GS-9219/VDC-1101 - a prodrug of the acyclic nucleotide PMEG has antitumor activity inspontaneous canine multiple myeloma

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• 作者：Douglas H Thamm (6) (7)
  David M Vail (8)
  Ilene D Kurzman (8)
  Darius Babusis (9)
  Adrian S Ray (9)
  Noel Sousa-Powers (9)
  Daniel B Tumas (9)
  
• 关键词：Dog ; Plasma cell ; Chemotherapy ; Guanine
• 刊名：BMC Veterinary Research
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：10
• 期：1
• 全文大小：291 KB
• 作者单位：Douglas H Thamm (6) (7)
  David M Vail (8)
  Ilene D Kurzman (8)
  Darius Babusis (9)
  Adrian S Ray (9)
  Noel Sousa-Powers (9)
  Daniel B Tumas (9)
  
  6. 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
  7. University of Colorado Comprehensive Cancer Center, Denver, CO, USA
  8. Barbara A. Suran Comparative Oncology Research Institute, School of Veterinary Medicine and the Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI, 53706, USA
  9. Departments of Drug Metabolism and Drug Safety Evaluation, Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA, 94404, USA
  
• ISSN：1746-6148

文摘

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 10-5?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.