JCT  Vol.5 No.5 , April 2014
Comparative Response of SC CAKI-1 Renal Tumor to Treatment with Doxorubicin HCl and Doxorubicin Orotate
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.
Cite this paper: Karmali, R. , Maxuitenko, Y. and Gorman, G. (2014) Comparative Response of SC CAKI-1 Renal Tumor to Treatment with Doxorubicin HCl and Doxorubicin Orotate. Journal of Cancer Therapy, 5, 427-441. doi: 10.4236/jct.2014.55049.

[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.

[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.

[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.

[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. DF

[6]   Volkova, M. and Russell, R. (2011) Anthracycline Cardiotoxicity: Prevalence, Pathogenesis and Treatment. Current Cardiology Reviews, 7, 214-2120. 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.

[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.

[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.

[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. 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.

[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.

[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.

[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.

[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.

[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.

[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.