Selective therapeutic benefit of X-rays and inhibitors of EGFR, PI3K/mTOR, and Bcl-2 in breast, lung, and cervical cancer cells.

Cancer continues to be a growing burden, especially in the resource limited regions of the world, and more effective and affordable therapies are highly desirable. In this study, the effect of X-ray irradiation and four inhibitors, viz. those against epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), mammalian target of rapamycin (mTOR) and B-cell lymphoma 2 (Bcl-2) was evaluated in lung, breast, and cervical cancer cell lines, including normal cell lines to determine and compare the potential therapeutic benefit of these treatment modalities. A clonogenic survival assay was used to determine the radiosensitivity and cytotoxicity of inhibitors of EGFR, PI3K/mTOR, and Bcl-2 in the cell lines. From the data, the equivalent dose at which 50% of the cell populations were killed, for cancer and normal cells, was used to determine the relative cellular sensitivity to X-ray irradiation and inhibitor treatment. It was found that breast cancer cell lines were more sensitive to X-ray irradiation, whilst cervical and lung cancer cell lines were more sensitive to EGFR and PI3K/mTOR inhibitor therapy. These data suggest that patients with breast cancer possessing similar characteristics to MDA-MB-231 and MCF-7 cells may derive therapeutic benefit from X-ray irradiation, whilst EGFR and PI3K/mTOR inhibitor therapy may potentially benefit cancer patients possessing cancers similar to HeLa and A549 cells.

Inhibition of DNA repair by Pentoxifylline and related methylxanthine derivatives.

The methylxanthine drug Pentoxifylline is reviewed for new properties which have emerged only relatively recently and for which clinical applications can be expected. After a summary on the established systemic effects of Pentoxifylline on the microcirculation and reduction of tumour anoxia, the role of the drug in the treatment of vasoocclusive disorders, cerebral ischemia, infectious diseases, septic shock and acute respiratory distress, the review focuses on another level of drug action which is based on in vitro observations in a variety of cell lines. Pentoxifylline and the related drug Caffeine are known radiosensitizers especially in p53 mutant cells. The explanation that the drug abrogates the G2 block and shortens repair in G2 by promoting early entry into mitosis is not anymore tenable because enhancement of radiotoxicity requires presence of the drug during irradiation and fails when the drug is added after irradiation at the G2 maximum. Repair assays by measurement of recovery ratios and by delayed plating experiments indeed strongly suggested a role in repair which is now confirmed for Pentoxifylline by constant field gel electrophoresis (CFGE) measurements and for Pentoxifylline and for Caffeine by use of a variety of repair mutants. The picture now emerging shows that Caffeine and Pentoxifylline inhibit homologous recombination by targeting members of the PIK kinase family (ATM and ATR) which facilitate repair in G2. Pentoxifylline induced repair inhibition between irradiation dose fractions to counter interfraction repair has been successfully applied in a model for stereotactic surgery. Another realistic avenue of application of Pentoxifylline in tumour therapy comes from experiments which show that repair events in G2 can be targeted directly by addition of cytotoxic drugs and Pentoxifylline at the G2 maximum. Under these conditions massive dose enhancement factors of up to 80 have been observed suggesting that it may be possible to realise dramatic improvements to tumour growth control in the clinic.