Mayo regimen plus three different second-line chemotherapy regimens in sequential therapy in patients with advanced colorectal cancer (ACRC)

As the number of active drugs for colorectal cancer increases, we continually revisit the question of how best to integrate them. We investigated whether sequential chemotherapy consisting of only bolus plus infusional 5-fluorouracil/folinic acid could be comparable, concerning overall survival, to sequential chemotherapy consisting of bolus 5-fluorouracil/folinic acid plus "new-generation" drugs like CPT-11 or oxaliplatin. Patients with histologically verified locally advanced disease and/or metastatic colorectal adenocarcinoma, without possibility for surgical resection, were eligible for the study. The treatments were: Cohort A--Mayo Clinic Regimen (MCR) in first line, "de Gramont" regimen in second line; Cohort B--MCR in first line, CPT-11 (350mg/m2) in second line; Cohort C--MCR in first line, oxaliplatin (85mg/m2) plus "de Gramont" regimen in second line. A total of 89 patients received first plus second line chemotherapy and all of them were analyzed for survival. Number of patients/cohort: A-32 B-27; C-30. The median survival time of the patients was 15, 11, and 17 months for the patients in cohorts A, B, and C, respectively. Survival of the patients in cohort C was significantly better than survival of the patients in cohort B (log-rank test, p=0.04). There was not a significant difference in overall survival between the cohorts A vs. C (log-rank test, p=0.52) and B vs. C (log-rank test, p=0.27). It is conceivable that infusional HD 5-FU could serve as a basis for first and second-line protocols in which other drugs are added to this regimen. Infusional 5-FU plus oxaliplatin in sequential pattern of application after bolus 5-FU has the best overall survival in comparison to other cohorts. CPT-11 applied as a single drug, was not effective enough in comparison to other treatment options.     

Release of sulfur mustard-modified DNA bases by Escherichia coli 3-methyladenine DNA glycosylase II

The toxic effects of sulfur mustard have been attributed toDNA modification with the formation of 7-hydroxyethyl-thioethylguanine, 3-hydroxyethylthioethyl adenine and the cross-link,di-(2-guanin-7-yl-ethyl)sulfide. To investigate the action ofbacterial 3-methyladenine DNA glycosylase II (Gly II) on theseadducts, calf thymus DNA was modified with [¹⁴C]sulfur mustardand used as a substrate for Gly II. Gly II releases both 3-hydroxyethylthioethyladenine and 7-hydroxyethylthioethyl guanine from this substrate.In comparison with the activity of Gly II towards methylatedDNA, 3-hydroxyethylthioethyl adenine is released somewhat moreslowly than 3-methyladenine, while 7-hydroxyethylthioethyl guanineis released much more readily than 7-methylguanine. Glycosylaseaction may play a role in protecting cells from the toxic effectsof sulfur mustard.     

Protection against chloroethylnitrosourea cytotoxicity by eukaryotic 3-methyladenine DNA glycosylase.

A eukaryotic 3-methyladenine DNA glycosylase gene, the Saccharomyces cerevisiae MAG gene, was shown to prevent N-(2-chloroethyl)-N-nitrosourea toxicity. Disruption of the MAG gene by insertion of the URA3 gene increased the sensitivity of S. cerevisiae cells to N-(2-chloroethyl)-N-nitrosourea, and the expression of MAG in glycosylase-deficient Escherichia coli cells protected against the cytotoxic effects of N-(2-chloroethyl)-N-nitrosourea. Extracts of E. coli cells that contain and express the MAG gene released 7-hydroxyethylguanine and 7-chloroethylguanine from N-(2-chloroethyl)-N-nitrosourea-modified DNA in a protein- and time-dependent manner. The ability of a eukaryotic glycosylase to protect cells from the cytotoxic effects of a haloethylnitrosourea and to release N-(2-chloroethyl)-N-nitrosourea-induced DNA modifications suggests that mammalian glycosylases may play a role in the resistance of tumor cells to the antitumor effects of the haloethylnitrosoureas.     

Release of N2,3-ethenoguanine from chloroacetaldehyde-treated DNA by Escherichia coli 3-methyladenine DNA glycosylase II.

The human carcinogen vinyl chloride is metabolized in the liver to reactive intermediates which form N2,3-ethenoguanine in DNA. N2,3-Ethenoguanine is known to cause G----A transitions during DNA replication in Escherichia coli, and its formation may be a carcinogenic event in higher organisms. To investigate the repair of N2,3-ethenoguanine, we have prepared an N2,3-etheno[14C]guanine-containing DNA substrate by nick-translating DNA with [14C]dGTP and modifying the product with chloroacetaldehyde. E. coli 3-methyladenine DNA glycosylase II, purified from cells which carry the plasmid pYN1000, releases N2,3-ethenoguanine from chloroacetaldehyde-modified DNA in a protein- and time-dependent manner. This finding widens the known substrate specificity of glycosylase II to include a modified base which may be associated with the carcinogenic process. Similar enzymatic activity in eukaryotic cell might protect them from exposure to metabolites of vinyl chloride.     

N-Terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) as a Diagnostic Biomarker of Left Ventricular Systolic Dysfunction in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD)

Introduction

Left ventricular systolic dysfunction (LVSD) and cardiac decompensation often accompany AECOPD. Differentiation between the two is difficult and mainly relies on clinical and echocardiographic diagnostic procedures. The value of biomarkers, such as NT-proBNP, as diagnostic tools is still insufficiently investigated. The main goals of this trial were to investigate the value of NT-proBNP as a diagnostic tool for LVSD in AECOPD patients and determine its cut-off value which could reliably diagnose LVSD during AECOPD.

Patients and Methods

This trial prospectively enrolled 209 patients with AECOPD. The patients were divided into four groups—AECOPD plus chronic pulmonary heart disease (CPHD) with or without left ventricular compromise (LVSD), and AECOPD patients without CPHD with or without LVSD. NT-proBNP was measured within first 48 h of hospitalization.

Results

Majority of patients were male (61%) active smokers (41.6%), average age of 68 years. High quality of echocardiography was obtained in 63.3 and 22.5% of the patients had LVSD. Average value of NT-proBNP in patients with LVSD was 3303.2 vs. 1092.5 pg/mL in patients without LVSD. Significant differences in NT-proBNP value (p?=?0.0001) were determined between observed patient groups. At the cut-off value of 1505 pg/mL, sensitivity, specificity, and positive and negative predictive values are 76.6, 83.3, 57.1, and 92.47%, respectively.

Conclusion

At the cut-off value of 1505 pg/mL NT-proBNP could be used as a diagnostic marker for LVSD in acute exacerbation of COPD.

     

A Case Report of Spontaneous Concurrent Bilateral Rupture of the Quadriceps Tendons in a Patient With Chronic Renal Failure

In patients with chronic renal failure, many complications may develop that involve all organ systems, especially the locomotor system. Spontaneous concurrent bilateral rupture of the quadriceps tendons is a very rare complication in patients with chronic renal failure, usually occurring in patients under 50 years of age. Although there are numerous causes that lead to tendon weakness and rupture, most authors agree that secondary hyperparathyroidism plays a major role in the pathogenesis of tendon rupture. Soft tissue and perivascular calcifications, diminished local circulation, reduced tendon elasticity, impaired collagen metabolism, nerve lesions, repeated trauma, and articular swelling contribute to tendon weakness and rupture. A patient is presented in whom spontaneous concurrent bilateral quadriceps tendon rupture occurred at the age of 34, after seven years of hemodialysis therapy. Timely diagnosis and operative management with primary tendon suturing followed by physiotherapy produced a good anatomical and functional result.     

Role of base excision repair in protecting cells from the toxicity of chloroethylnitrosoureas

The chloroethylnitrosoureas react extensively with cellular DNA to produce a variety of DNA adducts, including a deoxycytidine-deoxyguanosine (dC-dG) cross-link that is clearly cytotoxic. It is now well established that O6-alkylguanine-DNA-alkyltransferase can prevent formation of this dC-dG cross-link and thereby diminish the toxicity of the chloroethylnitrosoureas. Besides alkyltransferase, DNA glycosylases from various species can also contribute to cellular resistance to the chloroethylnitrosoureas, but the mechanism for this increased resistance has not been established. It is known, however, that several chloroethylnitrosoureas-modified DNA bases, including the exocyclic adduct, N2,3-ethanoguanine, are released by Escherichia coli 3-methyladenine DNA glycosylase II. In the study described here, we examined the possibility that this enzyme might act on the exocyclic intermediate in dC-dG formation, 1,O6-ethanodeoxyguanosine, and prevent-dC-dG cross-linking in this way. However, the presence of E. coli 3-methyladenine DNA glycosylase II does not decrease the amount of dC-dG cross-link formed when chloroethylnitrosourea reacts with DNA, and we conclude that this enzyme does not recognize 1,O6-ethanodeoxyguanosine. Therefore, its contribution to resistance probably resides in its action on other nitrosourea-induced DNA modifications.     

Hypothermia causes a reversible, p53-mediated cell cycle arrest in cultured fibroblasts.

Normal human fibroblasts grown in cell culture undergo a reversible growth arrest when incubated at 28 degrees C. During incubation at 28 degrees C, levels of p53 and p21 rise in these cells and cell cycle analysis shows that they have undergone a cell cycle arrest. To examine the importance of p53 in mediating this arrest, mouse embryo fibroblasts that are either wild-type or that are defective in p53 were also subjected to hypothermia. Only those cells with wild-type p53 undergo a cell cycle arrest, indicating that p53 has a role in mediating this response. Because many tumor cells have defective p53, this suggests that hypothermia may increase the selective toxicity of chemotherapeutic agents for tumor cells.     

Repair of sulfur mustard-induced DNA damage in mammalian cells measured by a host cell reactivation assay

DNA damage is thought to be the initial event that causes sulfur mustard (SM) toxicity, while the ability of cells to repair this damage is thought to provide a degree of natural protection. To investigate the repair process, we have damaged plasmids containing the firefly luciferase gene with either SM or its monofunctional analog, 2-chloroethyl ethyl sulfide (CEES). Damaged plasmids were transfected into wild-type and nucleotide excision repair (NER) deficient Chinese hamster ovary cells; these cells were also transfected with a second reporter plasmid containing RENILLA: luciferase as an internal control on the efficiency of transfection. Transfected cells were incubated at 37 degrees C for 27 h and then both firefly and RENILLA: luciferase intensities were measured on the same samples with the dual luciferase reporter assay. Bioluminescence in lysates from cells transfected with damaged plasmid, expressed as a percentage of the bioluminescence from cells transfected with undamaged plasmid, is increased by host cell repair activity. The results show that NER-competent cells have a higher reactivation capacity than NER-deficient cells for plasmids damaged by either SM or CEES. Significantly, NER-competent cells are also more resistant to the toxic effects of SM and CEES, indicating that NER is not only proficient in repairing DNA damage caused by either agent but also in decreasing their toxicity. This host cell repair assay can now be used to determine what other cellular mechanisms protect cells from mustard toxicity and under what conditions these mechanisms are most effective.