Drug and Alcohol Rehabilitation: GL3, a Novel 4?-Anilino-4′-O-Demethyl-4-Desoxypodophyllotoxin Analog, Traps Topoisomerase II Cleavage Complexes and Exerts Anticancer Activities.
GL3, a Novel 4?-Anilino-4′-O-Demethyl-4-Desoxypodophyllotoxin Analog, Traps Topoisomerase II Cleavage Complexes and Exerts Anticancer Activities.
Filed under: Drug and Alcohol Rehabilitation
Transl Oncol. 2013 Feb; 6(1): 75-82
Yang XC, Qian SJ, Wang L, Liao SD, Cao J, Hu YZ, He QJ, Zhu H, Yang B
A novel VP-16 derivative, 4?-[N -(4?-acetyloxyl-phenyl-1?-carbonyl)-4?-aminoanilino]-4′-O-demethyl-4-desoxypodophyllotoxin (GL3), displayed a wide range of cytotoxicity in a panel of human tumor cell lines, with half-maximal inhibitory concentration (IC(50)) values ranging from 0.82 to 4.88 µM, much less than that of VP-16 (4.18-39.43 µM). Importantly, GL3 induces more significant apoptosis and cell cycle arrest than VP-16. The molecular and cellular machinery studies showed that GL3 functions as a topoisomerase II (Top 2) poison through direct binding to the enzyme, and the advanced cell-killing activities of GL3 were ascribed to its potent effects on trapping Top 2-DNA cleavage complex, Moreover, GL3-triggered DNA double-strand breaks and apoptotic cell death were in a Top 2-dependent manner, because the catalytic inhibitor aclarubicin attenuated these biologic consequences caused by Top 2 poisoning in GL3-treated cells. Taken together, among a series of 4?-anilino-4′-O-demethyl-4-desoxypodophyllotoxin analog, GL3 stood out by its improved anticancer activity and well-defined Top 2 poisoning mechanisms, which merited the potential value of GL3 as an anticancer lead compound/drug candidate deserving further development.
HubMed – drug
Diverse responses to vascular disrupting agent combretastatin a4 phosphate: a comparative study in rats with hepatic and subcutaneous tumor allografts using MRI biomarkers, microangiography, and histopathology.
Filed under: Drug and Alcohol Rehabilitation
Transl Oncol. 2013 Feb; 6(1): 42-50
Li J, Chen F, Feng Y, Cona MM, Yu J, Verbruggen A, Zhang J, Oyen R, Ni Y
Differently located tumors of the same origin may exhibit diverse responses to the same therapeutics. To test this hypothesis, we compared the responses of rodent hepatic and subcutaneous engrafts of rhabdomyosarcoma-1 (R1) to a vascular disrupting agent Combretastatin A4 phosphate (CA4P).Twelve WAG/Rij rats, each bearing three R1 implanted in the right and left hepatic lobes and subcutaneously in the thoracic region, received CA4P intravenously at 5 mg/kg (n = 6) or solvent (n = 6). Therapeutic responses were compared interindividually and intraindividually among tumors of different sites till 48 hours after injection using in vivo MRI, postmortem digital microangiography, and histopathology.MRI revealed that the subcutaneous tumors (STs) significantly increased in volume than hepatic tumors (HTs) 48 hours after CA4P (P < .05). Relative to vehicle controls and treated group at baseline, necrosis ratio, apparent diffusion coefficient, and enhancement ratio changed slightly with the STs but significantly with HTs (P < .05) after CA4P treatment. Vessel density derived from microangiography was significantly lower in STs compared to HTs without CA4P treatment. CA4P treatment resulted in decreased vessel density in HTs, while it did not affect vessel density in STs. MRI and microangiography outcomes were supported by histopathologic findings.MRI and microangiography allowed quantitative comparison of therapeutic responses to CA4P in rats with multifocal tumors. The discovered diverse effects of the same drug on tumors of the same origin but different locations emphasize the presence of cancer heterogeneity and the importance of individualization of drug delivery. HubMed – drug
A Comprehensive Gene Expression Analysis of Resistance Formation upon Metronomic Cyclophosphamide Therapy.
Filed under: Drug and Alcohol Rehabilitation
Transl Oncol. 2013 Feb; 6(1): 1-9
Kubisch R, Meissner L, Krebs S, Blum H, Günther M, Roidl A, Wagner E
Resistance formation is one of the major hurdles in cancer therapy. Metronomic anti-angiogenic treatment of xenografted prostate cancer tumors in severe combined-immunodeficiency (SCID) mice with cyclophosphamide (CPA) results in the appearance of resistant tumors. To investigate the complex molecular changes occurring during resistance formation, we performed a comprehensive gene expression analysis of the resistant tumors in vivo. We observed a multitude of differentially expressed genes, e.g., PAS domain containing protein 1, annexin A3 (ANXA3), neurotensin, or plasminogen activator tissue (PLAT), when comparing resistant to in vivo passaged tumor samples. Furthermore, tumor cells from in vivo and in vitro conditions showed a significant difference in target gene expression. We assigned the differentially expressed genes to functional pathways like axon guidance, steroid biosynthesis, and complement and coagulation cascades. Most of these genes were involved in anti-coagulation. Up-regulation of anticoagulatory ANXA3 and PLAT and down-regulation of PLAT inhibitor serpin peptidase inhibitor clade A were validated by quantitative real-time polymerase chain reaction. In contrast, coagulation factor F3 was upregulated, accompanied by the expression of an altered gene product. These findings give insights into the resistance mechanisms of metronomic CPA treatment, suggesting an important role of anti-coagulation in resistance formation.
HubMed – drug
Illicit Stimulant Use Is Associated with Abnormal Substantia Nigra Morphology in Humans.
Filed under: Drug and Alcohol Rehabilitation
PLoS One. 2013; 8(2): e56438
Todd G, Noyes C, Flavel SC, Della Vedova CB, Spyropoulos P, Chatterton B, Berg D, White JM
Use of illicit stimulants such as methamphetamine, cocaine, and ecstasy is an increasing health problem. Chronic use can cause neurotoxicity in animals and humans but the long-term consequences are not well understood. The aim of the current study was to investigate the long-term effect of stimulant use on the morphology of the human substantia nigra. We hypothesised that history of illicit stimulant use is associated with an abnormally bright and enlarged substantia nigra (termed ‘hyperechogenicity’) when viewed with transcranial sonography. Substantia nigra morphology was assessed in abstinent stimulant users (n?=?36; 31±9 yrs) and in two groups of control subjects: non-drug users (n?=?29; 24±5 yrs) and cannabis users (n?=?12; 25±7 yrs). Substantia nigra morphology was viewed with transcranial sonography and the area of echogenicity at the anatomical site of the substantia nigra was measured at its greatest extent. The area of substantia nigra echogenicity was significantly larger in the stimulant group (0.273±0.078 cm(2)) than in the control (0.201±0.054 cm(2); P<0.001) and cannabis (0.202±0.045 cm(2); P<0.007) groups. 53% of stimulant users exhibited echogenicity that exceeded the 90(th) percentile for the control group. The results of the current study suggest that individuals with a history of illicit stimulant use exhibit abnormal substantia nigra morphology. Substantia nigra hyperechogenicity is a strong risk factor for developing Parkinson's disease later in life and further research is required to determine if the observed abnormality in stimulant users is associated with a functional deficit of the nigro-striatal system. HubMed – drug
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