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 fromTSP-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 21days; 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.

Thrombospondin and Apoptosis: Molecular Mechanisms and Use for Design of Complementation Treatments

“…In the studies above the in vivo dosing of cytotoxic drugs was reduced to 1/20–1/50 of the maximally tolerated dose. Further studies demonstrated the validity of this approach: ABT-526 showed cooperative effect with cytotoxic agent lomustine (CeeNu, Bristol-Meyers-Squibb) in pet dogs with relapsed non-Hodgkin’s lymphoma [114] and with gemcitabine in the mouse model of pancreatic cancer [99, 115]. …”

Assessment of GS-9219 in a Pet Dog Model of Non-Hodgkin's Lymphoma

“…Canine non-Hodgkin's lymphoma has proven to be a relevant model for preclinical evaluation of new therapeutics for both initial induction and rescue of drug-resistant relapse (8)(9)(10)(11)(12)(13)(14). Evaluation of novel therapeutic approaches in dogs with spontaneous cancer offers potential benefit to canine patients and a rapid assessment of therapeutic index.…”

Comparative oncology: Integrating human and veterinary medicine

“…8(1): 25-34 ________________________________________________________________________________________________________ (Knapp et al, 1992) Breast cancer BCG combined with surgery (Parodi et al, 1983) Immunotherapy (Teske et al, 1998) Non-Hodgkin's lymphoma Liposomal L-asparaginase (MacEwen et al, 1992) Antiangiogenic thrombospondin-I peptide (ABT526) (Rusk et al, 2006) Soft tissue sarcoma Antiangiogenic thrombospondin-I mimetic peptides (Sahora et al, 2012) Hyperthermia combined with irradiation (Gillette et al, 1992) Apart from these, canine osteosarcomas show overexpression of IL-8 and SLC1A3 which are related to poor outcome of human osteosarcoma . In a comparative study new genes (CDC5L, MYC, RUNX2 and CDKN2A/CDKN2B), that had not been described previously, were revealed in addition to genes (ADAM15, CTC1, MEN1, CDK7) with the known association in osteosarcoma (Angstadt et al, 2012).…”