- In Silico Prediction of O⁶-Methylguanine-DNA Methyltransferase Inhibitory Potency of Base Analogs with QSAR and Machine Learning Methods. [Journal Article]
- MMolecules 2018 Nov 06; 23(11)
- O⁶-methylguanine-DNA methyltransferase (MGMT), a unique DNA repair enzyme, can confer resistance to DNA anticancer alkylating agents that modify the O⁶-position of guanine. Thus, inhibition of MGMT a...
O⁶-methylguanine-DNA methyltransferase (MGMT), a unique DNA repair enzyme, can confer resistance to DNA anticancer alkylating agents that modify the O⁶-position of guanine. Thus, inhibition of MGMT activity in tumors has a great interest for cancer researchers because it can significantly improve the anticancer efficacy of such alkylating agents. In this study, we performed a quantitative structure activity relationship (QSAR) and classification study based on a total of 134 base analogs related to their ED50 values (50% inhibitory concentration) against MGMT. Molecular information of all compounds were described by quantum chemical descriptors and Dragon descriptors. Genetic algorithm (GA) and multiple linear regression (MLR) analysis were combined to develop QSAR models. Classification models were generated by seven machine-learning methods based on six types of molecular fingerprints. Performances of all developed models were assessed by internal and external validation techniques. The best QSAR model was obtained with Q²Loo = 0.83, R² = 0.87, Q²ext = 0.67, and R²ext = 0.69 based on 84 compounds. The results from QSAR studies indicated topological charge indices, polarizability, ionization potential (IP), and number of primary aromatic amines are main contributors for MGMT inhibition of base analogs. For classification studies, the accuracies of 10-fold cross-validation ranged from 0.750 to 0.885 for top ten models. The range of accuracy for the external test set ranged from 0.800 to 0.880 except for PubChem-Tree model, suggesting a satisfactory predictive ability. Three models (Ext-SVM, Ext-Tree and Graph-RF) showed high and reliable predictive accuracy for both training and external test sets. In addition, several representative substructures for characterizing MGMT inhibitors were identified by information gain and substructure frequency analysis method. Our studies might be useful for further study to design and rapidly identify potential MGMT inhibitors.
- Childhood Cancer Treatments and Associated Endocrine Late Effects: A Concise Guide for the Pediatric Endocrinologist. [Review]
- HRHorm Res Paediatr 2018 Nov 07; :1-9
- Endocrine complications are frequently observed in childhood cancer survivors (CCS); in many instances, these complications develop months to years after the completion of cancer therapy. The estimat...
Endocrine complications are frequently observed in childhood cancer survivors (CCS); in many instances, these complications develop months to years after the completion of cancer therapy. The estimated prevalence of endocrine late effects is 50% among CCS; the main risk factors are external beam radiation that includes key endocrine organs (the hypothalamus/pituitary, thyroid and gonads) and/or alkylating agents. Novel agents targeting tumor growth have increased the options available to a small number of patients albeit with the need for treatment over long periods of time. Some of these agents, such as certain tyrosine kinase inhibitors and immune system modulators have been shown to cause permanent endocrine deficits. This chapter offers a brief summary of the conventional treatment strategies for the most common cancers of childhood and a brief overview of the endocrine late effects most commonly associated with these exposures. The impact of targeted therapies on the endocrine system will also be discussed. The aim of this chapter is to provide basic guidance to the consulting pediatric endocrinologist in preparation for the clinical encounter with a CCS. A more detailed discussion of the management of specific endocrine late effects can be found in the other chapters in this series.
- Current Developments in Pt(IV) Prodrugs Conjugated with Bioactive Ligands. [Review]
- BCBioinorg Chem Appl 2018; 2018:8276139
- To overcome the side effects of and resistance to cisplatin, a variety of Pt(IV) prodrugs were designed and synthesized via different modifications including combination with lipid chains to increase...
To overcome the side effects of and resistance to cisplatin, a variety of Pt(IV) prodrugs were designed and synthesized via different modifications including combination with lipid chains to increase hydrophobicity, conjugation with short peptide chains or nanoparticles to improve drug delivery, or addition of bioactive ligands to the axial positions of Pt(IV) complexes to exert dual-function effects. This review summarizes the recent progress in the development of Pt(IV) prodrugs conjugated with bioactive-targeting ligands, including histone deacetylase inhibitors, p53 agonists, alkylating agents, and nonsteroidal anti-inflammatory agents. Although Pt(IV) complexes that conjugated with bioactive ligands show satisfactory anticancer effects, none has been approved for clinical use. Therefore, we hope that this review will contribute to further study and development of Pt(IV) complexes conjugated with bioactive and other ligands.
- Deregulation of the SRC Family Tyrosine Kinases in Gastric Carcinogenesis in Non-human Primates. [Journal Article]
- ARAnticancer Res 2018; 38(11):6317-6320
- CONCLUSIONS: SRC family kinases play a key role in tumor progression and metastasis and may be a promising target for the treatment of gastric cancer.
- Anticancer Therapy-Induced Atrial Fibrillation: Electrophysiology and Related Mechanisms. [Review]
- FPFront Pharmacol 2018; 9:1058
- Some well-established immunotherapy, radiotherapy, postoperation, anticancer drugs such as anthracyclines, antimetabolites, human epidermal growth factor receptor 2 blockers, tyrosine kinase inhibito...
Some well-established immunotherapy, radiotherapy, postoperation, anticancer drugs such as anthracyclines, antimetabolites, human epidermal growth factor receptor 2 blockers, tyrosine kinase inhibitors, alkylating agents, checkpoint inhibitors, and angiogenesis inhibitors, are significantly linked to cardiotoxicity. Cardiotoxicity is a common complication of several cancer treatments. Some studies observed complications of cardiac arrhythmia associated with the treatment of cancer, including atrial fibrillation (AF), supraventricular arrhythmias, and cardiac repolarization abnormalities. AF increases the risk of cardiovascular morbidity and mortality; it is associated with an almost doubled risk of mortality and a nearly 5-fold increase in the risk of stroke. The occurrence of AF is also usually researched in patients with advanced cancer and those undergoing active cancer treatments. During cancer treatments, the incidence rate of AF affects the prognosis of tumor treatment and challenges the treatment strategy. The present article is mainly focused on the cardiotoxicity of cancer treatments. In our review, we discuss these anticancer therapies and how they induce AF and consequently provide information on the precaution of AF during cancer treatment.
- An Update on Drug-Induced Pigmentation. [Review]
- AJAm J Clin Dermatol 2018 Oct 29
- Drug-induced pigmentation accounts for up to 20% of all cases of acquired pigmentation. A thorough review of medical history and previous and ongoing medications as well as a complete skin examinatio...
Drug-induced pigmentation accounts for up to 20% of all cases of acquired pigmentation. A thorough review of medical history and previous and ongoing medications as well as a complete skin examination can guide diagnosis. Implicated agents include alkylating/cytotoxic agents, analgesics, antiarrhythmics, anticoagulants, antiepileptics, antimalarials, antimicrobials, antiretrovirals, metals, prostaglandin analogs, and psychotropic agents, among others. Confirming true drug associations can be challenging, especially in the setting of delayed onset of pigmentation and coexisting polypharmacy.
- Polygenic Determinants for Subsequent Breast Cancer Risk in Survivors of Childhood Cancer: The St Jude Lifetime Cohort Study (SJLIFE). [Journal Article]
- CCClin Cancer Res 2018 Oct 26
- Purpose: The risk of subsequent breast cancer among female childhood cancer survivors is markedly elevated. We aimed to determine genetic contributions to this risk, focusing on polygenic determinan...
Purpose: The risk of subsequent breast cancer among female childhood cancer survivors is markedly elevated. We aimed to determine genetic contributions to this risk, focusing on polygenic determinants implicated in breast cancer susceptibility in the general population.Experimental Design: Whole-genome sequencing (30×) was performed on survivors in the St Jude Lifetime Cohort, and germline mutations in breast cancer predisposition genes were classified for pathogenicity. A polygenic risk score (PRS) was constructed for each survivor using 170 established common risk variants. Relative rate (RR) and 95% confidence interval (95% CI) of subsequent breast cancer incidence were estimated using multivariable piecewise exponential regression.Results: The analysis included 1,133 female survivors of European ancestry (median age at last follow-up = 35.4 years; range, 8.4-67.4), of whom 47 were diagnosed with one or more subsequent breast cancers (median age at subsequent breast cancer = 40.3 years; range, 24.5-53.0). Adjusting for attained age, age at primary diagnosis, chest irradiation, doses of alkylating agents and anthracyclines, and genotype eigenvectors, RRs for survivors with PRS in the highest versus lowest quintiles were 2.7 (95% CI, 1.0-7.3), 3.0 (95% CI, 1.1-8.1), and 2.4 (95% CI, 0.1-81.1) for all survivors and survivors with and without chest irradiation, respectively. Similar associations were observed after excluding carriers of pathogenic/likely pathogenic mutations in breast cancer predisposition genes. Notably, the PRS was associated with the subsequent breast cancer rate under the age of 45 years (RR = 3.2; 95% CI, 1.2-8.3).Conclusions: Genetic profiles comprised of small-effect common variants and large-effect predisposing mutations can inform personalized breast cancer risk and surveillance/intervention in female childhood cancer survivors. Clin Cancer Res; 1-6. ©2018 AACR.
- The carbonic anhydrase IX inhibitor SLC-0111 sensitises cancer cells to conventional chemotherapy. [Journal Article]
- JEJ Enzyme Inhib Med Chem 2019; 34(1):117-123
- Drug combination represents one of the most accredited strategies of cancer therapy able to improve drug efficacy and possibly overcome drug resistance. Among the agents used to complement convention...
Drug combination represents one of the most accredited strategies of cancer therapy able to improve drug efficacy and possibly overcome drug resistance. Among the agents used to complement conventional chemotherapy, carbonic anhydrase IX (CAIX) inhibitors appear as one of the most suitable, as markers of hypoxic and acidic cancer cells which do not respond to chemo- and radiotherapy. We performed preclinical in vitro assays to evaluate whether the SLC-0111 CAIX inhibitor co-operates and potentiates the cytotoxic effects of conventional chemotherapeutic drugs in A375-M6 melanoma cells, MCF7 breast cancer cells, and HCT116 colorectal cancer cells. Here, we demonstrate that the SLC-0111 CAIX inhibitor potentiates cytotoxicity of Dacarbazine and Temozolomide currently used for advanced melanoma treatment. SLC-0111 also increases breast cancer cell response to Doxorubicin and enhances 5-Fluorouracil cytostatic activity on colon cancer cells. These findings disclose the possibility to extend the use of CAIX inhibitors in the combination therapy of various cancer histotypes.
- Rhodium-catalyzed triazole-directed C-H bond functionalization of arenes with diazo compounds. [Journal Article]
- OBOrg Biomol Chem 2018 Nov 07; 16(43):8191-8195
- Heterocyclic compounds bearing 1,2,3-triazole scaffolds have found wide application both in medicinal chemistry and materials science. In this paper, rhodium(iii)-catalyzed triazole-directed alkylati...
Heterocyclic compounds bearing 1,2,3-triazole scaffolds have found wide application both in medicinal chemistry and materials science. In this paper, rhodium(iii)-catalyzed triazole-directed alkylation reactions of arenes using diazo compounds as the alkylating agents are described. A number of polysubstituted arenes were provided from easily available materials in good yields under mild conditions. The reactions proceed via triazole-directed ortho C-H bond activation and subsequent carbene insertion originating from diazo compounds.
New Search Next
- LncRNA KCNQ1OT1 Mediates Pyroptosis in Diabetic Cardiomyopathy. [Journal Article]
- CPCell Physiol Biochem 2018; 50(4):1230-1244
- CONCLUSIONS: Kcnq1ot1 is overexpressed in DCM, and silencing Kcnq1ot1 inhibits pyroptosis by influencing miR-214-3p and caspase-1 expression. We clarified for the first time that Kcnq1ot1 could be a new therapeutic target for DCM.