A pilot study on tumor dormancy therapy by anti-angiogenesis and differ entiation agents administered to dogs with advanced spontaneous tumors.

2001 Fiscal Year Final Research Report Summary

• Project/Area Number: 12833001
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Institution: HOKKAIDO UNIVERSITY
• Principal Investigator: KADOSAWA Tsuyoshi Hokkaido Univ., Graduate School of Veterinary Medicine, Lecturer, 大学院・獣医学研究科, 講師 (70214418)
• Co-Investigator(Kenkyū-buntansha): KUSAKA Masami Pharmaceutical Research Laboratories, Takeda Chemical Industries, Ltd., Research Head, 薬理研究所, 主席研究員 ; OOIZUMI Iwao Pharmaceutical Research Laboratories, Chugai Pharmaceutical Co. Ltd., Researcher, 創薬第2研究所, 研究員 ; OCHIAI Kenji Hokkaido Univ., Graduate School of Veterinary Medicine, Associate Professor, 大学院・獣医学研究科, 助教授 (80214162)
• Project Period (FY): 2000 – 2001
• Keywords: Tumor / Tumor Dormancy Therapy / Differentiation / Anti-angiogenesis / Dog

Research Abstract

A pilot study of the novel angiogenesis inhibitor TNP-470 and differentiation agent OCT (22-oxacalcitriol) was performed. Dogs with advanced spontaneous malignant tumors and their owners' consent to a pilot study were eligible. The starting doses were low for inhibiting fatal side effects. Further doses were escalated every 2 or 4 weeks when side effects were not observed.
TNP-470, a dose of 12.5〜223mg/m^2 B.W., was administered to 42 dogs subcutaneously or intravenously 1〜3 times per week. Lameness and shivering were encountered in 7 dogs. Seizure was shown in 3 dogs, and bleeding, anorexia and vomiting were in a dog, respectively. Dose-dependency of these clinical signs was not clear. Blood examinations revealed decreased erythrocyte counts and increased leukocyte counts, serum creatinine and alkaline phosphatase, but these changes were not serious.
OCT, daily oral dose of 0.03〜0.1 2μg/kg B.W., was administered to 26 dogs. In 21 dogs receiving over 2 weeks, 7 dogs showed hypercalcemia. Five dogs of the 7 dogs showed hypercalcemia at the 0.03/ug/kg dose level within 6 weeks but remaining 2 dogs did at the 0.1 2μg/kg dose level approximately 6 months later. Hypercalcemia resolved, followed by a 7-day rest period. Other blood chemical analysis revealed increased leukocyte counts, but this change was not serious.
Evaluations of anti-tumor effects, such as inhibition of tumor growth and metastasis, were difficult without a control group. But primary or metastatic lesions shrank by these agents in a few dogs. A small number of dogs with highly metastasizing tumors such as osteosarcoma survived for a long time without progressive disease.
In this pilot study, dogs with advanced malignant tumors tolerated well to TNP-470 and OCT, and some encouraging anti-turner effects were shown. Further studies of tumor dormancy therapy by antiangiogenesis and differentiation agents are warranted.