1. bookVolume 67 (2017): Issue 4 (December 2017)
Journal Details
License
Format
Journal
eISSN
1820-7448
First Published
25 Mar 2014
Publication timeframe
4 times per year
Languages
English
access type Open Access

The in Vitro and in Vivo Anti-Cancer Potential of Mycobacterium Cell Wall Fraction (MCWF) Against Canine Transitional Cell Carcinoma of the Urinary Bladder

Published Online: 29 Dec 2017
Volume & Issue: Volume 67 (2017) - Issue 4 (December 2017)
Page range: 477 - 494
Received: 26 May 2017
Accepted: 03 Sep 2017
Journal Details
License
Format
Journal
eISSN
1820-7448
First Published
25 Mar 2014
Publication timeframe
4 times per year
Languages
English
Abstract

Transitional cell carcinoma (TCC), is the most common form of urinary bladder cancer in dogs and represents 2% of all reported canine cancers. Canine TCC is usually a high-grade invasive cancer and problems associated with TCC include urinary tract obstruction and distant metastases in more than 50% of affected dogs. TCC is most commonly located in the trigone region of the bladder precluding complete surgical resection. Current treatment options for TCC in dogs include medical therapy, surgery or radiation. Mycobacterium Cell Wall Fraction (MCWF) is a biological immunomodulator derived from non-pathogenic Mycobacterium phlei. MCWF possesses a potential in multiple veterinary areas such as anticancer therapy, palliative care and treatment of infectious diseases in both small and large animals. MCWF is considered a bifunctional anti-cancer agent that induces apoptosis of cancer cells and stimulates cytokine and chemokines synthesis by cells of the immune system. Here we report the results from in vitro and in vivo studies that could suggest use of MCWF as an additional treatment option for TCC in dogs. Particularly, we demonstrated that MCWF induces a concentration dependent inhibition of proliferation of K9TCC cells which was associated with the induction of apoptosis as measured by the proteolytic activation of caspase-3 and the degradation of PARP. Furthermore, we demonstrated the safety and potential for in vivo MCWF treatment efficacy in dogs bearing stage T2 TCC by reducing clinical signs, and improving the quality of life in dogs with TCC.

Keywords

1. Mutsaers AJ, Widmer WR, Knapp DW. Canine transitional cell carcinoma. J Vet Intern Med. 2003;17: 136-144.10.1111/j.1939-1676.2003.tb02424.xSearch in Google Scholar

2. Knapp DW, Ramos-Vara JA, Moore GE, Dhawan D, Bonney PL, Young KE. Urinary bladder cancer in dogs, a naturally occurring model for cancer biology and drug development. ILAR J. 2014;55: 100-118.10.1093/ilar/ilu018Search in Google Scholar

3. Raghavan M, Knapp DW, Bonney PL, Dawson MH, Glickman LT. Evaluation of the effect of dietary vegetable consumption on reducing risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers. J Am Vet Med Assoc. 2005;227: 94-100.10.2460/javma.2005.227.94Search in Google Scholar

4. Raghavan M, Knapp DW, Dawson MH, Bonney PL, Glickman LT. Topical fl ea and tick pesticides and the risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers. J Am Vet Med Assoc. 2004;225: 389-394.10.2460/javma.2004.225.389Search in Google Scholar

5. Glickman LT, Raghavan M, Knapp DW, Bonney PL, Dawson MH. Herbicide exposure and the risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers. J Am Vet Med Assoc. 2004;224: 1290-1297.10.2460/javma.2004.224.1290Search in Google Scholar

6. Withrow SJ, Vail DM, Page RL. Small Animal Clinical Oncology. In: Knapp DW, McMillan SK, editors. Tumors of the urinary System: Elsevier, 2013.Search in Google Scholar

7. Knapp DW, Glickman NW, Denicola DB, Bonney PL, Lin TL, Glickman LT. Naturallyoccurring canine transitional cell carcinoma of the urinary bladder A relevant model of human invasive bladder cancer. Urol Oncol. 2000;5: 47-59.10.1016/S1078-1439(99)00006-XSearch in Google Scholar

8. Valli VE, Norris A, Jacobs RM, Laing E, Withrow S, Macy D, Tomlinson J, McCaw D, Ogilvie GK, Pidgeon G, Henderson RA. Pathology of canine bladder and urethral cancer and correlation with tumour progression and survival. J Comp Pathol. 1995;113: 113-130.10.1016/S0021-9975(05)80027-1Search in Google Scholar

9. L.N. O. TNM Classifi cation of Tumors in Domestic Animals. In: WHO, editor. Geneva: World Health Organization (WHO), 1980.Search in Google Scholar

10. Fulkerson CM, Knapp DW. Management of transitional cell carcinoma of the urinary bladder in dogs: a review. Vet J. 2015;205: 217-225.10.1016/j.tvjl.2015.01.01725747698Search in Google Scholar

11. Knapp DW, Henry CJ, Widmer WR, Tan KM, Moore GE, Ramos-Vara JA, Lucroy MD, Greenberg CB, Greene SN, Abbo AH, Hanson PD, Alva R, Bonney PL. Randomized trial of cisplatin versus fi rocoxib versus cisplatin/fi rocoxib in dogs with transitional cell carcinoma of the urinary bladder. J Vet Intern Med. 2013;27: 126-133.10.1111/jvim.1201323205923Search in Google Scholar

12. Cannon CM, Allstadt SD. Lower urinary tract cancer. Vet Clin North Am Small Anim Pract. 2015;45: 807-824.10.1016/j.cvsm.2015.02.00825824392Search in Google Scholar

13. Morales A, Cohen Z. Mycobacterium phlei cell wall-nucleic acid complex in the treatment of nonmuscle invasive bladder cancer unresponsive to bacillus Calmette-Guerin. Expert Opin Biol Ther. 2016;16: 273-283.10.1517/14712598.2016.1134483Search in Google Scholar

14. Morales A, Phadke K, Steinhoff G. Intravesical mycobacterial cell wall-DNA complex in the treatment of carcinoma in situ of the bladder after standard intravesical therapy has failed. J Urol. 2009;181: 1040-1045.10.1016/j.juro.2008.11.019Search in Google Scholar

15. Morales A. Evolution of intravesical immunotherapy for bladder cancer: mycobacterial cell wall preparation as a promising agent. Expert Opin Investig Drugs. 2008;17: 1067-1073.10.1517/13543784.17.7.1067Search in Google Scholar

16. Morales A, Chin JL, Ramsey EW. Mycobacterial cell wall extract for treatment of carcinoma in situ of the bladder. J Urol. 2001;166: 1633-1637; discussion 1637-1638.10.1016/S0022-5347(05)65642-XSearch in Google Scholar

17. Chin JL, Kadhim SA, Batislam E, Karlik SJ, Garcia BM, Nickel JC, Morales A. Mycobacterium cell wall: an alternative to intravesical bacillus Calmette Guerin (BCG) therapy in orthotopic murine bladder cancer. J Urol. 1996;156: 1189-1193.10.1016/S0022-5347(01)65748-3Search in Google Scholar

18. Alkemade. SJ, Buckley TC, McRae. G. Immunostimulatory bacterial cell wall fraction. In: USPTO, editor. Unated States of America: Vetrepharm, Inc, 1998.Search in Google Scholar

19. Filion MC, Phillips NC. Therapeutic potential of mycobacterial cell wall-DNA complexes. Expert Opin Investig Drugs. 2001;10: 2157-2165.10.1517/13543784.10.12.2157Search in Google Scholar

20. Rodrigues L, Masic A. Mycobacterium Cell Wall Fraction (Immunocidin®) for Canine Transitional Cell Carcinoma Treatment. Veterinary Cancer Society Conference 2015. Tysons, VA, 2015:29.Search in Google Scholar

21. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65: 55-63.10.1016/0022-1759(83)90303-4Search in Google Scholar

22. Veterinary cooperative oncology group - common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.1. Vet Comp Oncol. 2011.Search in Google Scholar

23. McMillan SK, Boria P, Moore GE, Widmer WR, Bonney PL, Knapp DW. Antitumor effects of deracoxib treatment in 26 dogs with transitional cell carcinoma of the urinary bladder. J Am Vet Med Assoc. 2011;239: 1084-1089.10.2460/javma.239.8.108421985349Search in Google Scholar

24. Lynch S, Savary-Bataille K, Leeuw B, Argyle DJ. Development of a questionnaire assessing health-related quality-of-life in dogs and cats with cancer. Vet Comp Oncol. 2011;9: 172-182.10.1111/j.1476-5829.2010.00244.x21848620Search in Google Scholar

25. Naughton JF, Widmer WR, Constable PD, Knapp DW. Accuracy of three-dimensional and two-dimensional ultrasonography for measurement of tumor volume in dogs with transitional cell carcinoma of the urinary bladder. Am J Vet Res. 2012;73: 1919-1924.10.2460/ajvr.73.12.191923176418Search in Google Scholar

26. Nguyen SM, Thamm DH, Vail DM, London CA. Response evaluation criteria for solid tumours in dogs (v1.0): a Veterinary Cooperative Oncology Group (VCOG) consensus document. Vet Comp Oncol. 2013.10.1111/vco.1203223534501Search in Google Scholar

27. D. W. Knapp BF, M. C. Filion and N. C. Phillips. Antitumor activity of mycobacterial cell wall-DNA complex (MCC) against canine urinary bladder transitional cell carcinoma cells. Veterinary Cancer Society Annual Conference Kansas City. Kansas City Missouri, , : Blackwell Publishing Ltd, 2004:46-47.10.1111/j.1476-5810.2005.0064w.xSearch in Google Scholar

28. Azuma I, Taniyama T, Hirao F, Yamamura Y. Antitumor activity of cell-wall skeletons and peptidoglycolipids of mycobacteria and related microorganisms in mice and rabbits. Gan. 1974;65: 493-505.Search in Google Scholar

29. Filion MC, Lepicier P, Morales A, Phillips NC. Mycobacterium phlei cell wall complex directly induces apoptosis in human bladder cancer cells. Br J Cancer. 1999;79: 229-235.10.1038/sj.bjc.669003823621919888462Search in Google Scholar

30. Fumuso EA, Aguilar J, Giguere S, Rivulgo M, Wade J, Rogan D. Immune parameters in mares resistant and susceptible to persistent post-breeding endometritis: effects of immunomodulation. Vet Immunol Immunopathol. 2007;118: 30-39.10.1016/j.vetimm.2007.04.00917559943Search in Google Scholar

31. Reader S, Menard S, Filion B, Filion MC, Phillips NC. Pro-apoptotic and immunomodulatory activity of a mycobacterial cell wall-DNA complex towards LNCaP prostate cancer cells. Prostate. 2001;49: 155-165.10.1002/pros.113011746260Search in Google Scholar

32. Yamanaka K, Hara I, Nagai H, Miyake H, Gohji K, Micallef MJ, Kurimoto M, Arakawa S, Kamidono S. Synergistic antitumor effects of interleukin-12 gene transfer and systemic administration of interleukin-18 in a mouse bladder cancer model. Cancer Immunol Immunother. 1999;48: 297-302.10.1007/s00262005057810473804Search in Google Scholar

33. Filion MC, Filion B, Reader S, Menard S, Phillips NC. Modulation of interleukin-12 synthesis by DNA lacking the CpG motif and present in a mycobacterial cell wall complex. Cancer Immunol Immunother. 2000;49: 325-334.10.1007/s00262000012110946815Search in Google Scholar

34. Knapp DW, Richardson RC, Chan TC, Bottoms GD, Widmer WR, DeNicola DB, Teclaw R, Bonney PL, Kuczek T. Piroxicam therapy in 34 dogs with transitional cell carcinoma of the urinary bladder. J Vet Intern Med. 1994;8: 273-278.10.1111/j.1939-1676.1994.tb03232.x7983623Search in Google Scholar

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