Increasing levels of environmental mutagens: Potential for affecting viral evolution and pathogenicity a speculative review

Kava is a traditional beverage of various Pacific Basin countries. Kava has been introduced into the mainstream U.S. market principally as an anti-anxiety preparation. The effects of the long-term consumption of kava have not been documented adequately. Preliminary studies suggest possible serious organ system effects. The potential carcinogenicity of kava and its principal constituents are unknown. As such, kava extract was nominated for the chronic tumorigenicity bioassay conducted by the National Toxicology Program (NTP). At present toxicological evaluation of kava extract is being conducted by the NTP. The present review focuses on the recent findings on kava toxicity and the mechanisms by which kava induces hepatotoxicity.     

Titanium dioxide in our everyday life; is it safe?

BACKGROUND: Titanium dioxide (TiO(2)) is considered as an inert and safe material and has been used in many applications for decades. However, with the development of nanotechnologies TiO(2) nanoparticles, with numerous novel and useful properties, are increasingly manufactured and used. Therefore increased human and environmental exposure can be expected, which has put TiO(2) nanoparticles under toxicological scrutiny. Mechanistic toxicological studies show that TiO(2) nanoparticles predominantly cause adverse effects via induction of oxidative stress resulting in cell damage, genotoxicity, inflammation, immune response etc. The extent and type of damage strongly depends on physical and chemical characteristics of TiO(2) nanoparticles, which govern their bioavailability and reactivity. Based on the experimental evidence from animal inhalation studies TiO(2) nanoparticles are classified as "possible carcinogenic to humans" by the International Agency for Research on Cancer and as occupational carcinogen by the National Institute for Occupational Safety and Health. The studies on dermal exposure to TiO(2) nanoparticles, which is in humans substantial through the use of sunscreens, generally indicate negligible transdermal penetration; however data are needed on long-term exposure and potential adverse effects of photo-oxidation products. Although TiO(2) is permitted as an additive (E171) in food and pharmaceutical products we do not have reliable data on its absorption, distribution, excretion and toxicity on oral exposure. TiO(2) may also enter environment, and while it exerts low acute toxicity to aquatic organisms, upon long-term exposure it induces a range of sub-lethal effects. CONCLUSIONS: Until relevant toxicological and human exposure data that would enable reliable risk assessment are obtained, TiO(2) nanoparticles should be used with great care.     

Triclosan inhibits enoyl-reductase of type I fatty acid synthase in vitro and is cytotoxic to MCF-7 and SKBr-3 breast cancer cells

BACKGROUND AND PURPOSE: Human type I fatty acid synthase has been proposed as a chemotherapeutic target for the treatment of breast cancer based on the inactivation of human beta-ketoacyl synthase activity by cerulenin. Triclosan, a common antibiotic, functions by inhibiting the enoyl-reductase enzymes of type II fatty acid synthases in susceptible bacteria. If triclosan is an inhibitor of human fatty acid synthase and if inhibition of fatty acid synthase is toxic to breast cancer cell lines, triclosan could prove to be a lead compound for the treatment of breast cancer. Consequently, the inhibitory activity of triclosan against vertebrate type I fatty acid synthases and its effects on breast cancer lines in cell culture were investigated. METHODS: The inhibitory activities of triclosan against human and goose fatty acid synthases and each of the partial reactions were investigated using spectrophotometric assays. The ability of triclosan at various concentrations to inhibit growth and reduce the viability of MCF-7 and SKBr-3 cells in culture was evaluated. RESULTS: Kinetic studies showed triclosan to be a slow binding inhibitor of human and goose type I fatty acid synthase and to inhibit the partial activity of enoyl-reductase with IC(50) values between 10 and 50 microM. Triclosan at similar concentrations was also shown to inhibit both viability and growth of MCF-7 and SKBr-3 cells in culture. CONCLUSIONS: The results corroborate the hypothesis that fatty acid synthase may be a target of breast cancer chemotherapy and suggest that inhibitors of the enoyl-reductase partial activity of fatty acid synthase may have chemotherapeutic potential.     

NTP summary report on the metabolism, disposition, and toxicity of 1,4-butanediol (CAS No. 110-63-4)

1,4-Butanediol is an industrial chemical used in the manufacture of other organic chemicals. It was nominated by the National Cancer Institute and selected for evaluation by the NTP because of high production volume, the potential for worker exposure, the lack of adequate toxicological characterization, and the lack of evaluation for carcinogenic potential. As documented in the scientific literature, 1,4-butanediol is rapidly absorbed and metabolized to gamma-hydroxybutyric acid in animals and humans. A metabolism and disposition study conducted in F344/N rats by the NTP confirmed the rapid and extensive conversion of 1-[14C]-1,4-butanediol to 14CO2. Because of this rapid and extensive conversion, the toxicological profile of 1,4-butanediol reflects that of gamma-hydroxybutyric acid. gamma-Hydroxybutyric acid is a naturally occurring chemical found in the brain and peripheral tissues which is converted to succinate and processed through the tricarboxylic acid cycle. Although the function of gamma-hydroxybutyric acid in peripheral tissues is unknown, in the brain and neuronal tissue it is thought to function as a neuromodulator. gamma-Hydroxybutyric acid readily crosses the blood-brain barrier, and oral, intraperitoneal, or intravenous administration elicits characteristic neuropharmacologic responses. These same responses are observed after administration of 1,4-butanediol. The lactone of gamma-hydroxybutyric acid, gamma-butyrolactone, is also rapidly converted to gamma-hydroxybutyric acid by enzymes in the blood and liver of animals and humans. gamma-Butyrolactone was previously evaluated by the NTP in 14-day and 13-week toxicology studies and 2-year toxicology and carcinogenesis studies in F344/N rats and B6C3F1 mice. No organ-specific toxicity occurred in the toxicology studies. In the carcinogenesis studies, an equivocal response occurred in male mice, based on a marginal increase in the incidence of pheochromocytomas of the renal medulla. Because of the rapid and extensive conversion of gamma-butyrolactone to gamma-hydroxybutyric acid, the evaluation of gamma-butyrolactone was in fact an evaluation of gamma-hydroxybutyric acid. This summary report presents a review of the current literature which documents that both 1,4-butanediol and gamma-butyrolactone are rapidly metabolized to gamma-hydroxybutyric acid, and the pharmacologic and toxicologic responses to these chemicals are due to their metabolic conversion to gamma-hydroxybutyric acid. Because the toxicity and carcinogenicity of gamma-hydroxybutyric acid was fully evaluated in the NTP studies of gamma-butyrolactone, and a lack of organ-specific toxicity or carcinogenic potential was demonstrated, it is concluded that there is a high likelihood that 1,4-butanediol would be negative in a similar set of studies. For these reasons, it is the opinion of the NTP that 1,4-butanediol should be considered not carcinogenic in animals and no further evaluation of 1,4-butanediol is needed at this time.     

Endocrine effects in the hazard assessment of drugs used in animal production

Criteria of toxicological assessment are currently reviewed to ensure an adequate protection to susceptible groups, such as infants and children; in particular, concern arises about altered endocrine homeostasis in the developing organism, eliciting possible persistent effects such as reproductive disturbances and increased risk of tumours in target organs. Such items are obviously relevant also for veterinary drugs, whose main safety issue is potential lifetime exposure to residues. Two groups of chemicals, nitroimidazoles and imidazole antifungals, are reviewed as examples of the relevance of endocrine toxicity to the hazard assessment of compounds used in animal production. Nitroimidazoles are metabolized into genotoxic intermediates; in rodents they induce testicular toxicity and carcinogenicity. In particular, mammary neoplasms, mostly fibroadenomas, are consistently induced in rats as the most important effect in chronic studies; this may hint to possible endocrine-related mechanisms. Accordingly, evidences on other chemicals (e.g., triazines) show mammary tumorigenicity in rodents associated to hormonal alterations. In fact, nitroimidazoles affect synthesis of both pituitary and steroid hormones in vitro and rise progesterone and FSH levels in rats; also, limited clinical data in humans indicate endocrine-related effects. Overall, nitroimidazoles appear to affect the endocrine balance; however, the actual importance of such alterations, especially in regards to rat mammary tumours, has yet to be clarified. Imidazole antimycotics are broad-spectrum inhibitors of steroid synthesis; accordingly, diverse reproductive and developmental alterations are observed, depending on age and sex of animals exposed. Effects include pregnancy loss, delayed pup growth as well as reduced weight of androgen-dependent tissue; however, it is still difficult to identify the most susceptible biological phase. Overall the potential for inducing endocrine-related alterations should be carefully evaluated also for drugs used in animal production. A screening battery should produce a distinct fingerprint for each major endocrine activity, thus targeting longer-term tests (such as the two-generation study) on the most relevant endpoints. Moreover, the validation of molecular approaches would contribute to a biologically-based evaluation, by providing insights on such items as early effects and species-specificity.     

Review of Usnic Acid and Usnea Barbata Toxicity

Usnic acid is a prominent secondary lichen metabolite that has been used for various purposes worldwide. Crude extracts of usnic acid or pure usnic acid have been marketed in the United States as dietary supplements to aid in weight loss. The US Food and Drug Administration (FDA) received 21 reports of liver toxicity related to the ingestion of dietary supplements that contain usnic acid. This prompted the FDA to issue a warning about one such supplement, LipoKinetix, in 2001 (http://www.cfsan.fda.gov/~dms/ds-lipo.html). Subsequently, usnic acid and Usnea barbata lichen were nominated by the National Toxicology Program (NTP) for toxicity evaluations. At present, a toxicological evaluation of usnic acid is being conducted by the NTP. This review focuses on the recent findings of usnic acid-induced toxicities and their underlying mechanisms of action.     

ROS implication in a new antitumor strategy based on non-thermal plasma

Non-thermal plasma (NTP) is generated by ionizing neutral gas molecules/atoms leading to a highly reactive gas at ambient temperature containing excited molecules, reactive species and generating transient electric fields. Given its potential to interact with tissue or cells without a significant temperature increase, NTP appears as a promising approach for the treatment of various diseases including cancer. The aim of our study was to evaluate the interest of NTP both in vitro and in vivo. To this end, we evaluated the antitumor activity of NTP in vitro on two human cancer cell lines (glioblastoma U87MG and colorectal carcinoma HCT-116). Our data showed that NTP generated a large amount of reactive oxygen species (ROS), leading to the formation of DNA damages. This resulted in a multiphase cell cycle arrest and a subsequent apoptosis induction. In addition, in vivo experiments on U87MG bearing mice showed that NTP induced a reduction of bioluminescence and tumor volume as compared to nontreated mice. An induction of apoptosis was also observed together with an accumulation of cells in S phase of the cell cycle suggesting an arrest of tumor proliferation. In conclusion, we demonstrated here that the potential of NTP to generate ROS renders this strategy particularly promising in the context of tumor treatment.     

Review of Ginkgo biloba-induced toxicity,from experimental studies to human case reports

Ginkgo biloba seeds and leaves have been used as a traditional herbal remedy for thousands of years, and its leaf extract has been consumed as a botanical dietary supplement for decades. Ginkgo biloba extract is a complex mixture with numerous components, including flavonol glycosides and terpene lactones, and is one of the most widely sold botanical dietary supplements worldwide. Concerns about potential health risks for the general population have been raised because of the widespread human exposure to Ginkgo biloba and its potential toxic and carcinogenic activities in rodents. The National Toxicology Program conducted 2-year gavage studies on one Ginkgo biloba leaf extract and concluded that there was clear evidence of carcinogenic activity of this extract in mice based on an increased incidence of hepatocellular carcinoma and hepatoblastoma. Recently, Ginkgo biloba leaf extract has been classified as a possible human carcinogen (Group 2B) by the International Agency for Research on Cancer. This review presents updated information on the toxicological effects from experimental studies both in vitro and in vivo to human case reports (caused by ginkgo seeds or leaves), and also summarizes the negative results from relatively large clinical trials.     

Dermal toxicity of topical (-)epigallocatechin-3-gallate in BALB/c and SKH1 mice

(-)Epigallocatechin-3-gallate (EGCG), the major polyphenolic component of green tea, inhibits experimental chemical and physical carcinogenesis, yet little toxicological data has been reported. Therefore, we performed studies on the dermal toxicity of EGCG applied in an ointment formulation in mice. Female BALB/c mice were dehaired with a topical depilatory and administered 75 microl EGCG in hydrophilic Ointment U.S.P. at three concentrations (10, 3, and 1%, all w/w) daily for 30 days. At the 10% concentration, gross toxicity was manifested by the formation of erythema and papular lesions by day 5. A 7% reduction in weight was observed by day 15. No toxicity was observed at the two lower concentrations or in the vehicle control group. Also, no toxicity was observed when mice were dehaired by shaving. This study was repeated in female SKH1 mice, an outbred hairless strain that does not require depilation. No toxicity was observed in the SKH1 mice, indicating that daily topical EGCG appears non-toxic in normal skin. However, use of topical depilatories may potentiate dermal toxicity of EGCG.     

Critical Review on the Carcinogenic Potential of Pesticides Used in Korea

Pesticides used in Korea are grouped by four classes of hazard (extremely, highly, moderately and slightly hazardous) based on acute oral and dermal toxicity in the rat. However, there is little information of carcinogenic effects. The aim of this study was to evaluate potential carcinogenicity for active ingredients of pesticides used in Korea. A total of 1,283 pesticide items were registered under the Pesticide Control Act of which 987 were commercially available. Of these 987 items, 360 active ingredients not duplicated were evaluated for carcinogenicity using the carcinogen list established by the US Environmental Protection Agency (EPA). Some 25 out of 360 ingredients were classified as likely to be carcinogenic (probable) to humans and 52 had suggestive evidence of carcinogenic potential (suspected) based on the US EPA classification. Some 31% of 987 items contained probable or suspected human carcinogenic ingredients. Carcinogenic pesticides accounted for 24% (5,856/24,795 tons) of the total volume of consumption in Korea. Interestingly, pesticides with lower acute toxicity were found to have higher carcinogenic potential. Based on these findings, the study suggests that it is important to provide information on long-term toxicity to farmers, in addition to acute toxicity data.     

Airborne Particulate Matter and Human Health: Toxicological Assessment and Importance of Size and Composition of Particles for Oxidative Damage and Carcinogenic Mechanisms

Air pollution has been considered a hazard to human health. In the past decades, many studies highlighted the role of ambient airborne particulate matter (PM) as an important environmental pollutant for many different cardiopulmonary diseases and lung cancer. Numerous epidemiological studies in the past 30 years found a strong exposure-response relationship between PM for short-term effects (premature mortality, hospital admissions) and long-term or cumulative health effects (morbidity, lung cancer, cardiovascular and cardiopulmonary diseases, etc). Current research on airborne particle-induced health effects investigates the critical characteristics of particulate matter that determine their biological effects. Several independent groups of investigators have shown that the size of the airborne particles and their surface area determine the potential to elicit inflammatory injury, oxidative damage, and other biological effects. These effects are stronger for fine and ultrafine particles because they can penetrate deeper into the airways of the respiratory tract and can reach the alveoli in which 50% are retained in the lung parenchyma. Composition of the PM varies greatly and depends on many factors. The major components of PM are transition metals, ions (sulfate, nitrate), organic compound, quinoid stable radicals of carbonaceous material, minerals, reactive gases, and materials of biologic origin. Results from toxicological research have shown that PM have several mechanisms of adverse cellular effects, such as cytotoxicity through oxidative stress mechanisms, oxygen-free radical-generating activity, DNA oxidative damage, mutagenicity, and stimulation of proinflammatory factors. In this review, the results of the most recent epidemiological and toxicological studies are summarized. In general, the evaluation of most of these studies shows that the smaller the size of PM the higher the toxicity through mechanisms of oxidative stress and inflammation. Some studies showed that the extractable organic compounds (a variety of chemicals with mutagenic and cytotoxic properties) contribute to various mechanisms of cytotoxicity; in addition, the water-soluble faction (mainly transition metals with redox potential) play an important role in the initiation of oxidative DNA damage and membrane lipid peroxidation. Associations between chemical compositions and particle toxicity tend to be stronger for the fine and ultrafine PM size fractions. Vehicular exhaust particles are found to be most responsible for small-sized airborne PM air pollution in urban areas. With these aspects in mind, future research should aim at establishing a cleared picture of the cytotoxic and carcinogenic mechanisms of PM in the lungs, as well as mechanisms of formation during internal engine combustion processes and other sources of airborne fine particles of air pollution.     

Pediatric medulloblastoma: toxicity of current treatment and potential role of protontherapy

Post-operative craniospinal irradiation and systemic chemotherapy are both necessary in the treatment of pediatric medulloblastoma. Late toxicity is a major problem in long term survivors and significantly affects their quality of life. We have systematically reviewed the literature to examine data on late toxicity, specifically focusing on: endocrine function, growth and bone development, neurocognitive development, second cancers, ototoxicity, gynecological toxicity and health of the offspring, cardiac toxicity and pulmonary toxicity. In this paper, we describe qualitatively the kind of detected side effects and, whenever possible, try to assess their incidence and the relative role of craniospinal irradiation (as opposed to other treatments and to the disease itself) in producing them. Subsequently we examine the possible approach to reduce unwanted effects from craniospinal irradiation to target and non-target tissues and we consider briefly the role of hyperfractionation, tomotherapy and IMRT. We describe the characteristics of protontherapy and its potential for non-target tissues toxicity reduction reviewing the existing physical and dosimetric studies and the (still very limited) clinical experiences. Finally we propose intensity modulated spot scanning protontherapy with multiportal simultaneous optimization (IMPT) as a possible tool for dose distribution optimization within different areas of CNS and potential reduction of target tissues toxicity.     

Apoptosis-induced cell death due to oleanolic acid in HaCaT keratinocyte cells--a proof-of-principle approach for chemopreventive drug development

Oleanolic acid (OA) is a naturally occurring triterpenoid in food materials and is a component of the leaves and roots of Olea europaea, Viscum album L., Aralia chinensis L. and more than 120 other plant species. There are several reports validating its antitumor activity against different cancer cells apart from its hepatoprotective activity. However, antitumor activity against skin cancer has not been studied well thus far. Hence the present study of effects of OA against HaCaT (immortalized keratinocyte) cells--a cell-based epithelial model system for toxicity/ethnopharmacology-based studies--was conducted. Radical scavenging activity (DPPH·) and FRAP were determined spectrophotometrically. Proliferation was assessed by XTT assay at 24, 48 and 72 hrs with exposure to various concentrations (12.5-200 μM) of OA. Apoptotic induction potential of OA was demonstrated using a cellular DNA fragmentation ELISA method. Morphological studies were also carried out to elucidate its antitumor potential. The results revealed that OA induces apoptosis by altering cellular morphology as well as DNA integrity in HaCaT cells in a dose-dependent manner, with comparatively low cytotoxicity. The moderate toxicity observed in HaCaT cells, with induction of apoptosis, possibly suggests greater involvement of programmed-cell death-mediated mechanisms. We conclude that OA has relatively low toxicity and has the potential to induce apoptosis in HaCaT cells and hence provides a substantial and sound scientific basis for further validation studies.     

三氯生对离体鹅尾臀腺和人乳腺癌细胞脂肪酸合成酶的抑制作用

背景与目的;研究表明,人乳腺癌早期和病程中癌细胞脂肪酸合成酶（fatty acid synthase,FAS)呈高效表达,抑制FAS可引起癌细胞凋亡。本研究采用酶促反应动力学实验观察三氯生对离体鹅尾臀腺FAS的影响,建立实验方法,研究三氯生对人乳腺癌SKBr3细胞FASS的抑制作用。方法：运用超速离心和Superdex PG200层析技术分离纯化鹅尾臀腺FAS,用超速离心技术部分纯化人乳腺癌SKBr3细胞FAS,不同浓度三氯生与FAS相互作用不同时间后,加入底物,用分光光度法观察三氯生对FAS的抑制作用。结果：在鹅尾臀腺组,FAS被纯化为SDS-PAGE电泳单条区带（分子量250kDa)。三种浓度三氯生（12.5,25.0,100.0μmol/L）与FAS在催化作用前相互作用0,5和10min,对FAS的抑制率分别为26.40%,28.30%和43.93%(12.5μmol/L）;46.22%,50.28%和97.05%(25μmol/L）;98.11%,97.75%和97.37%(100μmol/L）。在人乳腺癌SKBr3细胞组FAS被部分纯化,25,50,100和200μmol/L三氯生分别与FAS在催化前相互作用5min,对FAS活性的抑制率分别为20.00%,26.67%,60.00%和100.00%。结论：三氯生对离体鹅尾臀腺FAS和人乳腺癌SKBr3细胞FAS均具有抑制作用;作用强度既依赖于抑制剂浓度,又依赖于抑制剂与酶相互作用时间。     

Therapeutic activity of DCC-2036, a novel tyrosine kinase inhibitor,against triple-negative breast cancer patient-derived xenografts by targeting AXL/MET

Triple-negative breast cancer (TNBC) is insensitive to endocrine therapies and targeted therapies to human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER) and progesterone receptor (PR). New targets and new targeted therapeutic drugs for TNBC are desperately needed. Our study confirmed that DCC-2036 inhibited the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of TNBC cells as well as induced apoptosis. Moreover, the antiproliferative activity of DCC-2036 was more efficient than that of most clinical drugs. In addition, the combination of DCC-2036 and cisplatin or lapatinib had synergistic effects on TNBC cells. Mechanistically, DCC-2036 targeted AXL/MET, especially AXL, and regulated the downstream PI3K/Akt-NFκB signaling to exert its antitumor effect in TNBC. DCC-2036 also inhibited the growth and metastasis of xenografted MDA-MB-231 cells (AXL/MET-high TNBC cells) but not MDA-MB-468 cells (AXL-low TNBC cells) in NSG mice in vivo. Furthermore, DCC-2036 significantly inhibited tumor growth and invasion of AXL/MET-high TNBC PDX tumors but not AXL/MET-low TNBC PDX tumors. These results highlighted the roles of AXL/MET in cancer growth and metastasis and further verified that the critical targets of DCC-2036 are AXL and MET, especially AXL. In addition, there was no significant toxicity of DCC-2036 even at a high dosage. Therefore, DCC-2036 may be a potential compound to treat TNBC, especially for tumors with AXL/MET overexpression.     

Chemoprevention of breast cancer

Summary The hypothesis that oestrogen is an important promotor of human breast cancer raises the possibility that endrocrine intervention could prevent the disease. Various methods of reducing oestrogenic activity have been proposed including dietary control, progestin therapy, and ovarian ablation. Tamoxifen is a synthetic anti-oestrogen of low toxicity with proven anti-proliferative activity in endocrine sensitive breast cancer which makes it an attractive alternative for a trial of endocrine prevention. We have undertaken a doubleblind placebo-controlled pilot study to assess the feasibility of mounting a large multicentre study of tamoxifen in the prevention of breast cancer in high risk women. Two hundred women were randomised to tamoxifen or placebo during an 18 month accrual period. Acute toxicity was mild and serial studies of blood lipids, clotting factors, and bone mineral density suggested that no long-term deleterious effects are likely to be seen. It is estimated that 10,000 women would be required with a 10–15 year follow up in order to detect a 25% prevention effect.     

The next era of treatment for hormone receptor-positive,HER2-negative advanced breast cancer: Triplet combination-based endocrine therapies

Until recently, the standard of care for hormone receptor-positive (HR+) breast cancer was single-agent endocrine therapy, which aims to prevent estrogen receptor signaling. This therapeutic strategy has extended survival without the toxicity associated with chemotherapy, but primary endocrine therapy resistance is common, and secondary resistance develops over time. Adjunct downstream inhibition of the cyclin-dependent kinase (CDK)4/6 pathway, intended to delay and prevent endocrine therapy resistance, has further extended progression-free survival in patients receiving endocrine therapy; however, resistance still eventually develops in these patients. Addition of phosphatidylinositol-3 kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibitors to combined CDK4/6 and endocrine inhibitor regimens may help prolong CDK4/6 inhibitor sensitivity. Early trials combining CDK4/6 inhibitors, PI3K or mTOR inhibitors, and endocrine therapy have shown encouraging signs of clinical activity. However, further research is needed to help understand the extent of treatment benefit from triplet therapy and where this strategy will fit in the treatment sequence for patients with HR+ breast cancer.     

Ribociclib for the treatment of hormone receptor-positive,human epidermal growth factor receptor 2-negative advanced breast cancer

Introduction: The emergence of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors marked a significant advancement in the treatment of advanced breast cancer. Ribociclib is an orally bioavailable, highly selective inhibitor of CDK4/6. In combination with various endocrine therapies, ribociclib has demonstrated clinical activity as a first-line therapy for patients with HR+, HER2? advanced breast cancer, without compromising the favorable toxicity profile associated with endocrine therapy. Thus, ribociclib is now considered a new standard of care for HR+, HER2? advanced breast cancer.

Areas covered: This review provides a concise overview of the preclinical and clinical development of ribociclib, including evidence of its clinical activity and safety profile when combined with endocrine therapy in HR+, HER2? advanced breast cancer.

Expert commentary: CDK4/6 inhibition represents a promising treatment option for patients with HR+ metastatic breast cancer. Ribociclib significantly improved progression-free survival in patients receiving first-line endocrine therapy for HR+, HER2? advanced breast cancer. Planned and ongoing trials investigating ribociclib in combination with other endocrine therapies and in various clinical settings will help to determine the optimal treatment sequence for different patient populations.     

Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization

Purpose: The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacologic, toxicologic, metabolic and pharmacokinetic developmental potential. Methods: In vitro and in vivo assays were used to assess the compounds for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters. Results: BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin. Both BMS-286309 and −422461 were comparable to irinotecan regarding preclinical antitumor activity assessed in mice bearing distal site murine and human tumors. BMS-422461 was also found to be orally active. Both analogs were >100-fold more potent in vivo than irinotecan and both were superior to irinotecan with respect to toxicological assessment of GI injury in mice. The generation of parent compound from BMS-422461 was qualitatively similar in mouse, rat and human blood and liver S9 fractions. The percentage of BMS-286309 remaining as the active lactone form at equilibrium was comparable in mouse and human plasma. The pharmacokinetic profile in rat blood demonstrated that BMS-422461 was rapidly cleaved to BMS-286309. Conclusions: The favorable in vivo metabolic activation of BMS-422461, and the pharmacokinetic characteristics of BMS-286309, suggest that the good efficacy of BMS-422461 is derived from robust in vivo release of BMS–286309 in rodents and the likelihood that this biotransformation will be preserved in humans. The comparable antitumor activity of BMS-422461 to irinotecan, as well as reduced preclinical GI toxicity, make this novel camptothecin analog attractive for clinical development.     

Carcinogenesis and its modification by environmental endocrine disruptors: in vivo experimental and epidemiological findings

Although a great deal of concern has been raised about the hazard potential of endocrine disruptors present in the environment, the in vivo data available from both experimental and epidemiological studies suggest that the majority of those agents do not pose a risk with regard to cancer development. Indeed, naturally occurring examples such as isoflavonoids even appear to exert protective effects. Only for xenobiotics such as 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), polychlorinated biphenyls (PCBs) and tetrachloro-p-dioxin (TCDD) and special cases of phenols and phthalates is there unequivocal evidence of carcinogenicity and this appears to be directly linked to their toxicity. Thus, careful in vivo assessment is required before drawing any conclusions regarding agents capable of affecting the mammalian endocrine system.