Melatonin Administered before or after a Cytotoxic Drug Increases Mammary Cancer Stabilization Rates in HER2/Neu Mice.

INTRODUCTION: The effects of chemotherapy are known to depend on the time of administration. Circadian rhythms are disturbed in tumors and in tumor bearers. Agents involved in controlling the circadian rhythms (chronobiotics) potentially can modify the outcomes of chemotherapeutics administered at different times of the day. Pineal hormone melatonin (MT) is a prototypic chronobiotic. OBJECTIVE: The aim of the study was to investigate if MT can affect efficacy or toxicity of chemotherapy drugs administered at the extreme time points of the working day of hospital personnel. METHODS: Cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) and adriamycin and docetaxel (AT) cytotoxic drug combinations were administered on day 0 at 11:00 a.m. or at 5:00 p.m. (UTC+03:00) to 6-month-old female HER2/neu transgenic FVB/N mice bearing mammary adenocarcinomas. Some mice were additionally provided with MT in drinking water (20 mg/L) at night 1 week before or 3 weeks after treatment or during both periods. Tumor node sizes, body weight, and blood cell counts were determined right before treatment and on days 2, 7, 14, and 21. RESULTS: Significant decrease in the mean tumor node volume was found by days 14 and 21 upon all CAF and AT treatment schedules, except in animals treated with AT at 5:00 p.m. without supplementation with MT. In the latter case, mean tumor node volume on day 21 was the same as in the control. Supplementation of AT administered at 5:00 p.m. with MT improved the tumor response. CAF and AT regimens supplemented with MT also augmented the number of tumor nodes that did not increase by more than 20% by day 21 as compared to CAF or AT alone, respectively. This effect was significant in groups treated with AT at 5:00 p.m. and consistent upon other schedules. On day 7, leukopenia and anemia were registered in groups treated with CAF regimen; however, blood cell counts normalized by day 14. Both CAF and AT were associated with drop in the body weight registered on day 7. Supplementation with MT did not affect changes of the body weight and blood counts. CONCLUSIONS: MT supplementation to cytotoxic drugs can improve antitumor response, especially if it is blunted because of an inappropriate time of administration.

The Effect of Polyphenolic Composition BP-C3 on the Efficacy and Hematological Toxicity of Cyclophosphamide in the Chemotherapy of Mice Bearing Soft Tissue Sarcomas Induced by Benzo[a]pyrene.

This study aimed to evaluate the effect of lignin-derived polyphenolic composition BP-C3 on the efficacy and hematological toxicity of cyclophosphamide (CPA). Male and female Swiss-H derived mice bearing benzo[a]pyrene-induced soft tissue sarcomas were treated with CPA 300 mg/kg, BP-C3 75 mg/kg, or a combination. Tumor growth inhibition in male mice treated with CPA, BP-C3, or a combination of CPA and BP-C3 was significant and corresponded to 78%, 45%, and 82%, respectively, on day 21 after CPA administration on day 0. In female mice, tumor growth inhibition was 58%, -11%, and 35% when treated with CPA, BP-C3, or a combination of CPA and BP-C3, respectively. CPA administration resulted in significant hematological toxicity evidenced by a decreased white blood cell count on day 4 (2.43 ± 1.77 × 109/L in male mice and 1.19 ± 0.71 × 109/L in female mice) and anemia development on day 7 (6.55 ± 1.74 × 1012/L in male mice and 5.89 ± 2.24 × 1012/L in female mice). The red blood cell count measured on day 7 in animals treated with the combination of BP-C3 and CPA constituted 7.12 ± 1.17 × 1012/L and 7.36 ± 2.07 × 1012/L for male and female mice, respectively. The results of our study demonstrate the antitumor activity of BP-C3 in male mice bearing soft tissue sarcomas. Neither the antitumor activity nor the hematological toxicity of CPA were significantly influenced by BP-C3. A less pronounced effect of CPA on RBC count is demonstrated when this agent is given jointly with BP-C3.

Metformin for cancer and aging prevention: is it a time to make the long story short?

During the last decade, the burst of interest is observed to antidiabetic biguanide metformin as candidate drug for cancer chemoprevention. The analysis of the available data have shown that the efficacy of cancer preventive effect of metformin (MF) and another biguanides, buformin (BF) and phenformin (PF), has been studied in relation to total tumor incidence and to 17 target organs, in 21 various strains of mice, 4 strains of rats and 1 strain of hamsters (inbred, outbred, transgenic, mutant), spontaneous (non- exposed to any carcinogenic agent) or induced by 16 chemical carcinogens of different classes (polycycIic aromatic hydrocarbons, nitroso compounds, estrogen, etc.), direct or indirect (need metabolic transformation into proximal carcinogen), by total body X-rays and γ- irradiation, viruses, genetic modifications or special high fat diet, using one stage and two-stage protocols of carcinogenesis, 5 routes of the administration of antidiabetic biguanides (oral gavage, intraperitoneal or subcutaneous injections, with drinking water or with diet) in a wide ranks of doses and treatment regimens. In the majority of cases (86%) the treatment with biguanides leads to inhibition of carcinogenesis. In 14% of the cases inhibitory effect of the drugs was not observed. Very important that there was no any case of stimulation of carcinogenesis by antidiabetic biguanides. It was conclude that there is sufficient experimental evidence of anti-carcinogenic effect of antidiabetic biguanides.

Methods of testing pharmacological drugs effects on aging and life span in mice.

The methodology of testing antiaging drugs in laboratory mice is presented. It is based on more than 40-year-long authors' experience in the field and includes the selection of mouse strain, sex, age at start of treatment, housing conditions, design of the long-term study, some noninvasive methods of assessment of biomarkers of aging, life-span parameters, pathology examination, and statistical treatment of the results.

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.

Methods of evaluating the effect of pharmacological drugs on aging and life span in mice.

The methodology of testing anti-aging drugs in laboratory mice is presented. It includes the selection of mouse strain, sex, age at start of treatment, housing conditions, design of the long-term study, some noninvasive methods of assessment, pathology examination, and statistical treatment of the results.

Melatonin as antioxidant, geroprotector and anticarcinogen.

The effect of the pineal indole hormone melatonin on the life span of mice, rats and fruit flies has been studied using various approaches. It has been observed that in female CBA, SHR, SAM and transgenic HER-2/neu mice long-term administration of melatonin was followed by an increase in the mean life span. In rats, melatonin treatment increased survival of male and female rats. In D. melanogaster, supplementation of melatonin to nutrient medium during developmental stages produced contradictory results, but and increase in the longevity of fruit flies has been observed when melatonin was added to food throughout the life span. In mice and rats, melatonin is a potent antioxidant both in vitro and in vivo. Melatonin alone turned out neither toxic nor mutagenic in the Ames test and revealed clastogenic activity at high concentration in the COMET assay. Melatonin has inhibited mutagenesis and clastogenic effect of a number of indirect chemical mutagens. Melatonin inhibits the development of spontaneous and 7-12-dimethlbenz(a)anthracene (DMBA)- or N-nitrosomethylurea-induced mammary carcinogenesis in rodents; colon carcinogenesis induced by 1,2-dimethylhydrazine in rats, N-diethylnitrosamine-induced hepatocarcinogenesis in rats, DMBA-induced carcinogenesis of the uterine cervix and vagina in mice; benzo(a)pyrene-induced soft tissue carcinogenesis and lung carcinogenesis induced by urethan in mice. To identify molecular events regulated by melatonin, gene expression profiles were studied in the heart and brain of melatonin-treated CBA mice using cDNA gene expression arrays (15,247 and 16,897 cDNA clone sets, respectively). It was shown that genes controlling the cell cycle, cell/organism defense, protein expression and transport are the primary effectors for melatonin. Melatonin also increased the expression of some mitochondrial genes (16S, cytochrome c oxidases 1 and 3 (COX1 and COX3), and NADH dehydrogenases 1 and 4 (ND1 and ND4)), which agrees with its ability to inhibit free radical processes. Of great interest is the effect of melatonin upon the expression of a large number of genes related to calcium exchange, such as Cul5, Dcamkl1 and Kcnn4; a significant effect of melatonin on the expression of some oncogenesis-related genes was also detected. Thus, we believe that melatonin may be used for the prevention of premature aging and carcinogenesis.

Elucidation of the effect of brain cortex tetrapeptide Cortagen on gene expression in mouse heart by microarray.

OBJECTIVES: Aging is associated with significant alterations in gene expression in numerous organs and tissues. Anti-aging therapy with peptide bioregulators holds much promise for the correction of age-associated changes, making a screening for their molecular targets in tissues an important question of modern gerontology. The synthetic tetrapeptide Cortagen (Ala-Glu-Asp-Pro) was obtained by directed synthesis based on amino acid analysis of natural brain cortex peptide preparation Cortexin. In humans, Cortagen demonstrated a pronounced therapeutic effect upon the structural and functional posttraumatic recovery of peripheral nerve tissue. Importantly, other effects were also observed in cardiovascular and cerebrovascular parameters. DESIGN: Based on these latter observations, we hypothesized that acute course of Cortagen treatment, large-scale transcriptome analysis, and identification of transcripts with altered expression in heart would facilitate our understanding of the mechanisms responsible for this peptide biological effects. We therefore analyzed the expression of 15,247 transcripts in the heart of female 6-months CBA mice receiving injections of Cortagen for 5 consecutive days was studied by cDNA microarrays. RESULTS: Comparative analysis of cDNA microarray hybridisation with heart samples from control and experimental group revealed 234 clones (1,53% of the total number of clones) with significant changes of expression that matched 110 known genes belonging to various functional categories. Maximum up- and down-regulation was +5.42 and -2.86, respectively. CONCLUSION: Intercomparison of changes in cardiac expression profile induced by synthetic peptides (Cortagen, Vilon, Epitalon) and pineal peptide hormone melatonin revealed both common and specific effects of Cortagen upon gene expression in heart.

Effects of exogenous melatonin--a review.

The results of studies on the effect of pineal indole hormone melatonin on the life span of mice, rats, fruit flies, and worms are critically reviewed. In mice, long-term administration of melatonin was followed by an increase in their life span in 12 experiments and had no effect in 8 of 20 different experiments. In D. melanogaster, the supplementation of melatonin to the nutrient medium during developmental stages gave contradictory results, but when melatonin was added to food throughout the life span, an increase in the longevity of fruit flies has been observed. Melatonin decreased the survival of C. elegans but increased the clonal life span of planaria Paramecium tertaurelia. Available data suggest antioxidant and atherogenic effects of melatonin. Melatonin alone turned out to be neither toxic nor mutagenic in the Ames test and revealed clastogenic activity in high concentration in the COMET assay. Melatonin inhibits mutagenesis induced by irradiation and by indirect chemical mutagens and inhibits the development of spontaneous and chemical-induced tumors in mice and rats. Further studies and clinical trials are needed to verify that melatonin is both safe and has geroprotector efficacy for humans.