Assessment of antitumor activity of BP-C1, a platinum-based anticancer agent with a lignin-derived polymeric ligand, in autochthonous induced and spontaneous carcinogenesis rodent models.

BACKGROUND: A standard approach to study the anticancer activity of novel drugs is their testing in animals with inoculated tumors, which has some limitations. An alternative is the use of spontaneous or carcinogen-induced tumor models as they have better translation potential. The carcinogen-induced and transgenic tumor models were used to assess the antitumor activity of BP-C1, a platinum-containing drug with lignin-derived polymeric ligand. METHODS: We used female Swiss-H-derived mice and Wistar female rats to induce autochthonous tumors via exposure to benzo[a]pyrene and 1,2-dimethylhydrazine, respectively. Additionally, transgenic HER-2/neu FVB/N female mice, prone to the development of spontaneous mammary carcinomas, were used. RESULTS: Antitumor activity of BP-C1 was observed in soft tissue sarcomas, induced by benzo[a]pyrene. The animals treated with BP-C1 exhibited more stabilizations and therapy responses compared to placebo controls. The efficacy of BP-C1 was somewhat reduced compared to cyclophosphamide; however, their combination resulted in an enhanced antitumor effect. For the 1,2-dimethylhydrazine-induced rat colon cancer model, BP-C1 reduced tumor multiplicity by 21-41 %. For mammary adenocarcinomas in HER-2/neu FVB/N mice, short-termed complete responses were observed in the BP-C1 groups with a frequency of 12-13 %, while complete responses were absent in the placebo group. CONCLUSION: The results acquired indicated a wide spectrum of antitumor activity of BP-C1.

Polyphenolic drug composition based on benzenepolycarboxylic acids (BP-C3) increases life span and inhibits spontaneous tumorigenesis in female SHR mice.

Effects of long-term application of novel polyphenolic composition BP-C3, containing polyphenolic benzenepolycarboxylic acids, vitamins and minerals on some biomarkers of aging, life span and spontaneous tumorigenesis has been studied in female SHR mice. Administration of BP-C3 with drinking water (0.005%) did not exert any toxic effect (did not have effect on general condition of animals, weight dynamics and consumption of food), postponed age-related switch-off of estrous function, caused slight reduction of body temperature. An increased survival was observed in mice treated with BP-C3 (p=0.00164, log rank test). BP-C3 increased mean lifespan - by 8.4%, lifespan of the last 10% of animals - by 12.4%, and life span of tumor-free mice - by 11.6%. A tendency in ability of BP-C3 to inhibit development of spontaneous tumors in mice was detected, though it did not reach the level of statistical significance (p=0.166, log rank test). The number of malignant mammary tumors was 1.5 times less and total number of tumors of various localizations was 1.6 times less in BP-C3 treated animals. Multiple tumors were registered in 8% of mice in the сontrol group and no cases - in BP-C3 treated group. Thus, BP-C3 demonstrated some anti-carcinogenic and a pronounced geroprotective activity.

Rodent models for the preclinical evaluation of drugs suitable for pharmacological intervention in aging.

INTRODUCTION: There is a growing scientific and public interest in the development of new antiaging drugs for the purposes of extending mean and/or maximum life span, maintaining normal physiological function, and alleviating the onset and severity of age-associated diseases. This review looks at the current screening approaches used to evaluate the efficacy of such compounds, with a particular focus on those that extend life span. AREAS COVERED: This article reviews the current preclinical approaches for assessing longevity therapy including the assessment of antiaging drugs (aging reversal) and geroprotectors (drugs that prevent premature aging and/or slowdown or postpone aging). This article also discusses the methods and the importance in evaluating the anticarcinogenic potential and safety of antitumor drugs. EXPERT OPINION: Based on more than 30 years of experience in the field, the authors believe that the standard testing protocols for antiaging drugs should include the simultaneous evaluation of the drug's safety, as well as its antitumor and anticarcinogenic activity potential. The authors also believe that the principles of international programs for the expert critical evaluation of pharmacological interventions should be created to improve the range of antiaging interventions available for human studies.

Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo.

Population studies have shown that treatment with the antidiabetic biguanide metformin significantly reduced cancer risk. In our animal studies, metformin delayed the onset of mammary adenocarcinoma (MAC) in transgenic HER-2/neu mice but not the onset of spontaneous mammary tumors in female SHR mice. Pineal hormone also inhibits mammary carcinoma development in HER2/neu transgenic mice as well as in female SHR mice. Here we demonstrated that a combination of metformin and melatonin significantly inhibits growth of transplanted tumors in mice. Metformin (0.5 mg/ml in drinking water) increased mean life span by 8% and MAC latency by 13.2% (p < 0.05) in HER2/neu mice. The treatment with melatonin alone (2 mg/L in drinking water during the night time) or combined treatment with metformin (0.5 mg/ ml in drinking water during the day time) + melatonin (2 mg/L in drinking water during the night time) did not influence mammary carcinogenesis in the mice. The treatment metformin alone inhibited the growth of transplantable HER2 mammary carcinoma in FVB/N male mice by 46% at the 45(th) day after transplantation (p < 0.001). The combined treatment with metformin + melatonin significantly suppressed Ehrlich tumor growth (by 40%, p < 0.001). These results suggest that metformin may be useful in prevention and treatment of breast cancer.

Insulin in aging and cancer: antidiabetic drug Diabenol as geroprotector and anticarcinogen.

The effects of new antidiabetic drug Diabenol (9-beta-diethylaminoethyl-2,3-dihydroimidazo-(1,2-alpha)benzimidazol dihydrochloride) on life span and spontaneous tumor incidence in NMRI and transgenic HER-2/neu mice as well as on colon carcinogenesis induced by 1,2-dimethylhydrazine in rats are studied. It is shown that treatment with the drug failed influence body weight gain dynamics, food and water consumption and the body temperature, slowed down age-related disturbances in estrous function and increased life span of all and 10% most long-living NMRI mice. The treatment with Diabenol inhibited spontaneous tumor incidence and increased the mammary tumor latency in these mice. Diabenol treatment slowed down age-related changes in estrous function in HER-2/neu mice, failed influence survival of these mice and slightly inhibited the incidence and decreased the size of mammary adenocarcinoma metastases into the lung. In rats exposed to 1,2-dimethylhydrazine, treatment with Diabenol significantly inhibited multiplicity of all colon tumors, decreased by 2.2 times the incidence of carcinomas in ascending colon and by 3.1 times their multiplicity. Treatment with Diabenol was followed by higher incidence of exophytic and well-differentiated colon tumors as compared with the control rats exposed to the carcinogen alone (76.3% and 50%, and 47.4% and 14.7%, respectively). Thus, the drug increases survival and inhibits spontaneous carcinogenesis in mice and inhibits colon carcinogenesis in rats.

Central and peripheral effects of insulin/IGF-1 signaling in aging and cancer: antidiabetic drugs as geroprotectors and anticarcinogens.

Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. Insulin/insulin-like growth factor 1 (IGF-1) signaling molecules linked to longevity include DAF-2 and insulin receptor (InR) and their homologues in mammals and to inactivation of the corresponding genes followed by increased life span in nematodes, fruit flies, and mice. It is possible that the life-prolonging effect of caloric restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of life span-extending mutations in the insulin/IGF-1 signaling pathway and mimetics of effects of caloric restriction could be a direction in the regulation of longevity. Some literature and our own observations suggest that antidiabetic drugs could be promising candidates for both life span extension and prevention of cancer.

Effects of phentermine and phenformin on biomarkers of aging in rats.

BACKGROUND: Caloric restriction (CR) is the only treatment known to substantially prolong both average and maximal life span in experimental animals. Interventions that mimic certain effects of CR could be potential anti-aging treatments in humans. Drugs which reduce appetite (anorexiants) represent one class of candidate treatments. Agents that reduce the glucose utilization by the organism could also represent another class of candidate CR mimetics. OBJECTIVE: In our study, we addressed the following questions: (1) Does treatment with an anorexiant reduce caloric intake and body weight of experimental animals comparable to that caused by CR? (2) Does treatment with an antidiabetic agent influence caloric intake and body weight? (3) Does treatment with any of these drugs affect metabolic parameters of an organism in the way similar to that observed with CR? METHODS: One hundred and twenty 6-month-old female Wistar-derived LIO rats were randomly subdivided into four groups and exposed to: (1) ad libitum feeding with placebo (controls); (2) the antidiabetic drug phenformin (2 mg/kg); (3) the anorectic drug phentermine (1 mg/kg), and (4) the same amount of food as the group with the least food intake during the previous week (pair-fed controls). Food and water intake, body weight, and rectal temperature were measured weekly during 16 weeks. At the end of the 16th week of the experiment, serum levels of glucose, total beta-lipoprotein and pre-beta-lipoprotein fractions, cholesterol, triglycerides, insulin, total triiodothyronine, and free thyroxine were estimated. The contents of diene conjugates and Schiff's bases, total antioxidant activity, the activities of Cu/Zn superoxide dismutase, glutathione S-transferase, and glutathione peroxidase, and the generation of reactive oxygen species (ROS) were studied in brain and liver homogenates and in the serum. RESULTS: The controls exposed to pair feeding had a significantly reduced food consumption (about 20%) as compared with the ad libitum fed controls and thus exhibited a moderate CR. Treatment with phentermine reduced the caloric intake by about 12% as compared with the ad libitum fed controls. Body weight and water intake in this group were only slightly decreased (by about 2 and 5%, respectively) as compared with the controls. The mean rectal temperature in the phentermine group (38 degrees C) was significantly higher than in the ad libitum fed (37.8 degrees C) and pair-fed (37.6 degrees C) controls. Treatment with phentermine also resulted in significantly reduced ROS levels in all tissues studied, while the highest ROS production was found in ad libitum (blood serum) and pair-fed (brain) controls. Treatment with phenformin did not significantly influence food and water consumption, body weight, and temperature when compared with the ad libitum fed controls. Rats treated with this antidiabetic drug showed intermediate values of ROS generation. Differences among the groups in total antioxidant activity were not obvious. CONCLUSIONS: Treatment with phentermine reduces caloric intake slightly less than is commonly observed in CR studies. CR due to forcibly reduced feeding and CR due to substance-suppressed appetite appear to act through different metabolic mechanisms and thus may affect aging and longevity in different ways.