Cancer cell adaptation to chemotherapy

BACKGROUND: Tumor resistance to chemotherapy may be present at the beginning of treatment, develop during treatment, or become apparent on re-treatment of the patient. The mechanisms involved are usually inferred from experiments with cell lines, as studies in tumor-derived cells are difficult. Studies of human tumors show that cells adapt to chemotherapy, but it has been largely assumed that clonal selection leads to the resistance of recurrent tumors. METHODS: Cells derived from 47 tumors of breast, ovarian, esophageal, and colorectal origin and 16 paired esophageal biopsies were exposed to anticancer agents (cisplatin; 5-fluorouracil; epirubicin; doxorubicin; paclitaxel; irinotecan and topotecan) in short-term cell culture (6 days). Real-time quantitative PCR was used to measure up- or down-regulation of 16 different resistance/target genes, and when tissue was available, immunohistochemistry was used to assess the protein levels. RESULTS: In 8/16 paired esophageal biopsies, there was an increase in the expression of multi-drug resistance gene 1 (MDR1) following epirubicin + cisplatin + 5-fluorouracil (ECF) chemotherapy and this was accompanied by increased expression of the MDR-1 encoded protein, P-gp. Following exposure to doxorubicin in vitro, 13/14 breast carcinomas and 9/12 ovarian carcinomas showed >2-fold down-regulation of topoisomerase IIα (TOPOIIα). Exposure to topotecan in vitro, resulted in >4-fold down-regulation of TOPOIIα in 6/7 colorectal tumors and 8/10 ovarian tumors. CONCLUSION: This study suggests that up-regulation of resistance genes or down-regulation in target genes may occur rapidly in human solid tumors, within days of the start of treatment, and that similar changes are present in pre- and post-chemotherapy biopsy material. The molecular processes used by each tumor appear to be linked to the drug used, but there is also heterogeneity between individual tumors, even those with the same histological type, in the pattern and magnitude of response to the same drugs. Adaptation to chemotherapy may explain why prediction of resistance mechanisms is difficult on the basis of tumor type alone or individual markers, and suggests that more complex predictive methods are required to improve the response rates to chemotherapy

Nitric oxide: does it play a role in the heart of the critically ill?

Nitric oxide regulates many aspects of myocardial function, not only in the normal heart but also in ischemic and nonischemic heart failure, septic cardiomyopathy, cardiac allograft rejection, and myocarditis. Accumulating evidence implicates the endogenous production of nitric oxide in the regulation of myocardial contractility, distensibility, heart rate, coronary vasodilation, myocardial oxygen consumption, mitochondrial respiration, and apoptosis. The effects of nitric oxide promote left ventricular mechanical efficiency, ie, appropriate matching between cardiac work and myocardial oxygen consumption. Most of these beneficial effects are attributed to the low physiologic concentrations generated by the constitutive endothelial or neuronal nitric oxide synthase. By contrast, inducible nitric oxide synthase generates larger concentrations of nitric oxide over longer periods of time, leading to mostly detrimental effects. In addition, the recently identified beta3-adrenoceptor mediates a negative inotropic effect through coupling to endothelial nitric oxide synthase and is overexpressed in heart failure. An imbalance between beta 1 and beta2-adrenoceptor and beta3-adrenoceptor, with a prevailing influence of beta3-adrenoceptor, may play a causal role in the pathogenesis of cardiac diseases such as terminal heart failure. Likewise, changes in the expression of endothelial nitric oxide synthase or inducible nitric oxide synthase within the myocardium may alter the delicate balance between the effects of nitric oxide produced by either of these isoforms. New treatments such as selective inducible nitric oxide synthase blockade, endothelial nitric oxide synthase promoting therapies, and selective beta3-adrenoceptor modulators may offer promising new therapeutic approaches to optimize the care of critically ill patients according to their stage and specific underlying disease process

The role of copper(I) complexes in the selective formation of oxazoles from unsaturated nitriles and diazoesters

peer reviewedThe 1,3-dipolar addition of ketocarbenes (generated from diazoesters) to nitriles is promoted at room temperature by palladium acetate and even more efficiently by copper trifluoromethanesulphonate. The reduction of copper(II) to copper(I) is a key step in the catalytic process, as shown by kinetic studies, EPR and polarography. © 1975

Radical addition to 2‐isopropenyl‐5‐butoxyoxazole

The preparation and the spectroscopic analysis of a dimeric adduct (V) obtained from 2‐isopropenyl‐5‐butoxyoxazole (III) and α,α‐azobis‐isobutyronitrile (AIBN) (IV) are reported. It is noteworthy that (III) inhibits completely the homopolymerization of styrene. This is in strong opposition to the facile homopolymerization and copolymerization of 2‐isopropenyl‐4,5‐dimethyloxazole with styrene. The smooth formation of (V) is also in sharp contrast to the lack of reactivity of (III) towards cationic initiators. Copyright © 1986 John Wiley & Sons, Inc

Catalysed prototropic rearrangements. Part II. Metal carbonylcatalysed isomerization of n-allylamidesto prop-2-enyl derivatives

peer reviewedThe light-induced isomerization of olefins in the presence of pentacarbonyliron has been applied to nitrogen-containing compounds. Since the catalytic procedure was as effective in polar solvents (such as methanol and acetone) as in hydrocarbons, the isomerization of allylic compounds containing very polar functional groups (such as amides and ureas) into the corresponding propenyl derivatives could be effected in good yields. The reactions are however specific and whereas phenyl N-allylcarbamate was quantitatively isomerized to the expected N-propenylcarbamate, the allyl N-phenyl-ester did not react under the same conditions. As basic catalysts are, in general, not convenient for the isomerization of the title compounds, the procedure is of preparative interest

Usefulness of magnetic resonance imaging evaluation of congenital left ventricular aneurysms

Congenital left ventricular (LV) aneurysm is a rare malformation of unknown cause that is often associated with a poor prognosis. This study was undertaken to evaluate the usefulness of cardiac magnetic resonance imaging in patients with congenital LV aneurysms and to determine the relation between clinical manifestations and the morphologic and functional characteristics of the aneurysms. Among the 26 consecutive patients with congenital LV aneurysms included, the anomalies involved the apex or free wall in 15 and the submitral myocardium in 11. Cardiac magnetic resonance provided detailed anatomic and functional assessment of the aneurysms in all patients. Compared with submitral aneurysms, apical or free-wall aneurysms were larger (24 +/- 29 vs 3 +/- 2 ml/m(2), p = 0.02), were more frequently associated with scar tissue by myocardial delayed enhancement imaging (71% vs 0%, p = 0.03), and tended to be more commonly associated with symptoms (53% vs 18%, p = 0.08). Aneurysm volume but not location correlated with LV size (r = 0.735, p <0.0001) and the ejection fraction (r = 0.774, p <0.0001). Apical or free-wall aneurysms were resected in 5 patients, with no mortality. There was 1 death after aortic valve replacement in a patient with type B Niemann-Pick disease, which was not clearly related to the LV aneurysm. The remaining 25 patients are alive at a median age of 13.5 years. In conclusion, the experience with this cohort illustrates that cardiac magnetic resonance is well suited for the morphologic and functional evaluation of congenital LV aneurysms