GS-9219/VDC-1101--a prodrug of the acyclic nucleotide PMEG has antitumor activity in spontaneous canine multiple myeloma.
BACKGROUND
Multiple myeloma (MM) is an important human and canine cancer for which novel therapies remain necessary. VDC-1101 (formerly GS-9219), a novel double prodrug of the anti-proliferative nucleotide analog 9-(2-phosphonylmethoxyethyl) guanine (PMEG), possesses potent cytotoxic activity in vitro in human lymphoblasts and leukemia cell lines and in vivo in spontaneous canine lymphoma. Given the similarity in lineage between lymphoma and MM, we hypothesized that VDC-1101 would be active against MM.


RESULTS
We evaluated the in vitro antiproliferative effects of VDC-1101 against 3 human MM cell lines, and we performed a phase-II clinical trial in 14 dogs with spontaneous MM. Each dog was treated with a maximum of 6 doses of VDC-1101 monotherapy over 10-15 weeks. Dose-dependent antiproliferative activity was observed in all evaluated cell lines. Major antitumor responses (reduction of serum paraprotein and resolution of hypercalcemia, peripheral cytopenias and bone marrow plasmacytosis) were observed in 9 of 11 evaluable dogs for a median of 172 days, including a durable stringent complete response (>1047 days) in a dog with melphalan-refractory disease. 2 dogs were euthanized due to presumed pulmonary fibrosis; there were no other dose-limiting toxicities encountered.


CONCLUSIONS
In conclusion, VDC-1101 has significant anti-tumor activity at well-tolerated doses in spontaneous canine MM.
Flint Animal Cancer Center, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 300 W, Drake Rd, Fort Collins, CO 80523-1620, USA. dthamm@colostate.edu.
Douglas H
DH
Thamm
David M
DM
Vail
Ilene D
ID
Kurzman
Darius
D
Babusis
Adrian S
AS
Ray
Noel
N
Sousa-Powers
Daniel B
DB
Tumas
D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy / Q000662:veterinary*; D009943:Organophosphorus Compounds / Q000378:metabolism*; D011355:Prodrugs; D011687:Purines / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D011355:Prodrugs; D011687:Purines; C531423:rabacfosadine; C063380:9-((2-phosphonylmethoxy)ethyl)guanine; D006147:Guanine; D000409:Alanine