Local targeting of malignant gliomas by the diffusible peptidic vector 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid-substance p

Kneifel, Stefan; Cordier, Dominik; Good, Stephan; Ionescu, Mihai C S; Ghaffari, Anthony; Hofer, Silvia; Kretzschmar, Martin; Tolnay, Markus; Apostolidis, Christos; Waser, Beatrice; Arnold, Marlene; Mueller-Brand, Jan; Maecke, Helmut R; Reubi, Jean Claude; Merlo, Adrian (2006). Local targeting of malignant gliomas by the diffusible peptidic vector 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid-substance p. Clinical cancer research, 12(12), pp. 3843-50. Philadelphia, Pa.: American Association for Cancer Research 10.1158/1078-0432.CCR-05-2820

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PURPOSE: Malignant glial brain tumors consistently overexpress neurokinin type 1 receptors. In classic seed-based brachytherapy, one to several rigid (125)I seeds are inserted, mainly for the treatment of small low-grade gliomas. The complex geometry of rapidly proliferating high-grade gliomas requires a diffusible system targeting tumor-associated surface structures to saturate the tumor, including its margins. EXPERIMENTAL DESIGN: We developed a new targeting vector by conjugating the chelator 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid to Arg(1) of substance P, generating a radiopharmaceutical with a molecular weight of 1,806 Da and an IC(50) of 0.88 +/- 0.34 nmol/L. Cell biological studies were done with glioblastoma cell lines. neurokinin type-1 receptor (NK1R) autoradiography was done with 58 tumor biopsies. For labeling, (90)Y was mostly used. To reduce the "cross-fire effect" in critically located tumors, (177)Lut and (213)Bi were used instead. In a pilot study, we assessed feasibility, biodistribution, and early and long-term toxicity following i.t. injection of radiolabeled 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid substance P in 14 glioblastoma and six glioma patients of WHO grades 2 to 3. RESULTS: Autoradiography disclosed overexpression of NK1R in 55 of 58 gliomas of WHO grades 2 to 4. Internalization of the peptidic vector was found to be specific. Clinically, the radiopharmeutical was distributed according to tumor geometry. Only transient toxicity was seen as symptomatic radiogenic edema in one patient (observation period, 7-66 months). Disease stabilization and/or improved neurologic status was observed in 13 of 20 patients. Secondary resection disclosed widespread radiation necrosis with improved demarcation. CONCLUSIONS: Targeted radiotherapy using diffusible peptidic vectors represents an innovative strategy for local control of malignant gliomas, which will be further assessed as a neoadjuvant approach.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Service Sector > Institute of Pathology
UniBE Contributor:	Waser, Beatrice, Arnold, Marlene, Reubi-Kattenbusch, Jean-Claude
Subjects:	500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health
ISSN:	1078-0432
ISBN:	16778112
Publisher:	American Association for Cancer Research
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:48
Last Modified:	05 Dec 2022 14:15
Publisher DOI:	10.1158/1078-0432.CCR-05-2820
PubMed ID:	16778112
Web of Science ID:	000238415100024
URI:	https://boris.unibe.ch/id/eprint/20298 (FactScience: 3554)