PARENT SESSION
1:30 PM to 3:30 PM
Tuesday, April 23, 2002
Poster Session 21 Radiation-Drug Interaction
Room: Nevada Exhibition Center

(P26-269) Inhibition of EGF-receptor tyrosine kinase with BIBX1382BS prolongs growth delay but does not improve local tumor control in human FaDu SCC xenografts irradiated with 30 fractions in 6 weeks.

Baumann, Michael^*,1,2, Krause, Mechthild¹, Ahrens, Josephine¹, Zips, Daniel¹, Dörfler, Annegret¹, Eicheler, Wolfgang¹, Petersen, Cordula¹, Hilberg, Frank³, ¹ Department of Radiation Oncology, Dresden, Germany² Experimental Center, Dresden, Germany³ Boehringer Ingelheim Austria GmbH, Vienna, Austria

ABSTRACT-
Purpose: Repopulation of clonogenic cells during fractionated irradiation (RT) is a major cause of local failure in squamous cell carcinoma (SCC). The EGFR signal transduction pathway has been suggested to play an important regulative role in this process. The aim of our study was to investigate whether specific inhibition of the EGFR-TK by BIBX1382BS (BIBX) improves the results of fractionated irradiation in FaDu hSCC in nude mice. This tumor model was chosen because a) repopulation of clonogenic cells during fractionated RT has been demonstrated in previous experiments, b) FaDu is EGFR positive, and c) proliferation in unirradiated FaDu tumors can be effectively decreased by BIBX. Methods: Proliferation rate, cell cycle distribution, BrdUrd-LI, and clonogenic cell survival were determined in vitro after application of 5mol/l BIBX or carrier. Tumor-bearing nude mice received 50 mg/kg/d p.o. BIBX alone or simultaneouly with RT (30f/6w). Experimental endpoints were tumor growth delay (V5) and tumor control dose 50% (TCD50). In addition BrdUrd and Ki67-LI were determined in histological slides. Results: In line with decreased BrdUrd and Ki67-LI, BIBX significantly decreased the growth rate of unirradiated FaDu cells in vitro and of FaDu tumors in nude mice. In vitro BIBX was slightly cytotoxic but did not change radiosensitivity of FaDu cells when given over three days before and during RT. When given simultaneously with fractionated irradiation BIBX significantly prolonged tumor growth delay after subcurative doses of 30-60 Gy by factors between 1.2 and 3.4 . However, BIBX did not significantly change TCD50 (control 63.6 Gy [95%CI 55;73]; BIBX 67.7 Gy [59;77]; Likelihood-ratio-p= 0.5). Conclusion: Despite the fact that significant repopulation during fractionated RT has been demonstrated for FaDu hSCC and that EGFR-TK inhibition with BIBX1382BS significantly prolongs growth delay, local tumor control could not be improved by simultaneous application of this substance with fractionated RT. Further experiments are underway to address possible mechanisms for this discrepancy.

KEYWORDS: EGFR-inhibition, repopulation, fractionated radiotherapy, local tumor control