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

BMC Veterinary Research

Daniel B Tumas³  Noel Sousa-Powers³  Adrian S Ray³  Darius Babusis³  Ilene D Kurzman¹  David M Vail¹  Douglas H Thamm² 

[1]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

[2]University of Colorado Comprehensive Cancer Center, Denver, CO USA

[3]Departments of Drug Metabolism and Drug Safety Evaluation, Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404, USA

关键词: Guanine;    Chemotherapy;    Plasma cell;    Dog;   

Others  :  1119341
DOI  :  10.1186/1746-6148-10-30

 received in 2013-10-23, accepted in 2014-01-24,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Thamm et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Ries LAG, Melbert D, Krapcho M, Mariotto A, Miller BA, Feuer EJ, Clegg L, Horner MJ, Howlader N, Eisner MP, et al.: SEER Cancer Statistics Review, 1975–2004. Bethesda, MD: National Cancer Institute; 2007.
• [2]Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ: Cancer statistics, 2008. CA Cancer J Clin 2008, 58(2):71-96.
• [3]Reiser H, Wang J, Chong L, Watkins WJ, Ray AS, Shibata R, Birkus G, Cihlar T, Wu S, Li B, et al.: GS-9219–a novel acyclic nucleotide analogue with potent antineoplastic activity in dogs with spontaneous non-hodgkin’s lymphoma. Clin Cancer Res 2008, 14(9):2824-2832.
• [4]Kramata P, Downey KM, Paborsky LR: Incorporation and excision of 9-(2-phosphonylmethoxyethyl)guanine (PMEG) by DNA polymerase delta and epsilon in vitro. J Biol Chem 1998, 273(34):21966-21971.
• [5]Rose WC, Crosswell AR, Bronson JJ, Martin JC: In vivo antitumor activity of 9-[(2-phosphonylmethoxy)ethyl]-guanine and related phosphonate nucleotide analogues. J Natl Cancer Inst 1990, 82(6):510-512.
• [6]Naesens L, Hatse S, Segers C, Verbeken E, De Clercq E, Waer M, Balzarini J: 9-(2-phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine: a novel prodrug of 9-(2-phosphonylmethoxyethyl)guanine with improved antitumor efficacy and selectivity in choriocarcinoma-bearing rats. Oncol Res 1999, 11(4):195-203.
• [7]Valerianova M, Votruba I, Holy A, Mandys V, Otova B: Antitumour activity of N6-substituted PMEDAP derivatives against T-cell lymphoma. Anticancer Res 2001, 21(3B):2057-2064.
• [8]Lawrence J, Vanderhoek M, Barbee D, Jeraj R, Tumas DB, Vail DM: Use of 3’-deoxy-3’-[18 F]fluorothymidine PET/CT for evaluating response to cytotoxic chemotherapy in dogs with non-Hodgkin’s lymphoma. Vet Radiol Ultrasound 2009, 50(6):660-668.
• [9]Vail DM, Thamm DH, Reiser H, Ray AS, Wolfgang GH, Watkins WJ, Babusis D, Henne IN, Hawkins MJ, Kurzman ID, et al.: Assessment of GS-9219 in a pet dog model of non-Hodgkin’s lymphoma. Clin Cancer Res 2009, 15(10):3503-3510.
• [10]Vail DM, Thamm DH: Spontaneously occurring tumors in companion animals as models for drug development. In Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval. 2nd edition. Edited by Teicher BA, Andrews PA. Totowa, NJ: Humana Press; 2004:259-284.
• [11]Paoloni M, Khanna C: Translation of new cancer treatments from pet dogs to humans. Nat Rev Cancer 2008, 8(2):147-156.
• [12]Vail DM, Young KM: Canine lymphoma and lymphoid leukemia. In Small Animal Clinical Oncology. 4th edition. Edited by Withrow SJ, Vail DM. St. Louis (MO): Saunders; 2007:699-733.
• [13]Kisseberth WC, MacEwen EG, Helfand SC, Vail DM, London CL, Keller E: Response to liposome-encapsulated doxorubicin (TLC D-99) in a dog with myeloma. J Vet Intern Med 1995, 9(6):425-428.
• [14]Matus RE, Leifer CE, MacEwen EG, Hurvitz AI: Prognostic factors for multiple myeloma in the dog. J Am Vet Med Assoc 1986, 188(11):1288-1292.
• [15]Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, et al.: International uniform response criteria for multiple myeloma. Leukemia 2006, 20(9):1467-1473.
• [16]Lonial S: Multiple myeloma: novel approaches for relapsed disease. Clin Lymphoma Myeloma 2007, 8(Suppl 1):S18-S23.
• [17]Ponisch W, Niederwieser D: Bendamustine in the treatment of multiple myeloma: results and future perspectives. Semin Oncol 2002, 29(4 Suppl 13):23-26.
• [18]Hall JA, Campbell K, Mordecai S, Schaeffer DJ, Zuckermann FA: Comparison of three commercial radial immunodiffusion kits for the measurement of canine serum immunoglobulins. J Vet Diagn Invest 1995, 7(4):559-562.
• [19]Veterinary Co-operative Oncology Group: Veterinary Co-operative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.0. Vet Compar Oncol 2004, 2:194-213.
• [20]Burnett RC, Vernau W, Modiano JF, Olver CS, Moore PF, Avery AC: Diagnosis of canine lymphoid neoplasia using clonal rearrangements of antigen receptor genes. Vet Pathol 2003, 40(1):32-41.