essential amino acid-defined diets containing either 0.86% Met (control diet) or 0.17% Met (MR diet) and 1 wk later were given AOM (15 mg/kg/wk, s.c.) for 2 consecutive wk. Ten weeks after the final AOM treatment, ACF formation was markedly reduced in rats fed the MR diet with ACF containing > or = 4 crypts/focus being reduced by over 80% compared to controls (P < 0.001). A similar 83% reduction in ACF containing > or = 4 crypts/focus was observed in rats fed the MR diet only during the post-initiation period (after the final dose of AOM; P < 0.001). Five weeks after AOM administration, a 12% reduction in colonic cell proliferation was observed in MR rats compared to controls (P < 0.05). These results show that MR inhibits colonic tumor development in the rat, an effect that occurs primarily during post-initiation phases of carcinogenesis and may be due, in part, to an inhibition of colonic cell proliferation.