Low-Dose Fractionated Radiation Potentiates the Effects of Cisplatin Independent of the Hyper-Radiation Sensitivity in Human Lung Cancer Cells

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 Â 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 þ 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. Mol Cancer Ther; 10(2); 292-302. Ó2011 AACR.

Contribution of Dual Oxidase 2 (DUOX2) to Hyper-Radiosensitivity in Human Gastric Cancer Cells

“…The mechanisms underlying HRS are still not completely understood but are associated with a failure to arrest in early G 2 and increased apoptosis (26, 27). Nonetheless, it has been suggested that mechanisms other than a failure to arrest in early G 2 can lead to HRS since some cells lacking the capacity to arrest in G 2 after LDFRT are also negative for HRS (28). In an effort to identify biomarkers for HRS and improve our current understanding of chemopotentiation by LDFRT we analyzed different cellular pathways after exposure to a combined regimen of mDCF and LDFRT.…”

Primary systemic treatment and concomitant low dose radiotherapy for breast cancer: Final results of a prospective phase II study

“…Furthermore, HRS failed to induce prosurvival transcription factors, that are necessary for increasing the levels of MDR-1 gene [53]. Hence, no MDR-1 induction in response to LD-FRT will help to increase the effects of chemotherapy, that is often mitigated by MDR-1 [54]. The use of LD-FRT with chemotherapy provides a new strategy to improve tumor downstaging through the use of radiotherapy as a biological modifier of the chemotherapy response.…”

Low-Dose Hyperradiosensitivity: Is There a Place for Future Investigation in Clinical Settings?

“…Low-dose fractionated radiotherapy (LD-FRT), in particular, has been demonstrated to enhance the effectiveness of multiple chemotherapeutic agents, including carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, and paclitaxel, in a variety of tumor cell lines (24)(25)(26)(27). Preliminary results of clinical trials combining LD-FRT with chemotherapy have shown that this treatment can be both feasible and effective (28,29).…”