Induction of Cytotoxic Oxidative Stress by d-Alanine in Brain Tumor Cells Expressing Rhodotorula gracilis d-Amino Acid Oxidase: A Cancer Gene Therapy Strategy

Overview summary Gene-directed enzyme prodrug therapy (GDEPT) is an antineoplastic treatment strategy designed to overcome the systemic toxicity of chemotherapy by specifically expressing a foreign enzyme in malignant cells that converts a nontoxic prodrug into a cytotoxic metabolite. The relative inefficiency of current in situ gene transfer methodology suggests that enzyme/prodrug combinations that produce membrane permeable metabolites will elicit a more favorable therapeutic response. Ideally, the agent produced by the transduced cell “factories” would be cytotoxic toward both proliferating and quiescent cells. We describe a novel GDEPT approach using d-amino acid oxidase from the red yeast Rhodotorula gracilis and d-alanine as a substrate that generates hydrogen peroxide, a reactive metabolite of oxygen that has both these characteristics. We also demonstrate the ability to sensitize tumor cells to this GDEPT protocol by manipulating cellular antioxidant pathways.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63220/1/hum.1998.9.2-185.pd

Effect of transforming growth factor ß(2) on oestrogen metabolism in the MCF-7 breast cancer cell line

Transforming growth factor ß (TGF-ß) is a multifunctional regulator of cellular growth and differentiation in many cell types and has a growth inhibitory effect on mammary epithelial cells. The TGF-ß(2) isoform has been shown to be present in high concentrations in breast cyst fluid and might have a protective role in breast cancer. In addition, oestrogens play an important role in breast cancer development, and oestrone sulphate (E(1)S) might be the main source of active oestrogens in the breast. The aim of this study was to assess the effect of TGF-ß(2) on oestrogen synthesis in an attempt to understand the mechanism by which TGF-ß(2) may exert a protective effect in breast cancer. In this study, higher concentrations of TGF-ß(2) significantly inhibited the conversion of E(1)S to oestrone (E(1)) and the conversion of E(1) to the potent oestrogen, oestradiol (E(2)). TGF-ß(2) did not have any effect on MCF-7 cell growth or on E(2) to E(1) conversion. In conclusion, TGF-ß(2) might exert a protective role in breast cancer by reducing the amount of active oestrogens present in the breast. Key Words: transforming growth factor ß(2) • oestrone sulphatase • oestradiol-17ß hydroxysteroid dehydrogenase • breast cance

Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies

Over the last 40 years, great progress has been made in treating childhood and adult cancers. However, this progress has come at an unforeseen cost, in the form of emerging long-term effects of anthracycline treatment. A major complication of anthracycline therapy is its adverse cardiovascular effects. If these cardiac complications could be reduced or prevented, higher doses of anthracyclines could potentially be used, thereby further increasing cancer cure rates. Moreover, as the incidence of cardiac toxicity resulting in congestive heart failure or even heart transplantation dropped, the quality and extent of life for cancer survivors would improve. We review the proposed mechanisms of action of anthracyclines and the consequences associated with anthracycline treatment in children and adults. We summarise the most promising current strategies to limit or prevent anthracycline-induced cardiotoxicity, as well as possible strategies to prevent existing cardiomyopathy from worsenin