Low Dose Fractionated Radiation Potentiates the Effects of Taxotere in Nude Mice Xenografts of Squamous Cell Carcinoma of Head and Neck

Abstract

This study evaluated the combined effect of Low Dose Fractionated Radiation (LDFRT) and Taxotere (TXT) therapy on the growth of SCCHN (squamous cell carcinoma of head and neck; SQ-20B, a p53 mutant SCCHN cell line) tumors in a nude mouse model to exploit the increased hyper radiation sensitivity (HRS) phenomenon present in G 2 /M cell cycle phase when induced by low doses of radiation that was demonstrated in in vitro settings. Seventy-eight animals were randomized into one control group and 5 treatment groups (treatments were administered weekly for six weeks). Tumor regression was observed in all the groups, however, tumor regression was not significant in 2 Gy or TXT or 2 Gy plus TXT treated groups when compared to control group. The tumor regression was significant in both the LDFRT group (p < 0.0043) and LDFRT + TXT group (p < 0.0006) when compared to the other groups. A significantly prolonged tumor growth delay was observed in LDFRT group (p < 0.0081). Importantly, in combination of TXT and LDFRT, no tumor regrowth was observed in 12 out of 13 mice since LDFRT + TXT treatment caused a sustained regression of tumors for 9 weeks. Molecular analysis of resected tumor specimens demonstrated that Bax levels were elevated with a concomitant increase in cytochrome c release into the cytosol in treatment Group VI. These findings strongly suggest that LDFRT can be used in combination with TXT to potentiate the effects of drug on tumor regression through an apoptotic mode of death. Furthermore, the G 2 /M cell cycle arrest by TXT appears to be an important component of the enhanced apoptotic effect of TXT + LDFRT combined treatment.

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

“…However, in these cells, CER was not enhanced following either LDFRT or 2 Gy treatment compared to when cisplatin was added immediately prior to irradiation (Supplementary Table 5). This is in contrast to the earlier reports wherein LDFRT could enhance the chemopotentiation effects of paclitaxel that arrest cells in the G 2 -M phase (18,19). One explanation could be that the G 2 -M phase arrest induced by cisplatin is similar to the classical G 2 -M phase block induced by radiation due to the accumulation of damaged G 1 -and S-phase cells in the G 2 -M phase.…”

“…Cells synchronized in G 2 -M showed a significantly more pronounced HRS than synchronized cells in G 1 or S. These findings present an interesting explanation of the underlying mechanisms of chemopotentiation by LDFRT in the studies from our laboratory using paclitaxel or docetaxel (18,19). In the present study, incubation of cells with cisplatin for 24 hours resulted in a transient accumulation in the G 2 -M phase only in UKY-29 cells (Fig.…”

“…Our previous in vitro, in vivo, and clinical studies have shown that LDFRT could be used as a chemopotentiator of paclitaxel, carboplatin, and gemcitabine (18)(19)(20)30). However, the question that still remains unanswered is whether the presence of HRS is essential to potentiate the effects of chemotherapeutic drugs by LDFRT.…”

“…Our previous studies in head and neck tumor cell lines and mice xenografts showed increased apoptosis rather than clonogenic death in LDFRT-mediated chemopotentiation (18,19), suggesting that preferred mode of killing in chemopotentiation by LDFRT is apoptosis. This is supported by the TUNEL assay results of the present study wherein it was found that chemoenhancement ratio was significantly higher for apoptosis than for clonogenic inhibition in H-157 cells.…”

“…Recently, both in vitro and in vivo studies have shown that low doses of fractionated radiation can be used as enhancers (potentiators) of full-dose chemotherapy and circumvent the development of resistance observed with standard clinical doses of radiation and chemotherapy (17)(18)(19)(20). The effects of low-dose fractionated irradiation on cell survival have been now well studied and the phenomena of hyper-radiation sensitivity (HRS) at doses of less than 0.5 Gy and induced radiation resistance (IRR) at doses of less than 1 Gy are well documented (15,21).…”