P. Spring

Low dose fractionated radiation potentiates the effects of taxotere in nude mice xenografts of squamous cell carcinoma of head and neck

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 G2M 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

Lack of P-Glycoprotein Expression by Low-Dose Fractionated Radiation Results from Loss of Nuclear Factor-κB and NF-Y Activation in Oral Carcinoma Cells

Multidrug resistance (MDR) is associated with the overproduction of the 170-kDa transmembrane protein P-glycoprotein (MDR1) caused by transcriptional activation. However, the activity of the MDR1 promoter in response to different doses of ionizing radiation has not been investigated. In this study, two squamous cell carcinoma oral cavity cell lines, T-167 and T-409, were exposed to either a standard clinical dose of 2 Gy or low-dose fractionated radiation therapy (LDFRT), delivered as 0.5 Gy in four fractions. MDR1 gene expression and degree of cell death were assessed. Clinically relevant 2-Gy dose of radiation resulted in increased expression of MDR1 by reverse transcription-PCR and luciferase reporter assays in both cell lines (T-167 and T-409), whereas LDFRT did not. LDFRT caused enhanced apoptosis when compared with the 2-Gy dose in T-167 and T-409 cells as assessed by terminal nucleotidyl transferase–mediated nick end labeling (TUNEL) assays. Transcription of the MDR1 gene is regulated by numerous transcription factors, which include nuclear factor-κB (NF-κB), NF-Y, SP1, YB1, MEF1 (MDR1 promoter-enhancing factor 1), p53, and NF-R1. Interestingly, 2 Gy robustly induced both NF-κB and NF-Y in T-167 and T-409 cells, but did not show induction when exposed to LDFRT. Silencing the expression of the DNA binding subunit of NF-κB, p50, by small interfering RNA vector resulted in a decrease of MDR1 function by rhodamine 123 efflux assay in T167 cells exposed to 2 Gy. Together, these results provide evidence for the lack of induction of P-glycoprotein expression by LDFRT, which has important implications in combinatorial cancer therapy, including the use of LDFRT as an adjuvant for chemotherapy. (Mol Cancer Res 2008;6(1):89–98)

Long-term results of hyperfractionated radiation and high-dose intraarterial cisplatin for unresectable oropharyngeal carcinoma.

In this report, the authors present the results from a study of patients with unresectable oropharyngeal squamous cell carcinomas who were treated on a protocol of hyperfractionated radiation and high‐dose intraarterial cisplatin (HYPERRADPLAT) at the University of Kentucky.

Interval pathologic assessments in patients treated with concurrent hyperfractionated radiation and intraarterial cisplatin (HYPERRADPLAT)

To minimize surgical morbidity, surgery should be performed within 2 to 3 months of completion of radiation therapy with or without chemotherapy. Pathologic demonstration of cancer at this interval is commonly used to justify early surgical salvage of residual primary head and neck cancer. These assumptions regarding head and neck cancer in patients treated with concurrent hyperfractionated radiation therapy and intraarterial supradose cisplatin (HYPERRADPLAT) have never been evaluated.

Low-dose fractionated radiation (LDFRT) plus paclitaxel (P) and carboplatin (CBCDA) as induction therapy for locally advanced squamous cell carcinoma of the head and neck (SCCHN): Two-year follow-up

5593 Background: LDFRT (< 100cGy) induces cell death through a unique mechanism, hyper-radiosensitivity. Based on demonstrated synergy with chemotherapy, LDFRT was combined with P and C as induction therapy in locally advanced SSCHN. METHODS In this phase II trial, 39 patients with locally advanced SCCHN (77.5% stage IV, 45% T4 and 60% advanced neck disease) received P 225mg/m2 (Day 1), CB AUC 6 (Day 1), and four 80 cGy fractions of radiation (two each on Day 1 & 2) for two cycles. Definitive therapy began 3 weeks after the last dose of induction therapy and was based on response to induction and the decision of a multidisciplinary team. Nineteen patients (49%) received concurrent chemotherapy and radiation, 16 (41%) patients received radiation alone and 4 patients (10%) had surgery. RESULTS Median follow-up is 26 months. Overall response rate to induction was 82% (90% RR at the primary site). At two years, overall survival was 72%, DFS was 77%. The local control rate was 79% (the majority of failures occurred within the first year) and distant control 88%. CONCLUSIONS Induction LDFRT, P and CB appears to improve distant control rates in patients with locally advanced SCCHN. OS and DFS compare favorably to other aggressive chemoradiotherapy strategies in SCCHN. These results confirm the efficacy of induction LDFRT and chemotherapy followed by aggressive definitive therapy in SCCHN. Supported by a grant from Bristol-Myers Squibb. [Table: see text].