Comparative Response of SC CAKI-1 Renal Tumor to Treatment with Doxorubicin HCl and Doxorubicin Orotate

Rashida A. Karmali, Yulia Maxuitenko, Greg Gorman

Pharmaceutical Sciences Research Institute, Samford University, Birmingham, USA.
SavviPharm Inc. and Tactical Therapeutics Inc., New York, USA.

DOI: 10.4236/jct.2014.55049                

Abstract

Background: Doxorubicin (DOX) is an effective treatment for many cancers across the age spectrum, but its therapeutic potential is limited because of dose-dependent relation to both progressive and irreversible cardiomyopathy leading to congestive heart failure. While decreases in cardiotoxicity have been reported with liposomal doxorubicin, the long-term cardiac effects are not known. Orotate salts of cytotoxic drugs have been shown to confer antitumor effects with a better safety profile than unconverted drug, and therefore may offer an improved approach to cancer treatment. Materials and Methods: Male, athymic NCr-nu/nu mice with subcutaneously implanted CAKI-1 human renal tumor xenografts were treated with DOX and its orotate salt (DOX-O) to evaluate antitumor activity, measured by median tumor mass doubling time and tumor weight. Nontumored male, athymic NCr-nu/nu mice were treated with DOX, DOX-O and liposomal doxorubicin formulations to determine DOX concentration in liver and heart; and to evaluate their effect on body weight. Non-tumored female, athymic NCr-nu/nu mice were treated with daunorubicin and daunorubicin orotate to evaluate tolerance. Results: DOX and DOX-O exhibited significant, similar levels of antitumor activity. Mice treated with DOX-O had a lower percentage body weight loss. In the animals treated with DOX, DOX-O, or liposomal doxorubicin, liposomal doxorubicin was associated with the lowest percentage of body weight loss, but the highest concentration of DOX in heart. In daunorubicin tolerance experiments, animals showed a better tolerance for daunorubicin orotate as measured by a smaller percentage change in body weight. Conclusions: DOX-O is effective as an antitumor therapy and may offer a less toxic alternative to DOX for maintaining therapy. The lower percentage of body weight loss in animals treated with DOX-O and daunorubicin orotate is a measure of improved tolerance and may translate into better patient outcomes.

Keywords

Safer Toxicity Profile, Doxorubicin Orotate

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Ali, M., Kamjoo, M., Thomas, H.D., Kyle, S., Pavlovska, I., Babur, M., Telfer, B.A., et al. (2011) The Clinically Active PARP Inhibitor AG014699 Ameliorates Cardiotoxicity but Does Not Enhance the Efficacy of Doxorubicin, Despite Improving Tumor Perfusion and Radiation Response in Mice. Molecular Cancer Therapeutics, 10, 2320-2329. http://dx.doi.org/10.1158/1535-7163.MCT-11-0356
[2]	Burstein, H.J., Piccart-Gebhart, M.J., Perez, E.A., Hortobagyi, G.N., Wolmark, N., Albain, K.S., et al. (2012) Choosing the Best Trastuzumab-Based Adjuvant Chemotherapy Regimen: Should We Abandon Anthracyclines? Journal of Clinical Oncology, 30, 2179-2182. http://dx.doi.org/10.1200/JCO.2012.42.0695
[3]	Healy-Bird, B.R. and Swain, S.M. (2008) Cardiac Toxicity in Breast Cancer Survivors: Review of Potential Cardiac Problems. Clinical Cancer Research, 14, 14-24. http://dx.doi.org/10.1158/1078-0432.CCR-07-1033
[4]	Zoeller, L.S. (2012) Cardiotoxicity in Cancer Patients: Often More Malignant than Cancer. Interview. Oncology Statistics, 24.
[5]	Lebrecht, D., Setzer, B., Ketelsen, U.P., Haberstroh, J. and Walker, U.A. (2003) Time-Dependent and Tissue-Specific Accumulation of mtDNA and Respiratory Chain Defects in Chronic Doxorubicin Cardiomyopathy. Circulation, 108, 2423-2429. http://dx.doi.org/10.1161/01.CIR.0000093196.59829. DF
[6]	Volkova, M. and Russell, R. (2011) Anthracycline Cardiotoxicity: Prevalence, Pathogenesis and Treatment. Current Cardiology Reviews, 7, 214-2120. http://dx.doi.org/10.2174/1573403117999 60645
[7]	Lenihan, D.J. and Cardinale, D.M. (2012) Late Cardiac Effects of Cancer Treatment. Journal of Clinical Oncology. 30(30), 3657-3664. Epub 2012 Sep 24. http://dx.doi.org/10.1200/JCO.2012.45.2938
[8]	Cardinale, D., Sandri, M.T., Martinoni, A., Borghini, E., Civelli, M., Lamantia, G., et al. (2002) Myocardial Injury Revealed by Plasma Troponin I in Breast Cancer Treated with High-Dose Chemotherapy. Annals of Oncology, 13, 710-715. http://dx.doi.org/10.1093/annonc/mdf170
[9]	Giordano, S.H., Lin, Y.L., Kuo, Y.F., Hortobagyi, G.N. and Goodwin, J.S. (2012) Decline in the Use of Anthracyclines for Breast Cancer. Journal of Clinical Oncology, 30, 2232-2239. http://dx.doi.org/10.1200/JCO.2011.40.1273
[10]	Wang, X., Liu, W., Sun, C.L., Armenian, S.H., Hakonarson, H., Hageman, L., et al. (2014) Hyaluronan Synthase 3 Variant and Anthracycline-Related Cardiomyopathy: A Report from the Children’s Oncology Group. Journal of Clinical Oncology, 32, 647-653. http://dx.doi.org/10.1200/JCO.2013. 50.3557
[11]	Cardinale, D., Colombo, A., Torrisi, R., Sandri, M.T., Civelli, M., Salvatici, M., et al. (2010) Trastuzumab-Induced Cardiotoxicity: Clinical and Prognostic Implications of Troponin I Evaluation. Journal of Clinical Oncology, 28, 3910-3916. http://dx.doi.org/10.1200/JCO.2009.27.3615
[12]	El-Sayyad, H.I., Ismail, M.F., Shalaby, F.M., Abou-El-Magd, R.F., Gaur, R.L., Fernando, A., et al. (2009) Histopathological Effects of Cisplatin, Doxorubicin and 5-Flurouracil (5-FU) on the Liver of Male Albino Rats. International Journal of Biological Sciences, 5, 466-473. http://dx.doi.org/10.7150/ijbs.5.466
[13]	Childs, A.C., Phaneuf, S.L., Dirks, A.J., Phillips, T. and Leeuwenburgh, C. (2002) Doxorubicin Treatment in Vivo Causes Cytochrome C Release and Cardiomyocyte Apoptosis, as Well as Increased Mitochondrial Efficiency, Superoxide Dismutase Activity, and Bcl-2:Bax Ratio. Cancer Research, 62, 4592-4598.
[14]	Safra, T. (2003) Cardiac Safety of Liposomal Anthracyclines. Oncologist, 8, 17-24. http://dx.doi.org/10.1634/theoncologist.8-suppl_2-17
[15]	Kohn, E.C., Reed, E., Sarosy, G.A., Minasian, L., Bauer, K.S., Bostick-Bruton, F., et al. (2001) A Phase I Trial of Carboxyamido-Triazole and Paclitaxel for Relapsed Solid Tumors: Potential Efficacy of the Combination and Demonstration of Pharmacokinetic Interaction. Clinical Cancer Research, 7, 1600-1609.
[16]	Oliver, V.K., Patton, A.M., Desai, S., Lorang, D., Libutti, S.K. and Kohn, E.C. (2003) Regulation of the Pro-angiogenic Microenvironment by Carboxyamido-Triazole. Journal of Cellular Physiology, 197, 139-148. http://dx.doi.org/10.1002/jcp.10350
[17]	Grover, G.J., Kelly, J., Moore, G., Jacoby, H., Karmali, R.A. and Gorman, G.S. (2007) Comparative Pharmacokinetic Profile of Carboxyamidotriazole and Carboxyamidotriazole-Orotate. Cancer Therapy, 5, 437-442.
[18]	Corrado, C., Flugy, A.M., Taverna, S., Raimondo, S., Guggino, G., Karmali, R.A., et al. (2012) Carboxyamidotriazoleorotate Inhibits the Growth of Imatinib-Resistant Chronic Myeloid Leukaemia Cells and Modulates Exosomes-Stimulated Angiogenesis. PLoS One, 7, e42310. http://dx.doi.org/10.1371/journal.pone.0042310
[19]	Karmali, R.A., Maxuitenko, Y. and Gorman, G. (2013) Treatment with Paclitaxel Orotate and Carboxyamidotriazole Orotate in SC-Implanted OVCAR-5 Human Ovarian Tumor Xenografts. Journal of Cancer Therapy, 4, 857-871. http://dx.doi.org/10.4236/jct.2013.44098
[20]	Rosenfeldt, F.L. (1998) Metabolic Supplementation with Orotic Actic and Magnesium Orotate. Cardiovascular Drugs and Therapy, 12, 147-152.
[21]	Hess, L.M., Barakat, R., Tian, C., Ozols, R.F. and Alberts, D.S. (2007) Weight Change during Chemotherapy as a Potential Prognostic Factor for Stage III Epithelial Ovarian Carcinoma: A Gynecologic Oncology Group Study. Gynecologic Oncology, 107, 260-265.