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.

Radioprotective and radiomitigative effects of BP-C2, a novel lignin-derived polyphenolic composition with ammonium molybdate, in two mouse strains exposed to total body irradiation.

PURPOSE: There remains an unmet medical need for radioprotective and mitigative agents. BP-C2 is a novel lignin-derived polyphenolic composition with ammonium molybdate, developed as radioprotector/radiomitigator. OBJECTIVES: The present study evaluated BP-C2 for the mitigation of acute radiation syndrome (ARS). METHODS: A total-body irradiation mouse model (TBI, 4.0-8.0 Gy) was used in the study. RESULTS: In a 30-day survival study, performed in CBA mice, BP-C2, at a dosage of 81.0 mg/kg, improved survival (dose reduction factor (DRF) = 1.1) and increased the formation of endogenous spleen colony-forming units (CFU). In C57BL/6 mice, BP-C2, when administered daily for 7 days, starting 24 hours after TBI, also improved survival. In animals irradiated with 5.0 Gy, BP-C2 increased the number of CFUs (6.7 ± 5.1) compared to the 5.0 Gy placebo group (2.3 ± 2.3, p = .0245). The number of surviving intestinal crypts was maintained in the 5.0 Gy BP-C2 group (133.7 ± 13.9), in contrast to the 5.0 Gy placebo group (124.2 ± 10.5, p < .0023). BP-C2 also increased the number of LGR5 + positive cells in intestinal crypts. CONCLUSION: BP-C2 mitigates radiation-induced damage in mid-lethal range of radiation doses. Effects are mediated by enhancement of extramedullar hematopoiesis in the spleen and a protective effect on the intestinal epithelium.

Results and prospects of development of new polyphenolic drugs for cancer patients.

The conference "Results and prospects of development of new polyphenolic drugs for cancer patients" took place at the N.N. Petrov National Medical Research Center of Oncology (PNMRCO) on May 31, 2017, and gathered researchers involved in development and evaluation of medicinal products based on the novel lignin-derived soluble polyphenolic polymer BP-Cx-1. BP-Cx-1 is the platform for a portfolio of innovative pharmacological products such as BP-C1, BP-C2 and BP-C3.

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.

Vemurafenib-induced progression of breast cancer: a case report and review of the literature.

Vemurafenib, a specific inhibitor of mutated BRAF kinase, may activate wild-type BRAF and therefore induce squamous cell skin carcinomas in patients treated for melanoma. All vemurafenib clinical trials excluded patients with multiple primary malignant tumors; therefore, the action of this drug on concurrent BRAF wild-type malignancies remains insufficiently studied. We observed a patient, who was administered vemurafenib for BRAF mutation-containing melanoma, but experienced immediate relapse of previously controlled breast cancer disease. Interestingly, breast cancer lesions underwent regression soon after vemurafenib discontinuation. Therefore, caution must be taken while considering vemurafenib treatment for patients with multiple tumors.