The efficient method for the synthesis of novel cell permeable inhibitors of protein kinase CK2 with anticancer and proapoptotic activity has been developed. A series of polybrominated benzimiadazole derivatives substituted by various cyanoalkyl groups have been synthesized. Cyanoethyl derivatives were obtained by Michael type addition of 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi) and 4,5,6,7-tetrabromo-2-methyl-1H-benzimidazole to acrylonitrile, whilst cyanomethyl, cyanopropyl and cyanobutyl analogs by N-alkylation of 4,5,6,7-tetrabromo-1H-benzimidazole and 4,5,6,7-tetrabromo-2-methyl-1H-benzimidazole with appropriate cyanoalkyl halides. The inhibitory activity against protein kinase rhCK2α catalytic subunit and cytotoxicity against two human cancer cell lines: acute lymphocytic leukemia (CCRF-CEM) and breast (MCF-7) were evaluated for all newly synthesized compounds. Additionally, the proapoptotic activity toward leukemia cells and intracellular inhibition of CK2 for the most cytotoxic derivatives have been performed, demonstrating 4,5,6,7-tetrabromo-2-methyl-1H-benzimidazole as a new selective inhibitor of rhCK2 with twenty-fold better proapoptotic activity than parental compound (TBBi).

Members of the kinesin superfamily are involved in key functions during intracellular transport and cell division. Their involvement in cell division makes certain kinesins potential targets for drug development in cancer chemotherapy. The two most advanced kinesin targets are Eg5 and CENP-E with inhibitors in clinical trials. Other mitotic kinesins are also being investigated for their potential as prospective drug targets. One recently identified novel potential cancer therapeutic target is the Mitotic kinesin-like protein 2 (MKLP-2), a member of the kinesin-6 family, which plays an essential role during cytokinesis. Previous studies have shown that inhibition of MKLP-2 leads to binucleated cells due to failure of cytokinesis. We have previously identified compound 1 (paprotrain) as the first selective inhibitor of MKLP-2. Herein we describe the synthesis and biological evaluation of new analogs of 1. Our structure-activity relationship (SAR) study reveals the key chemical elements in the paprotrain family necessary for MKLP-2 inhibition. We have successfully identified one MKLP-2 inhibitor 9a that is more potent than paprotrain. In addition, in vitro analysis of a panel of kinesins revealed that this compound is selective for MKLP-2 compared to other kinesins tested and also does not have an effect on microtubule dynamics. Upon testing in different cancer cell lines, we find that the more potent paprotrain analog is also more active than paprotrain in 10 different cancer cell lines. Increased selectivity and higher potency is therefore a step forward toward establishing MKLP-2 as a potential cancer drug target.

We report DNA cleavage by ruthenium(II) arene anticancer complex [(η(6)-p-terp)Ru(II)(en)Cl](+) (p-terp=para-terphenyl, en=1,2-diaminoethane, complex 1) after its photoactivation by UVA and visible light, and the toxic effects of photoactivated 1 in cancer cells. It was shown in our previous work (T. Bugarcic et al., J. Med. Chem. 51 (2008) 5310-5319) that this complex exhibits promising toxic effects in several human tumor cell lines and concomitantly its DNA binding mode involves combined intercalative and monofunctional (coordination) binding modes. We demonstrate in the present work that when photoactivated by UVA or visible light, 1 efficiently photocleaves DNA, also in hypoxic media. Studies of the mechanism underlying DNA cleavage by photoactivated 1 reveal that the photocleavage reaction does not involve generation of reactive oxygen species (ROS), although contribution of singlet oxygen ((1)O2) to the DNA photocleavage process cannot be entirely excluded. Notably, the mechanism of DNA photocleavage by 1 appears to involve a direct modification of mainly those guanine residues to which 1 is coordinatively bound. As some tumors are oxygen-deficient and cytotoxic effects of photoactivated ruthenium compounds containing {Ru(η(6)-arene)}(2+) do not require the presence of oxygen, this class of ruthenium complexes may be considered potential candidate agents for improved photodynamic anticancer chemotherapy.

Angiosarcoma/lymphangiosarcoma is a rare malignancy with poor prognosis. We generated a mouse model with inducible endothelial-cell-specific deletion of Tsc1 to examine mTORC1 signaling in lymphangiosarcoma. Tsc1 loss increased retinal angiogenesis in neonates and led to endothelial proliferative lesions from vascular malformations to vascular tumors in adult mice. Sustained mTORC1 signaling was required for lymphangiosarcoma development and maintenance. Increased VEGF expression in tumor cells was seen, and blocking autocrine VEGF signaling abolished vascular tumor development and growth. We also found significant correlations between mTORC1 activation and VEGF, HIF1α, and c-Myc expression in human angiosarcoma samples. These studies demonstrated critical mechanisms of aberrant mTORC1 activation in lymphangiosarcoma and validate the mice as a valuable model for further study.

Intracranial tumors are the second most frequent malignancies in children and posterior fossa is a common location for these neoplasias during childhood. Recent advances in surgical techniques, radiotherapy and chemotherapy resulted in dramatic increase in the survival rates of these children, however they are still source of a significant morbidity and mortality. Endocrinological complications and late sequelae of childhood posterior fossa tumours are common among the survivors of these tumours and include growth retardation, hypothyroidism, pubertal disorders, gonadal dysfunction and osteopenia. These complications have significant impact on the quality of life of the survivors of childhood posterior fossa tumours. In this paper, the frequency, etiology, and management of these complications will be reviewed.

Angelica dahurica Radix is the common herbal medicine with anti-cancer activities. However, details of its anti-cancer activities are lacking.

Menopausal women are challenged by the adverse effects of estrogen loss on energy, mood, cognitive function, and memory. These stresses are compounded by increased risks for cardiovascular disease, osteoporosis, and cancer. Known to have neuroprotective, cardio-protective, anti-oxidative and anti-carcinogenic effects, Rhodiola rosea extracts have also been shown to improve energy, mood, cognitive function and memory.

During the last decade neoadjuvant endocrine therapy (NET) has moved from being reserved for elderly and frail non-chemotherapy candidates to a primary systemic modality in selected patients with hormone sensitive breast cancer. Neoadjuvant hormonal treatment in patients with hormone receptor positive, HER-2 negative early breast cancer is proven to be an effective and safe option; it is associated with a higher rate of breast conserving surgery (BCS), may reduce the need for adjuvant chemotherapy and enables a delay of surgery for medical or practical reasons. Clinical responses range from 13% to 100% with at least 3 months of NET. Methods of assessing response should include MRI of the breast, particularly in lobular tumours. In studies comparing tamoxifen with aromatase inhibitors (AI), AI proved to be superior in terms of tumour response and rates of BCS. Change in Ki67 is accepted as a validated endpoint for comparing endocrine neoadjuvant agents. Levels of Ki67 during treatment are more closely related to long-term prognosis than pretreatment Ki67. Neoadjuvant endocrine therapy provides a unique opportunity for studies of endocrine responsiveness and the development of new experimental drugs combined with systemic hormonal treatment.

Chemoimmunotherapy (CIT) such as FCR (fludarabine, cyclophosphamide, rituximab) has been the standard first-line therapy for younger patients with CLL. In the last few years, several novel targeted therapies have been developed for patients with CLL. These include B-cell receptor (BCR) inhibitors such as Bruton tyrosine kinase (BTK) inhibitors, PI3 kinase inhibitors, and Syk inhibitors, novel anti-CD20 monoclonal antibodies such as ofatumumab and obinutuzumab, and Bcl-2 antagonists such as venetoclax (ABT-199). Strategies targeting the immune system such as lenalidomide, chimeric antigen receptor (CAR) T cells, and more recently, checkpoint inhibitors, are in clinical development. Ibrutinib and idelalisib are already approved for patients with relapsed and refractory CLL. Ibrutinib is also approved for first-line treatment of CLL patients with del(17p). Several ongoing phase III clinical trials with novel therapies will further define the role of targeted agents in CLL.

Endocrine complications (particularly gonadal, hypothalamic-pituitary and metabolic) of childhood cancer treatments are common in young adults. Gonadal damage may be the result of chemotherapy or radiotherapy. Fertility preservation must be systematically proposed before initiation of gonadotoxic treatment if only the child is eligible. Hypothalamic-pituitary deficiency is common after brain or total-body irradiation, the somatotropic axis is the most sensitive to irradiation. Pituitary deficiency screening must be repeated since this endocrine consequence can occur many years after treatment. Hormone replacement must be prudent particularly in case of treatment with growth hormone or steroids. Metabolic syndrome, diabetes and cardiovascular damage resulting from cancer treatments contribute to the increase of morbidity and mortality in this population and should be screened routinely even if the patient is asymptomatic. The multidisciplinary management of these adults must be organized and the role of the endocrinologist is now well established.

Gemcitabine-based combinations in advanced pancreatic cancer have been reported to have superior activity compared with gemcitabine alone. The results of the commonly used endpoints of clinical trials after chemotherapy or targeted therapy have been poorly reported.

Juices obtained from cold-pressed saffron (Crocus sativus L.) floral by-products were evaluated as a potential source of compounds with antioxidant and cytotoxic activities. Floral by-products were split in two batches for extraction 24 and 48h after flower harvesting, respectively. The in vitro anti-oxidant activity of these extracts was tested using the FRAP and DPPH assays, and two biological models of lipid oxidation (activity in preventing cholesterol degradation and protection against Cu(2+)-mediated degradation of the liposomal unsaturated fatty acids). The cytotoxic activity was evaluated using the MTT assay. The results show that extracts obtained 48h post-harvest contained higher levels of total polar phenols and had the highest antioxidant activity in all of the performed assays. The LC-DAD and LC-ESI-(HR)MS(n) metabolic profiles showed high levels of kaempferol derivatives and anthocyanins. This study suggests that juices from saffron floral by-products could potentially be used to develop new products for the food and health industry.

Long-term disease-free survival in adult patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory, and the treatment options are limited for those patients with relapse or a failure to respond after initial therapy. We conducted a dose-escalation/expansion phase II, multicenter, single-arm study to determine the optimal dose of coltuximab ravtansine (SAR3419), an anti-CD19 antibody-drug conjugate, in this setting.

A 3-compartment model for metronomic chemotherapy that takes into account cancerous cells, the tumor vasculature and tumor immune-system interactions is considered as an optimal control problem. Metronomic chemo-therapy is the regular, almost continuous administration of chemotherapeutic agents at low dose, possibly with small interruptions to increase the efficacy of the drugs. There exists medical evidence that such administrations of specific cytotoxic agents (e.g., cyclophosphamide) have both antiangiogenic and immune stimulatory effects. A mathematical model for angiogenic signaling formulated by Hahnfeldt et al. is combined with the classical equations for tumor immune system interactions by Stepanova to form a minimally parameterized model to capture these effects of low dose chemotherapy. The model exhibits bistable behavior with the existence of both benign and malignant locally asymptotically stable equilibrium points. In this paper, the transfer of states from the malignant into the benign regions is used as a motivation for the construction of an objective functional that induces this process and the analysis of the corresponding optimal control problem is initiated.

Apoptosis resistance is a hallmark of human cancer, and tumor cells often become resistant due to defects in the programmed cell death machinery. Targeting key apoptosis regulators to overcome apoptotic resistance and promote rapid death of tumor cells is an exciting new strategy for cancer treatment, either alone or in combination with traditionally used anti-cancer drugs that target cell division. Here we present a multiscale modeling framework for investigating the synergism between traditional chemotherapy and targeted therapies aimed at critical regulators of apoptosis.

Tuftsin, a natural phagocytosis-stimulating tetrapeptide, had aroused much interest in tumor immunotherapy, but the poor pharmacokinetics hampered its clinical developments, for that it was extremely susceptible to degradation by enzymolysis in vivo. T Peptide (TP) was a newly designed tuftsin derivative aimed to enhance stability and was proved to have significant antitumor activity. In this study, the pharmacokinetics and bioavailability of TP was first clarified in beagles with subcutaneous administration, by using a simple and robust competitive ELISA method. Dose-dependency and non-linear dynamics of TP after single-dose (2, 6 and 18 mg kg(-1), respectively) were found, and the half-time of TP was proved to reach 1.3-2.8 h. Multiple dosing of 6 mg kg(-1) once a day for 7 days resulted in a slight accumulation (accumulation index was 1.92 ± 0.43), indicating that the dosing interval in the following clinical trial needs to be extended. The absolute bioavailability of TP was 31.1 ± 6.2% after subcutaneous administration. These results first demonstrated the pharmacokinetics and bioavailability data of TP in vivo, which illustrated the potential druggability of TP and provided useful information for the dosage regimen design in the following clinical trials, as well as a simple and feasible analytical method for clinical sample analysis.

Chemotherapy-induced diarrhea (CID) diminishes physical performance, raises anxiety and depression levels, and increases healthcare resource utilization.

The administration of carboplatin AUC 7 has become a standard adjuvant option for patients undergoing orchiectomy for stage I seminoma, in alternative to radiotherapy on retroperitoneal lymphnodes or surveillance. The toxicity of AUC 7 carboplatin appeared manageable in the pivotal trial of Oliver et al, but dose ranges were not reported. Fear of toxicity may induce arbitrary dose reductions, which may potentially compromise patients' outcome.

The tumor suppressor p53 controls DNA repair, cell cycle, apoptosis, autophagy and numerous other cellular processes. Imiquimod (IMQ), a synthetic toll-like receptor (TLR) 7 ligand for the treatment of superficial basal cell carcinoma (BCC), eliminates cancer cells by activating cell-mediated immunity and directly inducing apoptosis and autophagy in cancer cells.

Interstitial lung disease (ILD) is a widely recognized adverse consequence of gemcitabine administration, but data on gemcitabine-associated ILD are limited. This study aimed to elucidate the incidence and risk factors for this adverse event.