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


METHODS
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.
Rusk
Anthony
A
Animal Clinical Investigation, LLC, Bethesda, Maryland, USA. trusk@animalci.com
Cozzi
Elizabeth
E
Stebbins
Marty
M
Vail
David
D
Graham
Joanne
J
Valli
Victor
V
Henkin
Jack
J
Sharpee
Rick
R
Khanna
Chand
C
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018450:Disease Progression; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004311:Double-Blind Method; D005260:Female; D008130:Lomustine / Q000008:administration & dosage; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000662:veterinary*; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010446:Peptide Fragments / Q000627:therapeutic use*; D010919:Placebos; D016019:Survival Analysis; D019700:Thrombospondin 1 / Q000627:therapeutic use*; D013997:Time Factors
D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D010919:Placebos; D019700:Thrombospondin 1; C477606:acetyl-sarcosyl-glycyl-valyl-isoleucyl-threonyl-norvalyl-isoleucyl-arginyl-proline ethylamide; D008130:Lomustine