Treatment with Paclitaxel Orotate and Carboxyamidotriazole Orotate in SC-Implanted OVCAR-5 Human Ovarian Tumor Xenografts

Rashida A. Karmali, Yulia Maxuitenko, Greg Gorman

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

DOI: 10.4236/jct.2013.44098                

Abstract

Background: Paclitaxel (PTX) is approved for the treatment of refractory ovarian cancer and breast cancer, but is problematic due to severe, dose-dependent, potentially irreversible neurotoxicity. Alternative formulations using nanoparticles and liposomes have been developed to avoid solvent-related toxicity. These formulations allow improved delivery; however, toxicity, compensatory signaling, and drug resistance still pose challenges. Conversion of cytotoxic agents to their orotate compounds offers a potentially improved approach by increasing bioavailability and reducing toxicity. Orotate salts are neutral and acquire lipophilic properties, easing diffusion through lipid membranes. The orotate salt of PTX (PTXO) may yield an improved safety profile. Combination therapy with cytotoxic drugs, antiangiogenics and/or signal transduction pathway inhibitors has shown better efficacy than cytotoxic monotherapy. The combination of carboxyamidotriazole orotate (CTO, a calcium signal transduction pathway inhibitor) and PTX may be more effective than PTX alone at non-toxic doses. Materials and Methods: PTXO alone, and combinations of CTO with PTX and PTXO were first tested in female athymic NCr-nu/nu mice to evaluate tolerance of the combinations. The tolerated combinations, PTX monotherapy, and PTXO monotherapy were then tested to evaluate their antitumor activity in female athymic NCr-nu/nu mice with subcutaneously implanted OVCAR-5 human ovarian tumor. Antitumor activity was measured by median time to doubling, median tumor growth delay, and mean percent body weight loss. Results: CTO, PTX, and PTXO showed significant inhibition of growth of the human OVCAR-5 ovarian tumor xenografts. The combination of low PTX and CTO, or high PTXO monotherapy, had significant efficacy and it was less toxic than high PTX as measured by body weight loss. Conclusions: Low-dose CTO is effective and has low toxicity, suggesting the potential for maintenance therapy for ovarian cancer. PTXO offers efficacy and a strategy for minimizing body weight loss, and may improve outcomes for patients who demonstrate toxicity to PTX.

Keywords

Paclitaxel Orotate; Paclitaxel; Carboxyamidotriazole Orotate; Ovarian Cancer

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	C. Santiskulvong, G. E. Konecny, M. Fekete, K. Y. Chen, A. Karam, et al., “Dual Targeting of Phosphoinositide 3-Kinase and Mammalian Target of Rapamycin Using NVP-BEZ235 as a Novel Therapeutic Approach in Human Ovarian Carcinoma,” Clinical Cancer Research, Vol. 15, No. 17, 2011, pp. 2373-2384. doi:10.1158/1078-0432.CCR-10-2289
[2]	R. Wu, T. C. Hu, A. Rehemtulla, E. R. Fearon and K. R. Cho, “Preclinical Testing of PI3K/AKT/mTOR Signaling Inhibitors in a Mouse Model of Ovarian Endometrioid Adenocarcinoma,” Clinical Cancer Research, Vol. 12, No. 23, 2011, pp. 7359-7372. doi:10.1158/1078-0432.CCR-11-1388.
[3]	E. Chu and V. T. DeVita, “Chemotherapeutic and Biologic Drugs,” In: E. Chu and V. T. DeVita, Eds., Physicians’ Cancer Chemotherapy Drug Manual 2010, Jones and Bartlett Publishers, Massachusetts, 2010, pp. 297-301.
[4]	W. J. Gradishar, S. Tjulandin, N. Davidson, H. Shaw, N. Desai, et al., “Phase III Trial of Nanoparticle AlbuminBound Paclitaxel Compared with Polyethylated Castor Iil-Based Paclitaxel in Women with Breast Cancer,” Journal of Clinical Oncology, Vol. 23, No. 31, 2005, pp. 7794-7803. doi:10.1200/JCO.2005.04.937
[5]	B. P. Schneider, F. Zhao, M. Wang, V. Stearns, S. Martino, et al., “Neuropathy Is Not Associated with Clinical Outcomes in Patients Receiving Adjuvant Taxane-Containing Therapy for Operable Breast Cancer,” Journal of Clinical Oncology, Vol. 30, No. 25, 2012, pp. 3051-3057. doi:10.1200/JCO.2011.39.8446
[6]	M. Stenger, “Abraxane (Nanoparticle Albumin-Bound Paclitaxel) in Metastatic Breast Cancer,” Community Oncology, 2005, p. 214.
[7]	V. Roy, B. R. LaPlant, G. G. Gross, C. L. Bane, F. M. Palmieri and North Central Cancer Treatment Group, “Phase II Trial of Weekly nab (Nanoparticle Albuminbound)-paclitaxel(nab-paclitaxel) (Abraxane) in Combination with Gemcitabine in Patients with Metastatic Breast Cancer (N0531),” Annals of Oncology, Vol. 20, No. 3, 2009, pp. 449-453. doi:10.1093/annonc/mdn661
[8]	P. Vishnu and V. Roy, “Safety and Efficacy of Nab-Paclitaxel in the Treatment of Patients with Breast Cancer,” Breast Cancer (Auckl), Vol. 5, 2011, pp. 53-65. doi:10.4137/BCBCR.S5857
[9]	J. L. Blum, “Clinical Implications of Using Nab Paclitaxel in Metastatic Breast Cancer,” Community Oncology, 2005, pp. 21-216.
[10]	H. Rugo, W. T. Barry, A. Mareno-Aspitia, et al., “CALGB 40502/NCCTG N063H: Randomized Phase III Trial of Weekly Paclitaxel compared to Weekly Nanoparticle Albumin Bound Nab-Paclitaxel or Ixabepilone with or without Bevacizumab as First-Line Therapy for Locally Recurrent or Metastatic Breast Cancer,” 2012 ASCO Annual Meeting, Chicago, 1-5 June 2012, Abstract CRA1002.
[11]	R. Kunstfeld, G. Wickenhauser, U. Michaelis, M. Teifel, W. Umek, et al., “Paclitaxel Encapsulated in Cationic Liposomes Diminishes Tumor Angiogenesis and Melanoma Growth in a ‘Humanized’ SCID Mouse Model,” Journal of Investigative Dermatology, Vol. 120, No. 3, 2003, pp. 476-482. doi:10.1046/j.1523-1747.2003.12057.x
[12]	R. A. Karmali, Y. Y. Maxuitenko, G. S. Gorman and J. G. Page, “Carboxyamidotriazole Orotate and Cytotoxic Chemotherapy Have a Synergistic Effect on Tumor Inhibition in Glioblastoma and Colon Xenograft Mouse Models,” Cancer Therapy, Vol. 8, 2011, pp. 71-80.
[13]	R. A. Karmali, Y. Y. Maxuitenko, G S. Gorman and Z. Qu, “Combinatorial Treatment with Carboxyamidotriazoleorotate and Temozolomide in SC-Implanted Human LOX IMVI Melanoma Xenografts,” Journal of Solid Tumors, Vol. 2, No. 5, 2012, pp. 1-16. doi:10.5430/jst.v2n5p13
[14]	E. C. Kohn, E. Reed, G. A. Sarosy, L. Minasian, K. S. Bauer, et al., “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, Vol. 7, No. 6, 2001, pp. 1600-1609.
[15]	V. K. Oliver, A. M. Patton, S. Desai, D. Lorang, S. K. Libutti and E. C. Kohn, “Regulation of the Pro-Angiogenic Microenvironment by Carboxyamido-Triazole,” Journal of Cellular Physiology, Vol. 197, No. 1, 2003, pp. 139-148. doi:10.1002/jcp.10350
[16]	G. J. Grover, J. Kelly, G. Moore, H. Jacoby, R. A. Karmali and G. S. Gorman, “Comparative Pharmacokinetic Profile of Carboxyamidotriazole and Carboxyamidotriazole-Orotate,” Cancer Therapy, Vol. 5, No. 2, 2007, pp. 437-442.
[17]	C. Corrado, A. M. Flugy, S. Taverna, S. Raimondo, G. Guggino, et al., “Carboxyamidotriazole-Orotate Inhibits the Growth of Imatinib-Resistant Chronic Myeloid Leukaemia Cells and Modulates Exosomes-Stimulated Angiogenesis,” PLoS One, Vol. 7, No. 8, 2012, Article ID: e42310. doi:10.1371/journal.pone.0042310
[18]	M. M. Hussain, H. Kotz, L. Minasian, A. Premkumar, G. Sarosy, et al., “Phase II Trial of Carboxyamidotriazole in Patients with Relapsed Epithelial Ovarian Cancer,” Journal of Clinical Oncology, Vol. 21, No. 23, 2003, pp. 4356-4363. doi:10.1200/JCO.2003.04.136
[19]	L. M. Hess, R. Barakat, C. Tian, R. F. Ozols and D. S. Alberts, “Weight Change during Chemotherapy as a Potential Prognostic Factor for Stage III Epithelial Ovarian Carcinoma: A Gynecologic Oncology Group Study,” Gynecologic Oncology, Vol. 107, No. 2, 2007, pp. 260-265. doi:10.1016/j.ygyno.2007.06.010
[20]	C. M. Prado, V. E. Baracos, L. J. McCargar, M. Mourtzakis, K. E. Mulder, et al., “Body Composition as an Independent Determinant of 5-Fluorouracil-Based Chemotherapy Toxicity,” Clinical Cancer Research, Vol. 12, No. 11, 2007, pp. 3264-3268. doi:10.1158/1078-0432.CCR-06-3067
[21]	M. Gusella, S. Toso, E. Ferrazzi, M. Ferrari and R. Padrini, “Relationships between Body Composition Parameters and Fluorouracil Pharmacokinetics,” British Journal of Clinical Pharmacology, Vol. 54, No. 2, 2002, pp. 131-139. doi:10.1046/j.1365-2125.2002.01598.x
[22]	M. E. Rothenberg and S. P. Hogan, “The Eosinophil,” Annual Review of Immunology, Vol. 24, 2006, pp. 147-174. doi:10.1146/annurev.immunol.24.021605.090720
[23]	S. H. Giordano, D. J. Booser, J. L. Murray, N. K. Ibrahim, Z. U. Rahman, et al., “A Detailed Evaluation of Cardiac Toxicity: A Phase II Study of Doxorubicin and Oneor Three-Hour Infusion Paclitaxel in Patients with Metastatic Breast Cancer,” Clinical Cancer Research, Vol. 8, 2002, pp. 3360-3368.
[24]	F. L. Rosenfeldt, “Metabolic Supplementation with Orotic Actic and Magnesium Orotate,” Cardiovascular Drugs and Therapy, Vol. 12, No. 2, 1998, pp. 147-152. doi:10.1023/A:1007732131887