Experimental study on different combination schedules of VEGF-receptor inhibitor PTK787/ZK222584 and fractionated irradiation.

Abstract

BACKGROUND:

Inhibition of the vascular endothelial growth factor receptor (VEGFR) has been shown to improve the radiation response of several experimental tumors. The present experimental study compares the effect of neoadjuvant, concomitant and adjuvant treatment with PTK787/ZK222584, a specific inhibitor of the VEGFR, in combination with fractionated irradiation.

MATERIALS AND METHODS:

Growth delay after daily oral application of 50 mg per kg bodyweight PTK787/ZK222584 or carrier was tested in five different human squamous cell carcinoma growing in nude mice. Two of these tumor models, a responder (UT-SCC-14) and a non-responder (FaDu), were selected for the irradiation experiments (15 fractions of 2 Gy within 15 days). PTK787/ZK222584 was applied daily for 4-18 days and stopped before start of irradiation (neoadjuvant), for 15 days during fractionated irradiation (concomitant) or for 45 days after the course of irradiation (adjuvant).

RESULTS:

Adjuvant application of PTK787/ZK222584 after fractionated irradiation retarded regrowth of UT-SCC-14 tumors and, surprisingly, also of FaDu tumors which did not respond to the agent when given alone. No effects on radiation response were observed after short-term neoadjuvant or concomitant PTK787/ZK222584 application.

CONCLUSION:

Combined with fractionated irradiation, only adjuvant application of PTK787/ZK222584 retarded regrowth of UT-SCC-14 and FaDu tumors. The data suggest that preirradiated vasculature might be more sensitive to VEGFR inhibition compared to unirradiated vasculature. Whether the effect of adjuvant VEGFR inhibition on growth delay translates into improved local tumor control after irradiation needs further investigation.

• Authors: Daniel Zips, Mechthild Krause, Franziska Hessel, Jana Westphal, Kerstin Brüchner, Wolfgang Eicheler, Annegret Dörfler, Reidar Grenman, Cordula Petersen, Martin Haberey, Michael Baumann
• Journal: Anticancer research (Anticancer Res) 2003 Sep-Oct Vol. 23 Issue 5A Pg. 3869-76 ISSN: 0250-7005 [Print] Greece
• PMID: 14666690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Phthalazines
• Pyridines
• vatalanib

Topics

• Angiogenesis Inhibitors (administration & dosage)
• Animals
• Carcinoma, Squamous Cell (blood supply, drug therapy, radiotherapy)
• Cell Line, Tumor
• Chemotherapy, Adjuvant
• Dose Fractionation, Radiation
• Drug Administration Schedule
• Female
• Humans
• Male
• Mice
• Mice, Nude
• Neoadjuvant Therapy
• Phthalazines (administration & dosage)
• Pyridines
• Xenograft Model Antitumor Assays