Low-dose fractionated radiation potentiates the effects of cisplatin independent of the hyper-radiation sensitivity in human lung cancer cells

Mol Cancer Ther. 2011 Feb;10(2):292-302. doi: 10.1158/1535-7163.MCT-10-0630. Epub 2011 Jan 7.

Abstract

In this study, the role of hyper-radiation sensitivity (HRS) in potentiating the effects of cisplatin by low-dose fractionated radiation (LDFRT) was evaluated in four human non-small cell lung cancer cell lines. Presence of HRS and cisplatin enhancement ratio (CER) by LDFRT/2 Gy was assessed using colony-forming and apoptotic assays. Cell-cycle disturbances were studied by flow cytometry. Expression of genes involved in apoptosis was assessed using real-time reverse transcriptase PCR arrays. H-157 cells showed a distinct HRS region, followed by UKY-29 and A549 cells, whereas it was absent in H460 cells, which when lack HRS showed maximum CER with LDFRT (4 × 0.5 Gy) both by clonogenic inhibition and by apoptosis compared with single fraction of 2 Gy whereas the most radioresistant A549 cells had the least CER, with no significant differences between LDFRT or 2 Gy. Interestingly, in H-157 cells, a more pronounced CER was observed with LDFRT when assessed by apoptosis but clonogenic inhibition-CER was higher with 2 Gy than with LDFRT. Excluding H-157 cells, the CER by LDFRT was inversely proportional to radioresistance [(determined by D(0), the dose to reduce survival by 67% from any point on the linear portion of the survival curve or surviving fraction (SF) at 2 Gy (SF(2))] of the cells. LDFRT alone or in combination with cisplatin induced larger number of proapoptotic genes than 2 Gy or cisplatin + 2 Gy in cells showing HRS when compared to H460 cells that lack HRS. These findings indicate that chemopotentiation by LDFRT is correlated more with the intrinsic radiation sensitivity of the non-small lung cancer cells than the HRS phenomenon whereas the mode of cell killing is both through apoptosis and clonogenic inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Apoptosis / radiation effects*
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Cycle / drug effects
  • Cell Cycle / radiation effects
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Dose Fractionation, Radiation*
  • Dose-Response Relationship, Radiation
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Humans
  • Radiation Tolerance / physiology*

Substances

  • Antineoplastic Agents
  • Cisplatin