Novel Approach to Chemotherapy and Administration Selection with Metronomic/Fractionated Dosing
Aaron J. Smith*, John Oertle, Dino Prato
Envita, Scottsdale, AZ, USA.
DOI: 10.4236/jct.2015.65049   PDF    HTML   XML   3,188 Downloads   5,054 Views   Citations

Abstract

Metronomic dosing of chemotherapy was introduced in the early 2000s and has since gained recognition as a potential game changer in the manner of which chemotherapy can be administered. There are several known candidates for metronomic dosing of chemotherapy with the potential for many more to be elucidated in the future. Minimized overall side effects, longer durations of treatment, potential minimization of multidrug resistance (MDR) mutations, potential less refractory responses, and the potential to safely use more than one chemotherapy treatments also make metronomic dosing of chemotherapy attractive. Metronomic dosing reduces common side effects and has the potential to reduce neutropenia, lymphocytopenia, and cognitive changes associated with maximum tolerated dosages (MTD). Methods of enhancing chemotherapy including fasting and administration of insulin are also discussed. Metronomic dosing combined with a patient’s molecular profile derived from biomarkers is particularly exciting. It holds significant potential with regard to administrating the most relevant chemotherapies and offers maximal beneficial results.

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Smith, A. , Oertle, J. and Prato, D. (2015) Novel Approach to Chemotherapy and Administration Selection with Metronomic/Fractionated Dosing. Journal of Cancer Therapy, 6, 455-465. doi: 10.4236/jct.2015.65049.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Fidler, I.J. and Ellis, L.M. (2000) Chemotherapeutic Drugs—More Really Is Not Better. Nature Medicine, 6, 500-502.
http://dx.doi.org/10.1038/74969
[2] Hanahan, D., Bergers, G. and Bergsland, E. (2000) Less Is More, Regularly: Metronomic Dosing of Cytotoxic Drugs Can Target Tumor Angiogenesis in Mice. Journal of Clinical Investigation, 105, 1045-1047.
http://dx.doi.org/10.1172/JCI9872
[3] Browder, T., Butterfield, C.E., Kraling, B.M., et al. (2000) Antiangiogenic Scheduling of Chemotherapy Improves Efficacy against Experimental Drug-Resistant Cancer. Cancer Research, 60, 1878-1886.
[4] Klement, G., Baruchel, S., Rak, J., et al. (2000) Continuous Low-Dose Therapy with Vinblastine and VEGF Receptor-2 Antibody Induces Sustained Tumor Regression without Overt Toxicity. Journal of Clinical Investigation, 105, R15-R24.
http://dx.doi.org/10.1172/JCI8829
[5] Huang, P., Chubb, S., Hertel, L.W., Grindey, G.B. and Plunkett, W. (1991) Action of 20,20-Difluorodeoxycytidine on DNA Synthesis. Cancer Research, 51, 6110-6117.
[6] Heinemann, V., Xu, Y.-Z., Chubb, S., Sen, A., Hertel, L.W., Grindey, G.B., et al. (1992) Cellular Elimination of 20, 20-Difluorodeoxycytidine 50-Triphosphate: A Mechanism of Self-Potentiation. Cancer Research, 52, 533-539.
[7] Heinemann, V., Xu, Y.-Z., Chubb, S., Sen, A., Hertel, L., G.B.G., et al. (1990) Inhibition of Ribonucleotide Reduction in CCRF-CEM Cells by 20,20-Difluorodeoxycytidine. Molecular Pharmacology, 38, 567-572.
[8] Wang, J., Lohman, G.J.S. and Stubbe, J. (2007) Enhanced Subunit Interactions with Gemcitabine-50-Diphosphate Inhibit Ribonucleotide Reductases. Proceedings of the National Academy of Sciences of the United States of America, 104, 14324-14329.
http://dx.doi.org/10.1073/pnas.0706803104
[9] Pratt, S.E., Durland-Busbice, S., Shepard, R.L., Heinz-Taney, K. and Dantzig, A.H. (2013) Human Carboxylesterase 2 Hydrolyzes the Prodrug of Gemcitabine (LY2334737) and Confers Prodrug Sensitivity to Cancer Cells. Clinical Cancer Research, 19, 1159-1168.
http://dx.doi.org/10.1158/1078-0432.CCR-12-1184
[10] Sanghani, S., Sanghani, P., Schiel, M. and Bosron, W. (2009) Human Carboxylesterases: An Update on CES1, CES2 and CES3. Protein and Peptide Letters, 16, 1207-1214.
http://dx.doi.org/10.2174/092986609789071324
[11] Pratt, S.E., Durland-Busbice, S., Shepard, R.L., Donoho, G.P., Starling, J.J., Wickremsinhe, E.R., Perkins, E.J. and Dantzig, A.H. (2013) Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts. Molecular Cancer Therapeutics, 4, 481-490.
http://dx.doi.org/10.1158/1535-7163.MCT-12-0654
[12] Risau, W. (1997) Mechanisms of Angiogenesis. Nature, 386, 671-674.
http://dx.doi.org/10.1038/386671a0
[13] Hanahan, D. and Folkman, J. (1996) Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis. Cell, 86, 353-64.
http://dx.doi.org/10.1016/S0092-8674(00)80108-7
[14] Lawler, J. (2002) Thrombospondin-1 as an Endogenous Inhibitor of Angiogenesis and Tumor Growth. Journal of Cellular and Molecular Medicine, 6, 1-12.
http://dx.doi.org/10.1111/j.1582-4934.2002.tb00307.x
[15] Salven, P., Manpaa, H., Orpana, A., Alitalo, K. and Joensuu, H. (1997) Serum Vascular Endothelial Growth Factor Is often Elevated in Disseminated Cancer. Clinical Cancer Research, 3, 647-51.
[16] Mainetti, L.E., Rozados, V.R., Bonfil, R.D. and Scharovsky, O.G. (2005) Metronomic Therapy with Cyclophosphamide or Doxorubicin Inhibits Mouse Mammary Adenocarcinoma Growth and Metastasis Development. Proceedings of the American Association for Cancer Research, 46, 1337.
www.aacrmeetingabstracts.org/cgi/content/abstract/2005/1/1377-b
[17] Mainetti, L.E., Rozados, V.R., Bonfil, R.D. and Scharovsky, O.G. (2006) Sinergistic Inhibitory Effect of Metronomic Therapy with Oral Cyclophosphamide Combined with a Cox-2 Inhibitor in a Mouse Mammary Adenocarcinoma. Proceedings of the American Association for Cancer Research, 47, 503.
[18] Fersis, N., Smyczek-Gargya, B., Armeanu, S., et al. (2004) Changes in Vascular Endothelial Growth Factor (VEGF) after Chemoendocrine Therapy in Breast Cancer. European Journal of Gynaecological Oncology, 25, 45-50.
[19] Wu, Y.L., Fu, S.L., Zhang, Y.P., Qiao, M.M. and Chen, Y. (2005) Cyclooxygenase-2 Inhibitors Suppress Angiogenesis and Growth of Gastric Cancer Xenografts. Biomedicine & Pharmacotherapy, 59, S289-S292.
http://dx.doi.org/10.1016/S0753-3322(05)80048-4
[20] Colleoni, M., Orlando, L., Sanna, G., et al. (2006) Metronomic Low-Dose Oral Cyclophosphamide and Methotrexate Plus or Minus Thalidomide in Metastatic Breast Cancer: Antitumor Activity and Biological Effects. Annals of Oncology, 17, 232-238.
http://dx.doi.org/10.1093/annonc/mdj066
[21] Correale, P., Cerretani, D., Remondo, C., et al. (2006) A Novel Metronomic Chemotherapy Regimen of Weekly Platinum and Daily Oral Etoposide in High-Risk Non-Small Cell Lung Cancer Patients. Oncology Reports, 16, 133-140.
http://dx.doi.org/10.3892/or.16.1.133
[22] Rozados, V.R., Sanchez, A.M., Gervasoni, S.I., Berra, H.H., Matar, P. and Scharovsky, O.G. (2004) Metronomic Therapy with Cyclophosphamide Induces Rat Lymphoma and Sarcoma Regression, and Is Devoid of Toxicity. Annals of Oncology, 15, 1543-1550.
http://dx.doi.org/10.1093/annonc/mdh384
[23] Klement, G., Baruchel, S., Rak, J., et al. (2000) Continuous Low-Dose Therapy with Vinblastine and VEGF Receptor-2 Antibody Induces Sustained Tumor Regression without Overt Toxicity. The Journal of Clinical Investigation, 105, R15-R24.
http://dx.doi.org/10.1172/JCI8829
[24] Klement, G., Huang, P., Mayer, B., et al. (2002) Differences in Therapeutic Indexes of Combination Metronomic Chemotherapy and an Anti-VEGFR-2 Antibody in Multidrug-Resistant Human Breast Cancer Xenografts. Clinical Cancer Research, 8, 221-232.
[25] Pietras, K. and Hanahan, D. (2005) A Multitargeted, Metronomic, and Maximum-Tolerated Dose “Chemo-Switch” Regimen Is Antiangiogenic, Producing Objective Responses and Survival Benefit in a Mouse Model of Cancer. Journal of Clinical Oncology, 23, 939-952.
http://dx.doi.org/10.1200/JCO.2005.07.093
[26] Mancuso, P., Burlini, A., Pruneri, G., Goldhirsch, A., Martinelli, G. and Bertolini, F. (2001) Resting and Activated Endothelial Cells Are Increased in the Peripheral Blood of Cancer Patients. Blood, 97, 3658-3661.
http://dx.doi.org/10.1182/blood.V97.11.3658
[27] Rabascio, C., Muratori, E., Mancuso, P., et al. (2004) Assessing Tumor Angiogenesis: Increased Circulating Ve-Cadherin RNA in Patients with Cancer Indicates Viability of Circulating Endothelial Cells. Cancer Research, 64, 4373-4377.
http://dx.doi.org/10.1158/0008-5472.CAN-04-0265
[28] Dudek, A.Z. and Mahaseth, H. (2005) Circulating Angiogenic Cytokines in Patients with Advanced Non-Small Cell Lung Cancer: Correlation with Treatment Response and Survival. Cancer Investigation, 23, 193-200.
http://dx.doi.org/10.1081/CNV-200055949
[29] Stempak, D., Gammon, J., Halton, J., Moghrabi, A., Koren, G. and Baruchel, S. (2006) A Pilot Pharmacokinetic and Antiangiogenic Biomarker Study of Celecoxib and Low-Dose Metronomic Vinblastine or Cyclophosphamide in Pediatric Recurrent Solid Tumors. Journal of Pediatric Hematology/Oncology, 28, 720-728.
http://dx.doi.org/10.1097/01.mph.0000243657.64056.c3
[30] Monestiroli, S., Mancuso, P., Burlini, A., Pruneri, G., Dell’Agnola, C., Gobbi, A., Martinelli, G. and Bertonlini, F. (2001) Kinetics and Viability of Circulating Endothelial Cells as Surrogate Angiogenesis Marker in an Animal Model of Human Lymphoma. Cancer Research, 61, 4341-4344.
[31] Capillo, M., Mancuso, P., Gobbi, A., Monestiroli, S., Pruneri, G., Dell’Agnola, C., Martinelli, G., Shultz, L. and Bertolini, F. (2003) Continuous Infusion of Endostatin Inhibits Differentiation, Mobilization and Clonogenic Potential of Endothelial Cell Progenitors. Clinical Cancer Research, 9, 377-382.
[32] Kerbel, R.S. (1991) Inhibition of Tumor Angiogenesis as a Strategy to Circumvent Acquired Resistance to Anti-Cancer Therapeutic Agents. BioEssays, 13, 31-36.
http://dx.doi.org/10.1002/bies.950130106
[33] Klement, G., Huang, P., Mayer, B., Green, S.K., Man, S., Bohlen, P., Hicklin, D. and Kerbel, R.S. (2002) Differences in Therapeutic Indexes of Combination Metronomic Chemotherapy and an Anti-VEGFR-2 Antibody in Multidrug-Resistant Human Breast Cancer Xenografts. Clinical Cancer Research, 8, 221-232.
[34] Asahara, T., Takahashi, T., Masuda, H., Kalka, C., Chen, D., Iwaguro, H., Inai, Y., Silver, M. and Isner, J.M. (1999) VEGF Contributes to Postnatal Neovascularization by Mobilizing Bone Marrow-Derived Endothelial Progenitor Cells. The EMBO Journal, 18, 3964-3972.
http://dx.doi.org/10.1093/emboj/18.14.3964
[35] Twardowski, P.W., Smith-Powell, L., Carroll, M., VanBalgooy, J., Ruel, C., Frankel, P. and Synold, T.W. (2008) Biologic Markers of Angiogenesis: Circulating Endothelial Cells in Patients with Advanced Malignancies Treated on Phase I Protocol with Metronomic Chemotherapy and Celecoxib. Cancer Investigation, 26, 53-59.
http://dx.doi.org/10.1080/07357900701681541
[36] Bocci, G., Nicolaou, K.C. and Kerbel, R.S. (2002) Protracted Low-Dose Effects on Human Endothelial Cell Proliferation and Survival in Vitro Reveal a Selective Antiangiogenic Window for Various Chemotherapeutic Drugs. Cancer Research, 62, 6938-6943.
[37] Shaked, Y., Bertolini, F., Man, S., Rogers, M.S., Cervi, D., Foutz, T., Rawn, K., Voskas, D., Dumont, D.J., Ben-David, Y., Layler, J., Henkin, J., Huber, J., Hicklin, D.J., D’Amato, R.J. and Kerbel, R.S. (2005) Genetic Heterogeneity of the Vasculogenic Phenotype Parallels Angiogenesis; Implications for Cellular Surrogate Marker Analysis of Antiangiogenesis. Cancer Cell, 7, 101-111.
[38] Shaked, Y., Emmenegger, U., Man, S., Cervi, D., Bertolini, F., Ben-David, Y. and Kerbel, R.S. (2005) The Optimal Biological Dose of Metronomic Chemotherapy Regimens Is Associated with Maximum Antiangiogenic Activity. Blood, 106, 3058-3061.
http://dx.doi.org/10.1182/blood-2005-04-1422
[39] Jimenez, B., Volpert, O.V., Crawford, S.E., Febbraio, M., Silverstein, R.L. and Bouck, N. (2000) Signals Leading to Apoptosis-Dependent Inhibition of Neovascularization by Thrombospondin-1. Nature Medicine, 6, 41-48.
http://dx.doi.org/10.1038/71517
[40] Rozados, V.R., Mainetti, L.E., Rico, M.J., Zacarías Fluck, M.F., Matar, P. and Scharovsky, O.G. (2007) Antiangiogenic and Inmunomodulatory Effect of the Metronomic Therapy with Cyclophosphamide [Abstract]. Biocell, 3, 119.
[41] Bolhuis, H., Van Veen, H.W., Poolman, B., Driessen, A.J. and Konings, W.N. (1997) Mechanisms of Multidrug Transporters. FEMS Microbiology Reviews, 21, 55-84.
http://dx.doi.org/10.1111/j.1574-6976.1997.tb00345.x
[42] Kawase, M. and Motohashi, N. (2003) New Multidrug Resistance Reversal Agents. Current Drug Targets, 4, 31-43.
http://dx.doi.org/10.2174/1389450033347064
[43] Szakacs, G., Paterson, J.K., Ludwig, J.A., Booth-Genthe, C. and Gottesman, M.M. (2006) Targeting Multidrug Resistance in Cancer. Nature Reviews Drug Discovery, 5, 219-234.
http://dx.doi.org/10.1038/nrd1984
[44] Ozben, T. (2006) Mechanisms and Strategies to Overcome Multiple Drug Resistance in Cancer. FEBS Letters, 580, 2903-2909.
http://dx.doi.org/10.1016/j.febslet.2006.02.020
[45] Dubikovskaya, E.A., Thorne, S.H., Pillow, T.H., Contag, C.H. and Wender, P.A. (2008) Overcoming Multidrug Resistance of Small-Molecule Therapeutics through Conjugation with Releasable Octaarginine Transporters. Proceedings of the National Academy of Sciences of the United States of America, 105, 12128-12133.
http://dx.doi.org/10.1073/pnas.0805374105
[46] Baguley, B.C. (2010) Multidrug Resistance in Cancer. Methods in Molecular Biology, 596, 1-14.
http://dx.doi.org/10.1007/978-1-60761-416-6_1
[47] Ling, V. (1997) Multidrug Resistance: Molecular Mechanisms and Clinical Relevance. Cancer Chemotherapy and Pharmacology, 40, S3-S8.
http://dx.doi.org/10.1007/s002800051053
[48] Gillet, J.P., Efferth, T. and Remacle, J. (2007) Chemotherapy-Induced Resistance by ATP-Binding Cassette Transporter Genes. Biochimica et Biophysica Acta, 1775, 237-262.
[49] Ejendal, K.F. and Hrycyna, C.A. (2002) Multidrug Resistance and Cancer: The Role of the Human ABC Transporter ABCG2. Current Protein & Peptide Science, 3, 503-511.
http://dx.doi.org/10.2174/1389203023380521
[50] Sarkadi, B., Ozvegy-Laczka, C., Nemet, K. and Varadi, A. (2004) ABCG2—A Transporter for All Seasons. FEBS Letters, 567, 116-120.
http://dx.doi.org/10.1016/j.febslet.2004.03.123
[51] Loebinger, M.R., Giangreco, A., Groot, K.R., Prichard, L., Allen, K., Simpson, C., Bazley, L., Navani, N., Tibrewal, S., Davies, D. and Janes, S.M. (2008) Squamous Cell Cancers Contain a Side Population of Stem-Like Cells That Are Made Chemosensitive by ABC Transporter Blockade. British Journal of Cancer, 98, 380-387.
http://dx.doi.org/10.1038/sj.bjc.6604185
[52] Hadnagy, A., Gaboury, L., Beaulieu, R. and Balicki, D. (2006) SP Analysis May Be Used to Identify Cancer Stem Cell Populations. Experimental Cell Research, 312, 3701-3710.
http://dx.doi.org/10.1016/j.yexcr.2006.08.030
[53] Keshet, G.I., Goldstein, I., Itzhaki, O., Cesarkas, K., Shenhav, L., Yakirevitch, A., Treves, A.J., Schacter, J., Amariglio, N. and Rechavi, G. (2008) MDR1 Expression Identifies Human Melanoma Stem Cells. Biochemical and Biophysical Research Communications, 368, 930-936.
http://dx.doi.org/10.1016/j.bbrc.2008.02.022
[54] Roninson, I.B., Abelson, H.T., Housman, D.E., Howell, N. and Varshavsky, A. (1984) Amplification of Specific DNA Sequences Correlates with Multi-Drug Resistance in Chinese Hamster Cells. Nature, 309, 626-628.
http://dx.doi.org/10.1038/309626a0
[55] Roninson, I.B. (1983) Detection and Mapping of Homologous, Repeated and Amplified DNA Sequences by DNA renaturation in Agarose Gels. Nucleic Acids Research, 11, 5413-5431.
[56] Gros, P., Croop, J., Roninson, I., Varshavsky, A. and Housman, D.E. (1986) Isolation and Characterization of DNA Sequences Amplified in Multidrug-Resistant Hamster Cells. Proceedings of the National Academy of Sciences of the United States of America, 83, 337-341.
http://dx.doi.org/10.1073/pnas.83.2.337
[57] Comerford, K.M., Wallace, T.J., Karhausen, J., Louis, N.A., Montalto, M.C. and Colgan, S.P. (2002) Hypoxia-Inducible Factor-1-Dependent Regulation of the Multidrug Resistance (MDR1) Gene. Cancer Research, 62, 3387-3394.
[58] Liu, L., Ning, X., Sun, L., Zhang, H., Shi, Y., Guo, C., Han, S., Liu, J., Sun, S., Han, Z., Wu, K. and Fan, D. (2008) Hypoxiainducible Factor-1 Alpha Contributes to Hypoxia-Induced Chemoresistance in Gastriccancer. Cancer Science, 99, 121-128.
[59] Han, H.K., Han, C.Y., Cheon, E.P., Lee, J. and Kang, K.W. (2007) Role of Hypoxia-Inducible Factoralpha in Hepatitis-B-Virus X Protein-Mediated MDR1 Activation. Biochemical and Biophysical Research Communications, 357, 567-573.
http://dx.doi.org/10.1016/j.bbrc.2007.04.012
[60] Song, X., Liu, X., Chi, W., Liu, Y., Wei, L., Wang, X. and Yu, J. (2006) Hypoxiainduced Resistance to Cisplatin and Doxorubicin in Non-Small Cell Lung Cancer Is Inhibited by Silencing of HIF-1 Alpha Gene. Cancer Chemotherapy and Pharmacology, 58, 776-784.
http://dx.doi.org/10.1007/s00280-006-0224-7
[61] Krishnamurthy, P., Ross, D.D., Nakanishi, T., Bailey-Dell, K., Zhou, S., Mercer, K.E., Sarkadi, B., Sorrentino, B.P. and Schuetz, J.D. (2004) The Stem Cell Marker Bcrp/ABCG2 Enhances Hypoxic Cell Survival through Interactions with Heme. The Journal of Biological Chemistry, 279, 24218-24225.
http://dx.doi.org/10.1074/jbc.M313599200
[62] Kohno, K., Sato, S., Takano, H., Matsuo, K. and Kuwano, M. (1989) The Direct Activation of Human Multidrug Resistance Gene (MDR1) by Anticancer Agents. Biochemical and Biophysical Research Communications, 165, 1415-1421.
http://dx.doi.org/10.1016/0006-291X(89)92761-7
[63] Chaudhary, P.M. and Roninson, I.B. (1993) Induction of Multidrug Resistance in Human Cells by Transient Exposure to Different Chemotherapeutic Drugs. Journal of the National Cancer Institute, 85, 632-639.
http://dx.doi.org/10.1093/jnci/85.8.632
[64] Danial, N.N. (2007) BCL-2 Family Proteins: Critical Checkpoints of Apoptotic Cell Death. Clinical Cancer Research, 13, 7254-7263.
http://dx.doi.org/10.1158/1078-0432.CCR-07-1598
[65] Forte, M. and Bernardi, P. (2006) The Permeability Transition and BCL-2 Family Proteins in Apoptosis: Co-Conspirators or Independent Agents? Cell Death and Differentiation, 13, 1287-1290.
http://dx.doi.org/10.1038/sj.cdd.4401957
[66] Kramer, A., Lukas, J. and Bartek, J. (2004) Checking Out the Centrosome. Cell Cycle, 3, 1390-1393.
http://dx.doi.org/10.4161/cc.3.11.1252
[67] McDermott, K.M., Zhang, J., Holst, C.R., Kozakiewicz, B.K., Singla, V. and Tlsty, T.D. (2006) p16INK4a Prevents Centrosome Dysfunction and Genomic Instability in Primary Cells. PLoS Biology, 4, e51.
http://dx.doi.org/10.1371/journal.pbio.0040051
[68] Loeb, L.A., Bielas, J.H. and Beckman, R.A. (2008) Cancers Exhibit a Mutator Phenotype: Clinical Implications. Cancer Research, 68, 3551-3557.
http://dx.doi.org/10.1158/0008-5472.CAN-07-5835
[69] Bodey, G.P., Buckley, M., Sathe, Y.S. and Freireich, E.J. (1966) Quantitative Relationships between Circulating Leukocytes and Infection in Patients with Acute Leukemia. Annals of Internal Medicine, 64, 328-340.
http://dx.doi.org/10.7326/0003-4819-64-2-328
[70] Blackwell, S. and Crawford, J. (1994) Filgrastim (r-metHuG-CSF) in the Chemotherapy Setting. In: Morstyn, G., Dexter, T.M. and Foote, M., Eds., Filgrastim (r-metHuG-CSF) in Clinical Practice, Marcel Dekker, New York, 103-106.
[71] Su, Y.B., Sohn, S., Krown, S.E., et al. (2004) Selective CD4+ Lymphopenia in Melanoma Patients Treated with Temozolomide: A Toxicity with Therapeutic Implications. Journal of Clinical Oncology, 22, 610-616.
http://dx.doi.org/10.1200/JCO.2004.07.060
[72] Amato, R. and Stepankiw, M. (2013) Evaluation of Everolimus in Renal Cell Cancer. Drug Evaluations, 14, 1229-1240.
http://dx.doi.org/10.1517/14656566.2013.791677
[73] Layman, R.M., Ruppert, A.S., Lynn, M., Mrozek, E., Ramaswamy, B., Lustberg, M., Wesolowski, R., Ottman, S., Carthers, S., Bingman, A., Reinbolt, R., Kraut, E.H. and Shapiro, C.L. (2013) Severe and Prolonged Lymphopenia Observed in Patients Treated with Bendamustine and Erlotinib for Metastatic Triple Negative Breast Cancer. Cancer Chemotherapy and Pharmacology, 71, 1183-1190.
http://dx.doi.org/10.1007/s00280-013-2112-2
[74] Dighiero, G. (1996) Adverse and Beneficial Immunological Effects of Purine Nucleoside Analogs. Hematology and Cell Therapy, 38, S75-S81
[75] Ray-Coquard, I., Borg, C., Bachelot, T., Sebban, C., Phillip, I., Clapisson, G., Le Cesne, A., Biron, P., Chauvin, F. and Blay, J.Y. (2003) Baseline and Early Lymphopenia Predict for the Risk of Febrile Neutropenia after Chemotherapy. British Journal of Cancer, 88, 181-186.
http://dx.doi.org/10.1038/sj.bjc.6600724
[76] Ghiringhelli, F., Menard, C., Puig, P.E., et al. (2007) Metronomic Cyclophosphamide Regimen Selectively Depletes CD4+CD25+ Regulatory T Cells and Restores T and NK Effector Functions in End Stage Cancer Patients. Cancer Immunology, Immunotherapy, 56, 641-648.
http://dx.doi.org/10.1007/s00262-006-0225-8
[77] Tannock, I.F., Ahles, T.A., Ganz, P.A. and van Dam, F.S. (2004) Cognitive Impairment Associated with Chemotherapy for Cancer: Report of a Workshop. Journal of Clinical Oncology, 22, 2233-2239.
http://dx.doi.org/10.1200/JCO.2004.08.094
[78] Ahles, T.A. and Saykin, A.J. (2002) Breast Cancer Chemotherapy-Related Cognitive Dysfunction. Clinical Breast Cancer, 3, S84-S90.
http://dx.doi.org/10.3816/CBC.2002.s.018
[79] Ferguson, R.J. and Ahles, T.A. (2003) Low Neuropsychologic Performance among Adult Cancer Survivors Treated with Chemotherapy. Current Neurology and Neuroscience Reports, 3, 215-222.
http://dx.doi.org/10.1007/s11910-003-0081-2
[80] Anderson-Hanley, C., Sherman, M.L., Riggs, R., Agocha, V.V. and Compas, B.E. (2003) Neuropsychological Effects of Treatments for Adults with Cancer: A Meta-Analysis and Review of the Literature. Journal of the International Neuropsychological Society, 9, 967-982.
http://dx.doi.org/10.1017/s1355617703970019
[81] Saykin, A.J., Ahles, T.A. and McDonald, B.C. (2003) Mechanisms of Chemotherapy-Induced Cognitive Disorders: Neuropsychological, Pathophysiological and Neuroimaging Perspectives. Seminars in Clinical Neuropsychiatry, 8, 201-216.
[82] Stemmer, S., Stears, J.C., Burton, B.S., et al. (1994) White Matter Changes in Patients with Breast Cancer Treated with High-Dose Chemotherapy and Autologous Bone Marrow Support. American Journal of Neuroradiology, 15, 1267-1273.
[83] Wefel, J.S., Lenzi, R., Theriault, R., et al. (2004) “Chemobrain” in Breast Carcinoma? A Prologue. Cancer, 101, 466-475.
http://dx.doi.org/10.1002/cncr.20393
[84] Meyers, C.A., Albitar, M. and Estey, E. (2005) Cognitive Impairment, Fatigue, and Cytokine Levels in Patients with Acute Myelogenous Leukemia or Myelodysplastic Syndrome. Cancer, 104, 788-793.
http://dx.doi.org/10.1002/cncr.21234
[85] Ahles, T.A., Silberfarb, P.M., Maurer, L.H., et al. (1998) Psychological and Neuropsychological Functioning of Patients with Limited Smallcell Lung Cancer Treated with Chemotherapy and Radiation Therapy with or without Warfarin, a Study for Cancer and Leukemia Group B. Journal of Clinical Oncology, 16, 1954-1960.
[86] Wagner, L.I., Sweet, J.J., Butt, Z., et al. (2006) Trajectory of Cognitive Impairment during Breast Cancer Treatment: A Prospective Analysis. Journal of Clinical Oncology, 24, 8500.
[87] Heflin, L.H., Meyerowitz, B.E., Hall, P., et al. (2005) Cancer as a Risk Factor for Long-Term Cognitive Deficits and Dementia. Journal of the National Cancer Institute, 97, 854-856.
http://dx.doi.org/10.1093/jnci/dji137
[88] Smith, A.J., Oertle, J. and Prato, D. (2015) Genetically Targeted Fractionated Chemotherapy. Journal of Cancer Therapy, 6, 182-198.
http://dx.doi.org/10.4236/jct.2015.62021
[89] Kafka, M.S. (1974) The Effect of Insulin on the Permeability of Phosphatidyl Choline Bimolecular Membranes to Glucose. The Journal of Membrane Biology, 18, 81-94.
http://dx.doi.org/10.1007/BF01870104
[90] Lee, C., Raffaghello, L., Brandhorst, S., Safdie, F.M., Bianchi, G., Martin-Montalvo, A., Pistoia, V., Wei, M., Hwang, S., Merlino, A., Emionite, L., Cabo, R. and Longo, V. (2012) Fasting Cycles Retard Growth of Tumor and Sensitize a Range of Cancer Cell Types to Chemotherapy. Science Translational Medicine, 4, 124ra27.

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