Article Abstract

Clinical Cancer Research Vol. 11, 6218-6225, September 1, 2005

In vivo Generation of Angiostatin Isoforms by Administration of a Plasminogen Activator and a Free Sulfhydryl Donor: A Phase I Study of an Angiostatic Cocktail of Tissue Plasminogen Activator and Mesna

Gerald A. Soff^1,3, Hao Wang¹, Deborah L. Cundiff¹, Keyi Jiang¹, Brenda Martone³, Alfred W. Rademaker², Jennifer A. Doll¹ and Timothy M. Kuzel^1,3

Authors' Affiliations: ¹ Division of Hematology/Oncology, Department of Medicine; ² Department of Preventive Medicine, Feinberg School of Medicine; and ³ Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois

Purpose: Angiostatin_4.5 (AS4.5), the endogenous human angiostatin, is derived from plasminogen in a two-step process. A plasminogen activator converts plasminogen to plasmin, then plasmin undergoes autoproteolysis to AS4.5. A free sulfhydryl donor can mediate plasmin autoproteolysis. To translate this process to human cancer therapy, we conducted a phase I trial of administration of a tissue plasminogen activator (tPA) with a free sulfhydryl donor (mesna).

Patients and Methods: Fifteen patients with advanced solid tumors were treated. The dose of tPA was escalated (cohorts; 1, 2, 3, 5, and 7.5 mg/h for 6 hours). Mesna was administered as a 240 mg/m² bolus followed by an infusion of 50 mg/h, concurrent with tPA. Both tPA and mesna were administered 3 consecutive days every 14 days.

Results: No dose-limiting toxicity was observed. Two AS4.5 isoforms were generated, Lys-AS4.5 and Glu-AS4.5. Mean baseline Lys-AS4.5 level was 20.4 nmol/L (SE, 2.9). In the 5 mg/h tPA cohort, Lys-AS4.5 levels increased by an average of 143% or 24 nmol/L (SE, 4.9) above baseline. Glu-AS4.5 (M_r 62,000) was also generated (additional 77 amino acids at amino terminus compared with Lys-AS4.5). Glu-AS4.5 level at baseline was undetectable in four of five patients in the 5 mg/h tPA cohort, but at end of infusion, was 67 nmol/L (SE, 20). Two patients in the 5 mg/h tPA cohort experienced decreases in tumor markers with treatment, although no clinical objective responses were observed.

Conclusion: This study shows that in vivo generation of AS4.5 is safe in humans and may provide a practical approach to achieve antiangiogenic therapy.

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