PARENT SESSION
3:45 PM to 5:15 AM
Sunday, April 21, 2002
Mini-Symposium 5
Oxygenation and Stress Response
Room: Nevada 1-2
, Co-Chair: Koch, Cameron1; Mason, Kathy21University of Pennsylvania, Philadelphia, PA2MD Anderson Cancer Center, Houston, TX
(MS05-1) VEGFR tyrosine kinase inhibition by ZK 222584/ PTK 787 (ZK) combined with fractionated radiotherapy (RT) in human squamous cell carcinoma (hSCC) in nude mice.
Zips, Daniel*,1, Krause, Mechthild1, Westphal, Jana1, Brüchner, Kerstin2, Eicheler, Wolfgang1, Dörfler, Annegret1, Grenman, Reidar3, Baumann, Michael1,2, 1 Dept. of Radiation Oncology, Medical Faculty, University of Dresden, Dresden, Germany2 Experimental Center, Medical Faculty, University of Dresden, Dresden, Germany3 Dept. of Otorhinolarynology, Turku University Central Hospital, Turku, Finland
ABSTRACT-
Purpose: To investigate the effect of the antiangiogenetic substance ZK, a specific inhibitor of VEGFR tyrosine kinases, on the growth rate of different hSCC and on the growth delay after fractionated RT of hSCC. Materials and methods: Five hSCC lines (FaDu, UT-SCC-14, UT-SCC-33, UT-SCC-15, MKG7) were transplanted s.c. in NMRI nu/nu mice. Presence of murine VEGFR mRNA was confirmed by RT-PCR. At a mean tumor diameter of 6 mm animals were treated daily with ZK (joint development of Schering and Novartis; 50 mg/kg bodyweight per os) or with carrier (control). The specific growth delay (SGD) was determined. In a second set of experiments FaDu and UT-SCC-14 tumors were irradiated with 15 fractions of 2 Gy under ambient conditions (200 kV X-rays, 0.5 mm Cu, 1.2 Gy/min). ZK was given either before (4-8 days) , during (15 days) , or after (45 days) the course of fractionated RT. Results: ZK was well tolerated. A significant decrease of growth rate in tumors treated with ZK was observed in 3 of the 5 hSCC. The SGD to reach 10 times the starting volume was 0.1 for FaDu, 0.6 for UT-SCC-14, 0.5 for UT-SCC-33, 0.6 for UT-SCC-15, and 0.1 for MGK 7. For the combination experiments with RT a non-responding (FaDu) and a responding (UT-SCC-14) tumor model were chosen. Short-term application of ZK before and during fractionated irradiation did not significantly change the SGD of FaDu and UT-SCC-14 tumors. In both tumor models the longer application of ZK after fractionated RT showed a significant increased growth delay compared with irradiated controls. In UT-SCC-14 a significant increase in local control was observed. Conclusions: Short term neoadjuvant or simultaneous application of ZK did not decrease the efficacy of fractionated RT in non-responding FaDu and responding UT-SCC-14 tumors. Adjuvant application improved the effect of RT in both tumor models, i.e. also in FaDu tumors in which ZK alone had no effect. This might suggest enhanced sensitivity of irradiated tumor vessels to VEGFR-inhibition. Explanatory studies and experiments testing the effect of ZK on local tumor control are under way.
KEYWORDS: Antiangiogenesis, fractionated radiotherapy, xenograft, VEGFR