Comparison of the cytotoxic effects of single and divided treatment of 4-hydroxycyclophosphamide at the same total dosage amount in canine lymphoma cell lines

https://doi.org/10.17221/86/2019-VETMEDCitation:Liao A., Chen Y., Wang S. (2020): Comparison of the cytotoxic effects of single and divided treatment of 4-hydroxycyclophosphamide at the same total dosage amount in canine lymphoma cell lines. Veterinarni Medicina, 65: 56-61.
download PDF

Cyclophosphamide is widely used in combination chemotherapy to treat dogs with lymphoma. The metabolite of cyclophosphamide, acrolein, can irritate the urinary bladder and cause sterile haemorrhagic cystitis. The divided administration of cyclophosphamide across multiple days may reduce the occurrence of the cystitis. However, the therapeutic effect of this modification has not been evaluated and compared to the traditional single maximum-tolerated dose. It is difficult to evaluate the cytotoxic effect by the single chemotherapeutic drug in dogs. In order to verify the effect of the single and divided treatment of cyclophosphamide in canine lymphoma, we used two canine lymphoma cell lines (CLBL-1, B-cell lymphoma and UL-1, T-cell lymphoma) to imitate the clinical conditions. The cell viability in the CLBL-1 and UL-1 cells treated by a single dosage of 4-hydroxycyclophosphamide after 48 h were 70.4% and 61.5%, respectively. The cell viability in the CLBL-1 and UL-1 cells treated by the divided dosage of 4-hydroxycyclophosphamide after 48 h were 109.4% and 50.8%. There were no significant differences between the two administration methods in the T-cell lymphoma cell line (P = 0.215). The single full dosage of 4-hydroxycyclophosphamide exhibited a significant cytotoxic effect rather than the divided dosage in B-cell lymphoma cell line (P = 0.007) did. The maximum-tolerated dose of cyclophosphamide is still recommended to be used in dogs with B-cell lymphoma.

References:
Bennett AH. Cyclophosphamide and hemorrhagic cystitis. J Urol. 1974 May;111(5):603-6. https://doi.org/10.1016/S0022-5347(17)60025-9
 
Best MP, Fry DR. Incidence of sterile hemorrhagic cystitis in dogs receiving cyclophosphamide orally for three days without concurrent furosemide as part of a chemotherapeutic treatment for lymphoma: 57 cases (2007–2012). J Am Vet Med Assoc. 2013 Oct;243(7):1025-9. https://doi.org/10.2460/javma.243.7.1025
 
Crow S, Theilen G, Madewell B, Weller R, Henness A. Cyclophosphamide-induced cystitis in the dog and cat. J Am Vet Med Assoc. 1977 Aug;171(3):259-62.
 
Dobson J. Reducing the side effects of cyclophosphamide chemotherapy in dogs. Vet Rec. 2014 Mar;174(10):248-9. https://doi.org/10.1136/vr.g1887
 
Flory AB, Rassnick KM, Al-Sarraf R, Bailey DB, Balkman CE, Kiselow MA, Autio K. Combination of CCNU and DTIC chemotherapy for treatment of resistant lymphoma in dogs. J Vet Intern Med. 2008 Jan-Feb;22(1):164-71. https://doi.org/10.1111/j.1939-1676.2007.0005.x
 
Gaeta R, Brown D, Cohen R, Sorenmo K. Risk factors for development of sterile haemorrhagic cystitis in canine lymphoma patients receiving oral cyclophosphamide: A case-control study. Vet Comp Oncol. 2014 Dec;12(4):277-86. https://doi.org/10.1111/vco.12009
 
Hanasono G, Fischer L. Plasma levels and urinary excretion of [14C]eyclophosphanude and its radioactive metabolites in rats pretreated with prednisolone. Biochem Pharmacol. 1972 Jan;21(2):272-6. https://doi.org/10.1016/0006-2952(72)90280-8
 
Huitema A, Tibben M, Kerbusch T, Kettenes-Van Den Bosch J, Rodenhuis S, Beijnen J. High performance liquid chromatographic determination of the stabilized cyclophosphamide metabolite 4-hydroxycyclophosphamide in plasma and red blood cells. J Liq Chromatogr Relat Technol. 2000 Jan;23(11):1725-44. https://doi.org/10.1081/JLC-100100448
 
Laberke S, Zenker I, Hirschberger J. Mesna and furosemide for prevention of cyclophosphamide-induced sterile haemorrhagic cystitis in dogs – A retrospective study. Vet Rec. 2014 Mar;174(10):250. https://doi.org/10.1136/vr.101574
 
Lieberman HR. Estimating LD50 using the probit technique: A basic computer program. Drug Chem Toxicol. 1983 Feb;6(1):111-6. https://doi.org/10.3109/01480548309072465
 
Morrison-Collister K, Rassnick K, Northrup N, Kristal O, Chretin J, Williams L, Cotter S, Moore A. A combination chemotherapy protocol with MOPP and CCNU consolidation (Tufts VELCAP-SC) for the treatment of canine lymphoma. Vet Comp Oncol. 2003 Dec;1(4):180-90. https://doi.org/10.1111/j.1476-5810.2003.00027.x
 
Ren S, Kalhorn TF, McDonald GB, Anasetti C, Appelbaum FR, Slattery JT. Pharmacokinetics of cyclophosphamide and its metabolites in bone marrow transplantation patients. Clin Pharmacol Ther. 1998 Sep;64(3):289-301. https://doi.org/10.1016/S0009-9236(98)90178-3
 
Rutgen BC, Hammer SE, Gerner W, Christian M, de Arespacochaga AG, Willmann M, Kleiter M, Schwendenwein I, Saalmuller A. Establishment and characterization of a novel canine B-cell line derived from a spontaneously occurring diffuse large cell lymphoma. Leuk Res. 2010 Jul;34(7):932-8. https://doi.org/10.1016/j.leukres.2010.01.021
 
Saba C, Hafeman S, Vail D, Thamm D. Combination chemotherapy with continuous l-asparaginase, lomustine, and prednisone for relapsed canine lymphoma. J Vet Intern Med. 2009 Sep-Oct;23(5):1058-63. https://doi.org/10.1111/j.1939-1676.2009.0357.x
 
Stanton M, Legendre A. Effects of cyclophosphamide in dogs and cats. J Am Vet Med Assoc. 1986 Jun;188(11):1319-22.
 
Stone M, Goldstein M, Cotter S. Comparison of two protocols for induction of remission in dogs with lymphoma. J Am Anim Hosp Assoc. 1991;27(3):315-21.
 
Toru H, Nobuhiro K, Ryohei Y, Ryotaro K, Hiromu H, Heitaro M, Dennosuke J. Effect of steroid hormone on activation of endoxan (cyclophosphamide). Biochem Pharmacol. 1969 Jan;18(1):129-35. https://doi.org/10.1016/0006-2952(69)90017-3
 
Umeki S, Ema Y, Suzuki R, Kubo M, Hayashi T, Okamura Y, Yamazaki J, Tsujimoto H, Tani K, Hiraoka H. Establishment of five canine lymphoma cell lines and tumor formation in a xenotransplantation model. J Vet Med Sci. 2012 Nov;75(4):467-74. https://doi.org/10.1292/jvms.12-0448
 
Wang SL, Lee JJ, Liao AT. Assessment of temporal association of relapse of canine multicentric lymphoma with components of the CHOP protocol: Is cyclophosphamide the weakest link? Vet J. 2016 Jul;213:87-9. https://doi.org/10.1016/j.tvjl.2016.04.013
 
Wang SL, Lee JJ, Liao AT. Chemotherapy-induced neutropenia is associated with prolonged remission duration and survival time in canine lymphoma. Vet J. 2015 Jul;205(1):69-73. https://doi.org/10.1016/j.tvjl.2015.04.032
 
Warry E, Hansen RJ, Gustafson DL, Lana SE. Pharmacokinetics of cyclophosphamide after oral and intravenous administration to dogs with lymphoma. J Vet Intern Med. 2011 Jul-Aug;25(4):903-8. https://doi.org/10.1111/j.1939-1676.2011.0730.x
 
download PDF

© 2020 Czech Academy of Agricultural Sciences