Drug and Alcohol Rehabilitation: The Utility of Tumor-Specifically Internalizing Peptides for Targeted siRNA Delivery Into Human Solid Tumors.

The Utility of Tumor-specifically Internalizing Peptides for Targeted siRNA Delivery into Human Solid Tumors.

Filed under: Drug and Alcohol Rehabilitation

Anticancer Res. 2012 Nov; 32(11): 4685-90
Un F, Zhou B, Yen Y

Ribonucleotide reductase composed of the hRRM1 and hRRM2 subunits catalyzes the conversion of ribonucleotides to their corresponding deoxy forms for DNA replication. Anti-hRRM2 siRNA degrades hRRM2’s mRNA and suppresses tumorigenesis. A Phase I clinical trial demonstrated its therapy potential. HN-1 represents a tumor-specifically internalizing peptide for targeted-drug delivery into human head and neck squamous cell carcinoma.Internalization of peptide was monitored by fluorescence microscopy. The peptide-siRNA conjugate was chemically synthesized. The hRRM2 expression was monitored by western blot analysis.HN-1(TYR) (HN-1 with two N-terminally added tyrosines) was internalized by human head and neck or breast cancer cells. Anti-hRRM2 siRNA(R) (resistant to RNase degradation) was conjugated to HN-1(TYR) without compromising their properties. The treatment with HN-1(TYR)-anti-hRRM2 siRNA(R) partly suppressed the endogenously expressed hRRM2 in human breast cancer cells.Our results establish the utility of tumor-specifically internalizing peptides for targeted siRNA delivery into human cancer cells.
HubMed – drug


Antitumor Effects of Synthetic 6,7-Annulated-4-substituted Indole Compounds in L1210 Leukemic Cells In Vitro.

Filed under: Drug and Alcohol Rehabilitation

Anticancer Res. 2012 Nov; 32(11): 4671-84
Perchellet JP, Waters AM, Perchellet EM, Thornton PD, Brown N, Hill D, Neuenswander B, Lushington GH, Santini C, Chandrasoma N, Buszek KR

Because annulated indoles have almost no representation in the PubChem or MLSMR databases, an unprecedented class of an indole-based library was constructed, using the indole aryne methodology, and screened for antitumor activity. Sixty-six novel 6,7-annulated-4-substituted indole compounds were synthesized, using a strategic combination of 6,7-indolyne cycloaddition and cross-coupling reactions under both Suzuki-Miyaura and Buchwald-Hartwig conditions, and tested for their effectiveness against murine L1210 tumor cell proliferation in vitro.Various markers of tumor cell metabolism, DNA degradation, mitotic disruption, cytokinesis and apoptosis were assayed in vitro to evaluate drug cytotoxicity.Most compounds inhibited the metabolic activity of leukemic cells in a time- and concentration-dependent manner but only 9 of them were sufficiently potent to inhibit L1210 tumor cell proliferation by 50% in the low-?M range after 2 (IC(50): 4.5-20.4 ?M) and 4 days (0.5-4.0 ?M) in culture. However, the antiproliferative compounds that were the most effective at day 4 were not necessarily the most potent at day 2, suggesting different speeds of action. A 3-h treatment with antiproliferative annulated indole was sufficient to inhibit, in a concentration-dependent manner, the rate of DNA synthesis measured in L1210 cells over a 0.5-h period of pulse-labeling with (3)H-thymidine. Four of the antiproliferative compounds had weak DNA-binding activities but one compound reduced the fluorescence of the ethidium bromide-DNA complex by up to 53%, suggesting that some annulated indoles might directly interact with double-stranded DNA to disrupt its integrity and prevent the dye from intercalating into DNA base pairs. However, all 9 antiproliferative compounds induced DNA cleavage at 24 h in L1210 cells, containing (3)H-thymidine-prelabeled DNA, suggesting that these antitumor annulated indoles might trigger an apoptotic pathway of DNA fragmentation. Indeed the antiproliferative annulated indoles caused a time-dependent increase of caspase-3 activity with a peak at 6 h. Interestingly, the compounds with the most potent antiproliferative IC(50) values at day 2 were consistently the most effective at inhibiting DNA synthesis at 3 h and inducing DNA fragmentation at 24 h. After 24-48 h, antiproliferative concentrations of annulated indoles increased the mitotic index of L1210 cells and stimulated the formation of many bi-nucleated cells, multi-nucleated cells, apoptotic cells and micronuclei, suggesting that these antitumor compounds might enhance mitotic abnormality, induce chromosomal damage or missegregation, and block cytokinesis to induce apoptosis.Although annulated indoles may have interesting bioactivity, novel derivatives with different substitutions must be synthesized to elucidate structure-activity relationships, identify more potent antitumor lead compounds, and investigate their molecular targets and mechanisms of action.
HubMed – drug


Heart failure risk among patients with rheumatoid arthritis starting a TNF antagonist.

Filed under: Drug and Alcohol Rehabilitation

Ann Rheum Dis. 2012 Nov 15;
Solomon DH, Rassen JA, Kuriya B, Chen L, Harrold LR, Graham DJ, Lewis JD, Lii J, Liu L, Griffin MR, Curtis JR

BACKGROUND: While heart failure (HF) is associated with elevations in tumor necrosis factor (TNF)?, several trials of TNF antagonists showed no benefit and possibly worsening of disease in those with known severe HF. We studied the risk of new or recurrent HF among a group of patients receiving these agents to treat rheumatoid arthritis (RA). METHODS: We used data from four different US healthcare programmes. Subjects with RA receiving methotrexate were eligible to enter the study cohort if they added or switched to a TNF antagonist or another non-biological disease modifying antirheumatic drug (nbDMARD). These groups were compared in Cox regression models stratified by propensity score decile and adjusted for oral glucocorticoid dosage, prior HF hospitalisations, and the use of loop diuretics. RESULTS: We compared 8656 new users of a nbDMARD with 11 587 new users of a TNF antagonist with similar baseline covariates. The HR for the TNF antagonists compared with nbDMARD was 0.85 (95% CI 0.63 to 1.14). The HR was also not elevated in subjects with a history of HF. But, it was elevated prior to 2002 (HR 2.17, 95% CI 0.45 to 10.50, test for interaction p=0.036). Oral glucocorticoids were associated with a dose-related gradient of HF risk: compared with no use, 1?5 mg HR 1.30 (95% CI 0.91 to 1.85), ?5 mg HR 1.54 (95% CI 1.09 to 2.19). CONCLUSIONS: TNF antagonists were not associated with a risk of HF hospital admissions compared with nbDMARDs in this RA population.
HubMed – drug


Coma Blisters in Children: Case Report and Review of the Literature.

Filed under: Drug and Alcohol Rehabilitation

J Child Neurol. 2012 Nov 15;
Bosco L, Schena D, Colato C, Biban P, Girolomoni G

Coma-induced blisters is a rare condition associated with prolonged impairment of conscious level, which is relatively well-known in adults following overdose with barbiturates. However, it has been very rarely described in children. A case of coma-bullae occurring in an 11-year-old child with meningoencephalitis is herein reported. The bullous lesions occurred on the limbs and trunks, and evolved into necrotic ulcers in a few days. No correlation with any drug overdosage was found. A skin biopsy revealed epidermal and eccrine sweat gland necrosis with abundant neutrophils, and thrombosis of the vessels in the lower dermis. A comprehensive review of the literature showed that only 5 cases of coma-bullae in children have been published so far. Coma blistering resolves spontaneously within days or weeks. Diagnosis of coma-bullae may require careful clinical-pathologic correlation to exclude other blistering diseases in children.
HubMed – drug



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