Cooperative activity of cytotoxic chemotherapy with antiangiogenic thrombospondin-I peptides, ABT-526 in pet dogs with relapsed lymphoma.

Abstract

PURPOSE:

Thrombospondin-I (TSP-I) is a natural antiangiogenic protein that enhances apoptosis of activated endothelial cells. A modified nonapeptide from TSP-I, ABT-526, has been found to be active in mouse cancer models and in dogs with naturally occurring cancers. To further assist in the development of ABT-526, we report herein on its evaluation in combination with cytotoxic chemotherapy in pet dogs with relapsed non-Hodgkin's lymphoma (NHL).

EXPERIMENTAL DESIGN:

Ninety-four pet dogs with naturally occurring first-relapse NHL were entered into a prospective randomized placebo controlled double-blinded trial of ABT-526 plus CeeNu (Bristol-Myers Squibb, New York, NY) versus CeeNu alone. Endpoints included response rate, duration of response, time to progression, and incidence of toxicoses.

RESULTS:

No significant ABT-526-specific toxicities were seen. CeeNu-associated toxicities, including neutropenia, thrombocytopenia, gastroenteritis, and elevated alanine transaminase, were similar. No significant difference in objective response rate was seen (ABT-526 + CeeNu versus placebo + CeeNu, 23/49 versus 23/37; P > 0.25). Cooperative activity between ABT-526 and CeeNu chemotherapy was evident based on a significant increase in the median response duration of dogs receiving ABT-526 plus CeeNu compared with placebo plus CeeNu (35 versus 15 days; P < 0.05). The time to progression for responding cases was also significantly greater in dogs receiving ABT-526 plus CeeNu compared with placebo plus CeeNu (41 versus 21 days; P < 0.05).

CONCLUSIONS:

Results of this preclinical trial suggest that the activity of ABT-526 is sustained when combined with cytotoxic chemotherapy; furthermore, the activity seems to be associated with the maintenance of CeeNu-induced treatment responses. Further studies of TSP-I peptide antiangiogenic therapy in pet dogs and humans with NHL are warranted.

• Authors: Anthony Rusk, Elizabeth Cozzi, Marty Stebbins, David Vail, Joanne Graham, Victor Valli, Jack Henkin, Rick Sharpee, Chand Khanna
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 24 Pg. 7456-64 (Dec 15 2006) ISSN: 1078-0432 [Print] United States
• PMID: 17189419 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Angiogenesis Inhibitors
• Peptide Fragments
• Placebos
• Thrombospondin 1
• acetyl-sarcosyl-glycyl-valyl-isoleucyl-threonyl-norvalyl-isoleucyl-arginyl-proline ethylamide
• Lomustine

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Disease Progression
• Dog Diseases (drug therapy)
• Dogs
• Double-Blind Method
• Female
• Lomustine (administration & dosage)
• Lymphoma, Non-Hodgkin (drug therapy, veterinary)
• Male
• Neoplasm Recurrence, Local (drug therapy)
• Peptide Fragments (therapeutic use)
• Placebos
• Survival Analysis
• Thrombospondin 1 (therapeutic use)
• Time Factors