Thus, insulin resistance/hyperinsulinemia is associated with a more aggressive course of the disease in certain groups of the patients but--in contrast to excessive estrogenic stimulation--does not result in increased genotoxic damage in tumor and normal tissues. The data obtained once more confirm the need for treatment and prevention measures aimed at correcting hormonal-metabolic disturbances in endometrial cancer patients and groups at risk of this disease. Such an approach might include use of antidiabetic biguanides, thiazolidinediones (glitazones), and statins.

Thus, CYP19 polymorphism might be one of the genetic risk factors for endometrial cancer development.

The abundance of fat tissue surrounding normal and malignant epithelial mammary cells raises the questions whether such ''adipose milieu'' is important in the local proinflammatory/genotoxic shift, which apparently promotes tumor development and worsens prognosis, and what conditions stimulate this shift, or ''adipogenotoxicosis.'' We studied 95 mammary fat samples from 70 postmenopausal and 25 premenopausal breast cancer (BC) patients at a distance of 1.5-2.0 cm from tumors. The levels of leptin, adiponectin, TNFa and IL-6 release after 4-hr incubation of the samples were evaluated with ELISA, nitric oxide (NO) production by Griess reaction and lipid peroxidation by determination of thiobarbiturate-reactive products (TBRP). Infiltration of fat with macrophages (CD68-positive cells) and expression of cytochrome P450 1B1/estrogen 4-hydroxylase (CYP1B1) were detected by immunohistochemistry. Aromatase (CYP19) activity in mammary fat was measured by 3 H 2 O release from 3 H-1b-androstenedione. In the postmenopausal BC patients, NO and TNFa production by adipose tissue explants increased independent of BMI and in parallel with decreasing leptin and, especially, adiponectin release. In the premenopausal patients, higher CYP1B1 expression and TBRP level were found in mammary fat, while higher aromatase activity was combined with higher CYP1B1 expression as well as NO and IL-6 production. In the postmenopausal group, impaired glucose tolerance was associated with higher IL-6 release production by fat and with higher IL-6/adiponectin ratio. Thus, signs of adipogenotoxicosis in mammary fat can be found in both pre-and postmenopausal BC patients. This condition is likely being maintained through estrogen-and glucose-related factors and mechanisms presumably associated with less favorable types of hormonal carcinogenesis. ' 2007 Wiley-Liss, Inc.

The effects of administration of phenformin and clofibrate to 32 breast cancer patients who underwent radical mastectomy and suffered from hormonal metabolic disturbances involving a decline in immunologic response were investigated. It was demonstrated that treatment with these drugs during 2–7 months results in an improvement in metabolic parameters and delayed hypersensitivity reaction to DNCB, tuberculin and candidin (75.5% of cases), an increase in T lymphocyte count (56.3%) and an improvement of the reaction of lymphocyte blast transformation (66.6%). The improvement in the immunologic status of the patients persisted for 6–8 weeks after the stoppage of phenformin administration; a gradual decline in immunologic response and return to the original level were recorded 4–6 months after stoppage of phenformin therapy. The effect of clofibrate on metabolic and immunologic parameters did not manifest itself as soon as 6–8 weeks after stoppage. Elimination of metabolic immunodepression, which gradually develops in the course of normal ageing and tumor process, should be the main objective of metabolic immunotherapy. To this end, therapeutic means, other than phenformin and clofibrate, may be used provided they exert the same effects on carbohydrate-fat metabolism. The desirability of study of the effects of a long-term course of drugs of this kind on the therapy of cancer patients is discussed.

Metformin is a well-known antidiabetic medication, which, besides diabetes, may be involved into modulation of other age-related pathologies, including cancer. The study concerns 12 gene polymorphisms divided into 2 groups consisting of 6 genes each. The first group was composed from so-called "standard" (S) polymorphisms, for which the connection with metabolic response to metformin is already established. The second group included polymorphisms of genes encoding proteins possibly connected with diabetes mellitus type 2 (DM2), impaired glucose tolerance or cancer and entitled here as "associated" (A). A total of 156 postmenopausal women (average age 60.7 ± 0.7) were included, 37 of them healthy, 64 with type DM2 and concurrent treatment-naïve cancer (mostly breast, endometrial or colorectal cancer), 32 with DM2 without cancer, and 23 with treatment-naïve cancer and normal glucose tolerance. The leading metformin response S-marker in combined group of DM2 patients was the CC variant of OCT1-R61C polymorphism of organic cation transporter protein 1 gene. In cancer patients without DM2, this position belonged to AC and AA genotypes of OCT1_rs622342 polymorphism. Among the A-polymorphisms, GA variant of sex hormone-binding globulin gene SHBG_D356N was less frequently observed in DM2 patients with or without cancer. Besides, in diabetics, the same polymorphic variant of SHBG as well as GC genotype of oxidized lipoprotein receptor OLR1_G501C and GG genotype of locus rs11065987 near BRAP gene were carried rather often in combination with "metformin-positive" variant of OCT1_R61C. In addition, carriers of OCT1_R61C and OCT1_rs622342 polymorphisms with potentially positive reaction to metformin had higher insulin resistance score (HOMA-IR) values. Received data lead to the conclusion that postmenopausal diabetics, both with and without cancer, differ in genetic stigmata of potential response to metformin less than they differ from cancer patients without DM2. As genetic polymorphisms associated with metabolic and anticancer metformin (and, possibly, phenformin) effects may be different, this subject requires further investigation.

Background:As endometrial cancer (EC) prevalence increases with obesity, we aimed to determine whether EC characteristics depend upon obesity type: ‘standard’ (SO) or ‘metabolically healthy obesity’ (MHO).Patients & methods:258 EC patients were included. Data on anthropometry, blood hormones, lipids and glucose, and tumor features were collected.Results:EC clinicopathologic characteristics and clinical stage correlate differently with BMI and obesity type. BMI is related inversely with tumor grade while SO patients are characterized by a more advanced clinical stage than those with MHO. Besides typical insulin resistance signs, EC patients with SO often display a higher serum leptin/adiponectin ratio compared with MHO patients. Historical data suggest a gradual increase in EC patient height and weight, and a decrease in MHO prevalence.Conclusion:It is currently unknown whether the latter observation reflects the evolution of EC, or obesity alongside the current epidemic. Regardless, the reduced MHO prevalence demonstrates the need for more intensive preventive measures aimed at obesity and obesity-associated conditions, including different EC subtypes.

No abstract

The content of DNA damage marker 8-hydroxy-2-deoxyguanosine in 16 receptor-negative and 18 receptor-positive human breast neoplasms was measured by immunohistochemical methods. Positive staining was revealed in 81.3 and 50.0% samples of groups 1 and 2, respectively. The effect of arylhydrocarbon receptor agonist beta-naphthoflavone on the content of 8-hydroxy-2-deoxyguanosine and number of estrogen and progesterone receptors was evaluated in MCF-7 breast cancer cells. The degree of genotoxic damage significantly increased 1 h after combined treatment with estradiol and beta-naphthoflavone (in contrast to individual treatment) and remained practically unchanged in the follow-up period. According to the estrogen effect-switching phenomenon, genotoxic damage can contribute to the development of R(-)-breast cancer.