Epirubicin-[Anti-HER2/neu] Synthesized with an Epirubicin-(C13-imino)-EMCS Analog: Anti-Neoplastic Activity against Chemotherapeutic-Resistant SKBr-3 Mammary Carcinoma in Combination with Organic Selenium — Oak Academic Publishing
Research ArticleOpen AccessGoogle Scholar indexed
Epirubicin-[Anti-HER2/neu] Synthesized with an Epirubicin-(C13-imino)-EMCS Analog: Anti-Neoplastic Activity against Chemotherapeutic-Resistant SKBr-3 Mammary Carcinoma in Combination with Organic Selenium
Purpose: Discover the anti-neoplastic efficacy of epirubicin-(C13-imino)-[anti-HER2/neu] against chemotherapeutic- resistant SKBr-3 mammary carcinoma and delineate the capacity of selenium to enhance it’s cytotoxic anti-neoplastic potency. Methods: In molar excess, EMCH was combined with epirubicin to create a covalent epirubicin-(C13-imino)-EMCH-maleimide intermediate with sulfhydryl-reactive properties. Monoclonal immunoglobulin selective for HER2/neu was then thiolated with 2-iminothiolane at the terminal ε-amine group of lysine residues. The sulfhydryl-reactive epirubicin-(C13-imino)-EMCH intermediate was then combined with thiolated anti-HER2/neu monoclonal immunoglobulin. Western-blot analysis was utilized to characterize the molecular weight profiles while binding of epirubicin-(C13-imino)-[anti-HER2/neu] to membrane receptors was determined by cell-ELISA utilizing populations of SKBr-3 mammary carcinoma that highly over-expresses HER2/neu complexes. Anti-neoplastic potency of epirubicin-(C13-imino)-[anti-HER2/ neu] between the epirubicin-equivalent concentrations of 10–12 M and 10–7 M was determined by vitality staining analysis with and without the presence of selenium (5 μM). Results: Epiribucin-(C13-imino)-[anti-HER2/neu] between epirubicin-equivalent concentrations of 10–8 M to 10–7 M consistently evoked higher anti-neoplastic potency than “free” non- conjugated epirubicin which corresponded with previous investigations utilizing epirubicin-(C3-amide)-[anti-HER2/neu] and epirubicin-(C3-amide)-[anti-EGFR]. Selenium at 5 mM consistently enhanced the cytotoxic anti-neoplastic potency of epirubicin-(C13-imino)-[anti-HER2/neu] at epirubicin equivalent concentrations (10–12 to 10–7 M). Conclusions: Epirubicin-(C13-imino)-[anti-HER2/neu] is more potent than epirubicin against chemotherapeutic-resistant SKBr-3 mammary carcinoma and selenium enhances epirubicin-(C13-imino)-[anti-HER2/neu] potency. The methodology applied for synthesizing epirubicin-(C13-imino)-[anti-HER2/neu] is relatively time convenient and has low instrumentation requirements.
R. J. Pietras, M. D. Pegram, R. S. Finn, D. A. Maneval and D. J. Slamon, “Remission of Human Breast Cancer Xenografts on Therapy with Humanized Monoclonal Antibody to HER-2 Receptor and DNA-Reactive Drugs,” Oncogene, Vol. 17, No. 8, 1998, pp. 2235-2249. doi:10.1038/sj.onc.1202132
R. Marches and J. W. Uhr, “Enhancement of the p27Kip1-Mediated Antiproliferative Effect of Trastuzumab (Herceptin) on HER2-Overexpressing Tumor Cells,” International Journal of Cancer, Vol. 112, No. 3, 2004, pp. 492-501. doi:10.1002/ijc.20378
M. X. Sliwkowski, J. A. Lofgren, G. D. Lewis, T. E. Hotaling, B. M. Fendly and J. A. Fox, “Nonclinical Studies Addressing the Mechanism of Action of Trastuzumab (Herceptin),” Seminars Oncology, Vol. 26, No. 4, Suppl. 12, 1999, pp. 60-70.
N. U. Lin, L. A. Carey, M. C. Liu, J. Younger, S. E. Come and M. Ewend, “Phase II Trial of Lapatinib for Brain Metastases in Patients with Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer,” Journal of Clinical Oncology, Vol. 26 , No. 12, 2008, pp. 1993-1999. doi:10.1200/JCO.2007.12.3588
M. A. Cobleigh, C. L. Vogel, D. Tripathy, N. J. Robert, S. Scholl and L. Fehrenbacher, “Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer that Has Progressed After Chemotherapy for Metastatic Disease,” Journal of Clinical Oncology, Vol. 17, No. 9, 1999, pp. 2639-2648.
C. L. Vogel, M. A. Cobleigh, D. Tripathy, J. C.Gutheil, L. N. Harris and L. Fehrenbacher, “Efficacy and Safety of Trastuzumab as a Single Agent in First-line Treatment of HER2-Overexpressing Metastatic Breast Cancer,” Journal of Clinical Oncology, Vol. 20, No. 3, 2002, pp. 719- 726. doi:10.1200/JCO.20.3.719
G. C. Lewis Phillips, G. Li, D. L. Dugger, L. M. Crocker, K. L. Parsons and E. Mai, “Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody- Cytotoxic Drug Conjugat,” Cancer Research, Vol. 68, No. 22, 2008, pp. 9280-9290. doi:10.1158/0008-5472.CAN-08-1776
J. A. García-Sáenz, M. Martín, A. Calles, C. Bueno, L. Rodríguez and J. Bobokova, “Bevacizumab in Combination with Metronomic Chemotherapy in Patients with Anthracycline- and Taxane-Refractory Breast Cancer,” Journal of Chemotherapy, Vol. 20, No. 5, 2008, pp. 632- 639.
D. J. Slamon, B. Leyland-Jone, S. Shak, H. Fuchs, V. Paton and A. Bajamonde, “Use of Chemotherapy plus Monoclonal Antibody against HER2 for Metastatic Breast Cancer that Overexpress HER2,” The New England Journal of Medicine, Vol. 344, No. 11, 2001, pp. 786-792. doi:10.1056/NEJM200103153441101
C. P. Coyne, M. Ross, J. Bailey and T. Jones, “Dual Potency Anti-HER2/Neu and Anti-EGFR Anthracycline- Immune Conjugates in Chemotherapeutic-Resistant Ma- mmary Carcinoma Combined with Cyclosporin-A and Verapamil P-Glycoprotein Inhibition,” Journal Drug Targeting, Vol. 17, 2009, pp. 474-489. doi:10.1080/10611860903012802
A. Lau, G. Berube, C. H. J. Ford and M. Gallant, “Novel Doxorubicin-Monoclonal Anti-Carcinoembryonic Antigen Antibody Immunoconjugate Activity In-Vitro,” Bioorganic and Medicinal Chemistry, Vol. 3, No. 10, 1995, pp. 1305- 1312. doi:10.1016/0968-0896(95)00126-2
G. L. Bidwell, A. N. Davis, I. Fokt, W. Priebe and D. Raucher, “A Thermally Targeted Elastin-like Polypeptide- Doxorubicin Conjugate Overcomes Drug Resistance,” Investigational New Drugs, Vol. 25, 2007, pp. 313-326. doi:10.1007/s10637-007-9053-8
C. Ryppa, H. Mann-Steinberg, I. Fichtner, H. Weber, R. Satchi-Fainaro and M. L. Biniossek, “In-Vitro and In- Vivo Evaluation of Doxorubicin Conjugates with the Divalent Peptide E-[c(RGDfK)2] that Targets Integrin aVb3,” Bioconjugate Chemistry, Vol. 19, 2008, pp. 1414- 1422. doi:10.1021/bc800117r
G. Di Stefano, M. Lanza, F. Kratz, L. Merina and L. Fiume, “A Novel Method for Coupling Doxorubicin to Lactosaminated Human Albumin by an Acid Sensitive Hydrazone Bond: Synthesis, Characterization and Preliminary Biological Properties of the Conjugate,” European Journal of Pharmaceutical Sciences, Vol. 23, 2004, pp. 393- 397. doi:10.1016/j.ejps.2004.09.005
F. Kratz, A. Warnecke, K. Scheuermann, C. Stockmar, J. Schwab and P. Lazar, “Probing the Cysteine-34 Position of Endogenous Serum Albumin with Thiol-Binding Doxorubicin Derivatives. Improved Efficacy of an Acid-Sensitive Doxorubicin Derivative with Specific Albumin-Binding Properties Compared to that of the Parent Compound,” Journal of Medicinal Chemistry, Vol. 45, 2002, pp. 5523-5533. doi:10.1021/jm020276c
C. Unger, B. H?ring, M. Medinger, J. Drevs, S. Steinbild and F. Kratz, “Phase I and Pharmacokinetic Study of the (6-Maleimidocaproyl) Hydrazone Derivative of Doxorubicin,” Clinical Cancer Research, Vol. 13, No. 16, 2007, pp. 4858-4866. doi:10.1158/1078-0432.CCR-06-2776
D. Y. Furgeson, M. R. Dreher and A. Chilkoti, “Structural Optimization of a ‘Smart’ Doxorubicin-Polypeptide Conjugate for Thermally Targeted Delivery to Solid Tumors,” Journal of Controled Release, Vol. 110, 2006, pp. 362-369. doi:10.1016/j.jconrel.2005.10.006
T. Etrych, T. Mrkvan, B. Ríhová and K. Ulbrich, “Star- Shaped Immunoglobulin-Containing HPMA-Based ConJugates with Doxorubicin for Cancer Therapy,” Journal Control Release, Vol. 122, 2007, pp. 31-38. doi:10.1016/j.jconrel.2007.06.007
T. Etrych, M. Jelínková, B. Ríhová and K. J. Ulbrich, “New HPMA Copolymers Containing Doxorubicin Bound Via pH-Sensitive Linkage: Synthesis and Preliminary In-Vitro and In-Vivo Biological Properties,” Control Release, Vol. 73, 2001, pp. 89-102. doi:10.1016/S0168-3659(01)00281-4
P. C. Rodrigues, U. Beyer, P. Schumacher, T. Roth, H. H. Fiebig, C. Unger, L. Messori, P. Orioli, D. H. Paper, R. Mülhaupt and F. Kratz, “Acid-Sensitive Polyethylene Glycol Conjugates of Doxorubicin: Preparation, In-Vitro Efficacy and Intracellular Distribution.” Bioorganic Medicinal Chemistry, Vol. 7, 1999, pp. 2517-2524.
Y. F. Huang, D. Shangguan, H. Liu, J. A. Phillips, X. Zhang and Y. Chen, “Molecular Assembly of an Aptamer-Drug Conjugate for Targeted Drug Delivery to Tumor Cells,” Chem Bio Chem, Vol. 10, 2009, pp. 862- 868. doi:10.1002/cbic.200800805
U. Beyer, B. Rothen-Rutishauser, C. Unger, H. Wunderli- Allenspach and F. Kratz, “Difference in the Intracellular Distribution of Acid-Sensitive Doxorubicin-Protein Conjugates in Comparison to Free and Liposomal Formulated Doxorubicin as Shown by Confocal Microscopy,” Pharmaceutical Research, Vol. 18, 2001, pp. 29-38. doi:10.1023/A:1011018525121
M. Kruger, U. Beyer, P. Schumacher, C. Unger, H. Zahn and F. Kratz. “Synthesis and Stability of Four Maleimide Derivatives of the Anti-Cancer Drug Doxorubicin for the Preparation of Chemoimmuneconjugates,” Chemical & Pharmaceutical Bulletin, Vol. 45, 1997, pp. 399-401.
F. Kratz, G. Ehling, H. M. Kauffmann and C. Unger, “Acute and Repeat-Dose Toxicity Studies of the (6- Maleimi-docaproyl) Hydrazone Derivative of Doxorubicin (Doxo- Emch), an Albumin-Binding Prodrug of the Anticancer Agent Doxorubicin,” Human & Experimental Toxicology, Vol. 26, 2007, pp. 19-35. doi:10.1177/0960327107073825
D. Lebrecht, A. Geist, U. P. Ketelsen, J. Haberstroh, B. Setzer and F. Kratz, “The 6-Maleimidocaproyl Hydrazone Derivative of Doxorubicin (DOXO-EMCH) is Superior to Free Doxorubicin with Respect to Cardiotoxicity and Mitochondrial Damage,” International Journal of Cancer, Vol. 120, No. 4, 2007, pp. 927-934. doi:10.1002/ijc.22409
P. A. Trail, D. Willner, J. Knipe, A. J. Henderson, S. J. Lasch and M. E. Zoeckler, “Effect of Linker Variation on the Stability, Potency and Efficacy of Carcinoma- Reactive BR64-Doxorubicin Immunoconjugates,” Cancer Research, Vol. 57, 1997, pp. 100-105. doi:10.1021/bc980100i
H. D. King, D. Yurgaitis, D. Willner, R. A. Firestone, M. B. Yang and S. J. Lasch, “Monoclonal Antibody Conjugates of Doxorubicin Prepared with Branched Linkers: A Novel Method for Increasing the Potency of Doxorubicin Immunoconjugates,” Bioconjugate Chemistry, Vol. 10, No. 2, 1999, pp. 279-288.
D. Willner, P. A. Trail, S. J. Hofstead, H. D. King, S. J. Lasch and G. R. Braslawsky, “(6-Maleimidocaproyl) Hydrazone of Doxorubicin-A New Derivative for the Preparation of Immunoconjugates of Doxorubicin,” Bioconjugate Chemistry, Vol. 4, No. 6, 1993, pp. 521-527. doi:10.1021/bc00024a015
J. Reményi, B. Balázs, S. Tóth, A. Falus, G. Tóth and F. Hudecz, “Isomer-Dependent Daunomycin Release and In-Vitro Antitumour Effect of Cis-Aconityl-Daunomy- cin,” Biochemical and Biophysical Research Communications, Vol. 303, No. 2, 2003, pp. 556-561. doi:10.1016/S0006-291X(03)00394-2
J. R. Ogden, K. Leung, S. A. Kunda, M. W. Telander, B. P. Avner and S. K. Liao, “Immunoconjugates of Doxorubicin and Murine Antihuman Breast Carcinoma Monoclonal Antibodies Prepared via an N-Hydroxysuccinimide Active Ester Intermediate of Cis-Aconityl-Doxorubicin: Preparation and In Vitro Cytotoxicity,” Molecular Biotherapy, Vol. 1, No. 3, 1989, pp. 170-174.
P. A. Trail, D. Willner, S. J. Lasch, A. J. Henderson, S. Hofstead and A. M. Casazza, “Cure of Xenografted Human Carcinomas by BR96-Doxorubicin Immunoconjugates,” Science, Vol. 261, 1993, pp. 212-215. doi:10.1126/science.8327892
P. A. Trail, D. Willner, S. J. Lasch, A. J. Henderson, R. S. Greenfield and D. King, “Antigen-Specific Activity of Carcinoma-Reactive BR64-Doxorubicin Conjugates Eva- luated In-Vitro and in Human Tumor Xenograft Models,” Cancer Research, Vol. 52, 1992, pp. 5693-5700.
P. A. Trail, D. Willner, A. B. Bianchi, A. J. Henderson, M. D. Trail-Smith and E. Girit, “Enhanced Antitumor Activity of Paclitaxel in Combination with the Anticarcinoma Immunoconjugate BR96-Doxorubicin,” Clinical Cancer Research, No. 5, 1999, pp. 3632-3638.
A. F. Wahl, K. L. Donaldson, B. J. Mixan, P. A. Trail and C. B. Siegall, “Selective Tumor Sensitization to Taxanes with the mAb-Drug Conjugate cBR96-Doxorubicin,” International Journal of Cancer, Vol. 93, No. 4, 2001, pp. 590-600. doi:10.1002/ijc.1364
B. S. Hendriks, L. K. Opresko, H. S. Wiley and D. Lauffenburger, “Coregulaiton of Epidermal Growth Factor Receptor/Human Epidermal Growth Factor Receptor 2 (HER2) Levels and Locations: Quantitative Analysis of HER2 Overexpression Effects,” Cancer Research, Vol. 63, 2003, pp. 1130-1137.
H. O. Sj?gren, M. Isaksson, D. Willner, I. Hellstr?m, K. E. Hellstr?m and P. A. Trail, “Antitumor Activity of Carcinoma-Reactive BR96-Doxorubicin Conjugate against Human Carcinomas in Athymic Mice and Rats and Syngeneic Rat Carcinomas in Immunocompetent Rats,” Cancer Research, Vol. 57, No. 20, 1997, pp. 4530-4536.
U. Beyer, T. Roth, P. Schumacher, G. Maier, A. Unold, A. W. Frahm, H. H. Fiebig, C. Unger and F. Kratz, “Synthesis and In-Vitro Efficacy of Transferring Conjugates of the Anticancer Drug Chlorambucil,” Journal of Medicinal Chemistry, Vol. 41, 1998, pp. 2701-2708. doi:10.1021/jm9704661
L. C. Xu, M. Nakayama, K. Harada, A. Kuniyasu, H. Nakayama, S. Tomiguchi, A. Kojima, M. Takahashi, M. Ono, Y. Arano, H. Saji, Z. Yao, H. Sakahara, J. Konishi and Y. Imagawa, “Bis(hydroxamamide)-Based Bifunctional Chelating Agent for 99mTc Labeling of Polypeptides,” Bioconjugate Chemistry, Vol. 10, 1999, pp. 9-17. doi:10.1021/bc980024j
Y. Arano, T. Uezono, H. Akizawa, M. Ono, K. Wakisaka, M. Nakayama, H. Sakahara, J. Konishi and A. Yokoyama, “Reassessment of Diethyl-enetriamine-pentaacetic Acid (Dtpa) as a Chelating Agent for Indium-111 Labeling of Polypeptides Using a Newly Synthesized Monoreactive Dtpa Derivative,” Journal of Medicinal Chemistry, Vol. 39, 1996, pp. 3451-3460. doi:10.1021/jm950949+
K. Ulbrich, T. Etrych, P. Chytil, M. Jelinkova and B. Rihova, “HPMA Copolymers with Ph-Controlled Release of Doxorubicin: In-Vitro Cytotoxicity and In-Vivo Antitumor Activity,” Journal of Controlled Release, Vol. 87, 2003, pp. 33-47. doi:10.1016/S0168-3659(02)00348-6
G. Hempel, P. Schulze-Westhoff, S. Flege and N. Laubrock, “Therapeutic Drug Monitoring of Doxorubicin in Paediatric Oncology Using Capillary Electrophoresis,” Journal of Electrophoresis, Vol. 19, No. 16-17, 1998, pp. 2939-2943. doi:10.1002/elps.1150191624
S. Li, Y. Zhou, Y. Dong and C. Ip, “Doxorubicin and Selenium Cooperative Induce Fas Signaling in the Absence of Fas/Fas Ligand Interaction,” Anticancer Research, Vol. 27, 2007, pp. 3075-3082.
S. Li, Y. Zhou, R. Wang, H. Zhang, Y. Dong and C. Ip, “Selenium Sensitizes Mcf-7 Breast Cancer Cells to Doxorubicin-Induced Apoptosis through Modulation of Phospho-akt and Its Downstream Substrates,” Molecular Cancer Therapeutics, Vol. 6, No. 3, 2007, pp. 1031-1038. doi:10.1158/1535-7163.MCT-06-0643
S. Juliger, H. Goenaga-Infante, T. A. Lister, J. Fitzgibbon and S. P. Joel, “Chemosensitization of B-Cell Lymphomas by Methylseleninic Acid Involves Nuclear Factor-Kb Inhibition and the Rapid Generation of Other Selenium Species, Cancer Research, Vol. 67, No. 22, 2007, pp. 10984-10992. doi:10.1158/0008-5472.CAN-07-0519
K. Jonsson-Videsater, L. Jborkhem-Bergman, A. Hossain, A. Soderberg, L. C. Eriksson and C. Paul, “Selenite-Induced Apoptosis in Doxorubicin-Resistant Cells and Effects on the Thioredoxin System,” Biochemical Pharmacology, Vol. 67, 2004, pp. 513-522. doi:10.1016/j.bcp.2003.09.021
R. S. Greenfield, T. Kaneko T, A. Daues, M. A. Edson, K. A. Fitzgerald and L. J. Olech, “Evaluation In-Vitro of Adriamycin Immunoconjugates Synthesized Using an Acid-Sensitive Hydrazone Linker,” Cancer Research, Vol. 50, No. 20, 1990, pp. 6600-6607.
J. A. Sinkule, S. T. Rosen and J. A. Radosevich, “Monoclonal Antibody 44-3a6 Doxorubicin Immunoconjugates: Comparative In-Vitro Anti-Tumor Efficacy of Different Conjugation Methods,” Tumour Biology, Vol. 12, No. 4, 1991, pp. 198-206. doi:10.1159/000217705
H. Hu, C. Jiang, G. Li and J. Lü, “PKB/AKT and ERK Regulation of Caspase-Mediated Apoptosis by Methylseleninic Acid in Lncap Prostate Cancer Cells,” Carcinogenesis, Vol. 26, No. 8, 2005, pp. 1374-1381. doi:10.1093/carcin/bgi094
R. O. Dillman, D. E. Johnson, J. Ogden and D. Beidler, “Significance of Antigen, Drug, and Tumor Cell Targets in the Preclinical Evaluation of Doxorubicin, Daunorubicin, Methotrexate, and Mitomycin-C Monoclonal Antibody Immunoconjugates,” Molecular Biotherapy, Vol. 1, 1989, pp. 250- 255.
G. P. Sivam, P. J. Martin, R. A. Reisfeld and B. M. Mueller, “Therapeutic Efficacy of a Doxorubicin Immunoconjugate in a Preclinical Model of Spontaneous Metastatic Human Melanoma,” Cancer Research, Vol. 55, No. 11, 1995, pp. 2352-2356.
P. Sapra, R. Stein, J. Pickett, Z. Qu, S. V. Govindan and T. M. Cardillo, “Anti-CD74 Antibody-Doxorubicin Conjugate, IMMU-110, in a Human Multiple Myeloma Xenograph and in Monkeys,” Clinical Cancer Research, Vol. 11, No. 14, 2005, pp 5257-5264. doi:10.1158/1078-0432.CCR-05-0204
H. M. Yang and R. A. Reisfeld, “Doxorubicin Conjugated with Monoclonal Antibody Directed to a Human Melanoma-Associated Proteoglycan Suppresses the Growth of Established Tumor Xenografts in Nude Mice,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 85, 1988, pp. 1189-1193. doi:10.1073/pnas.85.4.1189
K. Ulbrich, T. Etrych, P. Chytil, M. Jelinkova and B. Rihova, “Anti-body Targeted Polymer-Doxorubicin Conjugates with pH-Controlled Activation. HPMA Copolymers with pH-Controlled Release of Doxorubicin. In-Vitro Cytotoxicity and In-Vivo Antitumor Activity,” Journal of Drug Targeting, Vol. 12, 2004, pp. 477-489. doi:10.1080/10611860400011869
G. L. Griffiths, M. J. Mattes, R. Stein, S. V. Govindan, I. D. Horak and H. J. Hansen, “Cure of SCID Mice Bearing Human B-lymphoma Xenografts by an Anti-CD74 Antibody-An-Thracycline Drug Conjugate,” Clinical Cancer Research, Vol. 9, No. 17, 2003, pp. 6567-6571.
J. Liu, H. Zhao, K. J. Volk, S. E. Klohr, E. H. Kerns and M. S. Lee, “Analysis of Monoclonal Antibody and Immunoconjugate Digests by Capillary Electrophoresis and Capillary Liquid Chromatography,” Journal of Chromatography A, Vol. 735, 1996, pp. 357-366. doi:10.1016/0021-9673(95)01054-8
K. Inoh, H. Muramatsu, S. Torii, S. Ikematsu, M. Oda and H. Kumai, “Doxorubicin-Conjugated Anti-Midkine Monoclonal Antibody as a Potential Anti-tumor Drug,” Japanese Journal of Clinical Oncology, Vol. 36, No. 4, 2006, pp. 207-211. doi:10.1093/jjco/hyl004
G. M. Dubowchik, S. Radia, H. Mastalerz, M. A. Walker, R. A. Firestone and H. Dalton King, “Doxorubicin Immunoconjugates Containing Bivalent, Lysosomally-Clea- vable Dipeptide Linkages,” Bioorganic & Medicinal Chemistry Letters, Vol. 12, No. 1, 2002, pp. 1529-1532. doi:10.1016/S0960-894X(02)00194-4
L. B. Shih, D. M. Goldenberg, H. Xuan, H. W. Lu, M. J. Mattes and T. C. Hall, “Internalization of an Intact Doxorubicin Immunoconjugate,” Cancer Immunol Immunother, Vol. 38, No. 2, 1994, pp. 92-98. doi:10.1007/BF01526203
Y. T. Zhang, N. Q. Wang, N. Li, T. Liu and Z. W. Dong, “The Antitumor Effect of Adriamycin Conjugated with Monoclonal Antibody against Gastric Cancer In-Vitro and In-Vivo,” Acta Pharmaceutica Sinica, Vol. 27, 1992, pp. 325-330.
H. J. Hansen, G. L. Ong and H. Diril, “Internalization and Catabolism of Radiolabeled Antibodies to the MHC Class-II Invariant Chain by B-cell Lymphomas,” Biochemical Journal, Vol. 320, 1996, pp. 293-300.
D. A. Johnson, S. L. Briggs, M. C. Gutowski and R. Barton, “Anti-Tumor Activity of CC49-Doxorubicin Immunoconjugates,” Anticancer Research, Vol. 15, No. 4, 1995, pp. 1387-1393.
C. Herbert, K. Norris and J. J. Sauk, “Targeting of Human Squamous Carcinomas by SPA470-Doxorubicin Immunoconjugates,” Journal of Drug Targeting, Vol. 11, No. 2, 2003, pp. 101-107. doi:10.1080/1061186031000121478
M. V. Pimm, M. A. Paul, T. Ogumuyiwa and R. W. Baldwin, “Biodistribution and Tumour Localization of a Daunomycin-Monoclonal Antibody Conjugate In Nude Mice and Human Tumour Xenografts,” Cancer Immunology Immunotherapy, Vol. 27, No. 3, 1988, pp. 267-271. doi:10.1007/BF00205450
A. C. Stan, D. L. Radu, S. Casares, C. A. Bona and T. D. Brumeanu, “Antineoplastic Efficacy of Doxorubicin Enzymatically Assembled on Galactose Residues of a Monoclonal Antibody Specific for the Carcinoembryonic Antigen,” Cancer Research, Vol. 59, 1999, pp. 115-121.
J. H. Liu, L. Cao, P. G. Luo, S. T. Yang, F. Lu and H. Wang, “Fullerene-Conjugated Doxorubicin in Cells.” ACS Applied Mater Interfaces, Vol. 2, No. 5, 2010, pp. 1384-1389.
M. Haas, F. Moolenaar, A. Elsinga, E. A. van der Wouden, P. E. De Jong and D. K. F. Meijer, “Targeting of Doxorubicin to the Urinary Bladder of the Rat Shows Increased Cytotoxicity in the Bladder Urine Combined with An Absence of Renal Toxicity,” Journal Drug Targeting, Vol. 10, 2002, pp. 81-89.
H. M. Yang and R. A. Reisfeld, “Pharmacokinetics and Mechanism of Action of a Doxorubicin-Monoclonal Antibody 9.2.27 Conjugate Directed to a Human Melanoma Proteoglycan,” Preview Journal of the National Cancer Institute, Vol. 80, No. 14, 1988, pp. 1154-1159.
S. V. Lutsenko, N. B. Feldman and S. E. Severin, “Cytotoxic and Antitumor Activities of Doxorubicin Conjugates with the Epidermal Growth Factor and Its Receptor-Binding Fragment,” Journal Drug Targeting, Vol. 10, No. 7, 2002, pp. 567-571.
E. Aboud-Pirak, E. Hurwitz, F. Bellot, J. Schlessinger and M. Sela, “Inhibition of Human Tumor Growth in Nude Mice by a Conjugate of Doxorubicin with Monoclonal AntiBodies to Epidermal Growth Factor Receptor,” PNAS, Vol. 86, No. 10, 1989, pp. 3778-3781.
H. Mueller, M. U. Kassack and M. Wiese, “Comparison of the Usefulness of the MTT, ATP and Calcein Assays to Predict the Potency of Cytotoxic Agents in Various Human Cancer Cell Lines.” Biomolecular Screening, Vol. 9, No. 6, 2004, pp. 506-515.
E. Ulukaya, F. Ozdikicioglu, A. Y. Oral and M. Dermirci, “The MTT Assay Yields a Relatively Lower Result of Growth Inhibition than the ATP Assay Depending on the Chemotherapeutic Drug Tested,” Toxicology In-Vitro, Vol. 22, No. 1, 2008, pp. 232-239.
M. Varache-Lembège, S. Larrouture, D. Montaudon, J. Robert and A. Nuhrich A, “Synthesis and Antiproliferative Activity of Aryl- and Heteroaryl-Hydrazones Derived from Xanthone Carbaldehydes,” European Journal Medicinal Chemistry, Vol. 43, No. 6, 2008, pp. 1336-1343.
M. D. Kars, O. D. Iseri, U. Gunduz and J. Molnar, “Reversal of Multidrug Resistance by Synthetic and Natural Compounds in Drug-Resistant MCF-7 Cell Lines,” Chemotherapy, Vol. 54, No. 3, 2008, pp. 194-200.
H. Huang, E. Pierstorff, E. Osawa and D. Ho, “Active Nanodiamond Hydrogels for Chemotherapeutic Delivery,” Nano Letter, Vol. 7, No. 11, 2007, pp. 3305-3314.
M. C. Dery, C. van Themsche, D. Provencher, A. M. Mes-Masson and E. Asselin, “Characterization of EN- 1078D, a Poorly Differentiated Human Endometrial Carcinoma Cell Line: A Novel Tool to Study Endometrial Invasion In-Vitro,” Reproductive Biology Endocrinology, Vol. 5, 2007, pp. 38-39.
L. Tan, X. Jia, X. Jiang, Y. Zhang, H. Tang and S. Yao. “In-Vitro Study on the Individual and Synergistic Cytotoxicity of Adriamycin and Selenium Nanoparticles against Bel7402 Cells with a Quartz Crystal Microbalance,” Biosens Bioelectron, Vol. 24, No. 7, 2009, pp. 2268-2272.
J. van Wijngaarden, E. van Beek, G. van Rossum, C. van der Bent, K. Hoekman and G. van der Pluijm, “Celecoxib Enhances Doxorubicin-Induced Cytotoxicity in Mda- Mb231 Cells by Nf-Kappab-Mediated Increase of Intracellular Doxorubicin Accumulation,” European Journal of Cancer, Vol. 43, No. 2, 2007, pp. 433-442.
S. Hashitani, M. Urade, N. Nishimura, T. Maeda, K. Takaoka and K. Noguchi, “Apoptosis Induction and Enhancement of Cytotoxicity of Anticancer Drugs by Celecoxib, a Selective Cyclooxygenase-2 Inhibitor, in Human Head and Neck Carcinoma Cell Lines,” International Journal of Oncology, Vol. 23, No. 3, 2003, pp. 665-672.
K. R. Roy, G. V. Reddy, L. Maitreyi, S. Agarwal, C. Achari and S. Vali, “Apoptosis Induction and Enhancement of Cytotoxicity of Anticancer Drugs by Celecoxib, a Selective Cyclooxygenase-2 Inhibitor, in Human Head and Neck Carcinoma Cell Lines. Celecoxib Inhibits mdr1 Expression through COX-2-Dependent Mechanism in Human Hepatocellular Carcinoma (hepg2) Cell Line,” Cancer Chemotherapy and Pharmacology, Vol. 65, No. 5, 2010, pp. 903-911.
W. M. Awara, A. E. El-Sisi, M. E. El-Sayad and A. E. Goda, “Apoptosis Induction and Enhancement of Cytotoxicity of Anticancer Drugs by Celecoxib, a Selective Cyclooxygenase-2 Inhibitor, in Human Head and Neck Carcinoma Cell Linesthe Potential Role of Cyclooxygenase-2 Inhibitors in the Treatment of Experimentally-Induced Mammary Tumour: Does Celecoxib Enhance the Anti-Tumour Activity of Doxorubicin?” Pharmacology Research, Vol. 50, No. 5, 2004, pp. 487-498.
K. W. Last, V. Cornelius, T. Delves, C. Sieniawska, J. Fitzgibbon and A. Norton, “Presentation Serum Selenium Predicts for Overall Survival, Dose Delivery, and First Treatment Response in Aggressive Non-Hodgkin’S Lymphoma,” International Journal of Oncology, Vol. 21, No. 12, 2003, pp. 2335-2341.
L. Guan, B. Han, J. Li, Z. Li, F. Huang and Y. Yang, “Exposure of Human Leukemia Nb4 Cells to Increasing Concentrations of Selenite Switches the Signaling From Pro-Survival to Pro-Apoptosis,” Annals of Hematology Vol. 88, No. 8, 2009, pp. 733-742.
P. Suchocki, I. Misiewicz, K. Skupinska, K. Waclawek, Z. Fijalek and T. Kasprzycka-Guttman, “The Activity of Selol in Multidrug-Resistant and Sensitive Human Leukemia Cells,” Oncology Report, Vol. 18, No. 4, 2007, pp. 893- 899.
M. Popovic, J. Kolarovic, M. Mikov, S. Trivic and B. Kaurinovic, “Anthracycline-Based Combined Chemotherapy in the Mouse Model,” European Journal of Drug Metab Pharmacokinet, Vol. 32, No. 2, 2007, pp. 101-108.
J. V. Vadgama, Y. Wu, D. Shen, S. Hsia and J. Block, “Effect of Selenium in Combination with Adriamycin or Taxol on Several Different Cancer Cells,” Anticancer Research, Vol. 20, No. 3A, 2000, pp. 1391-1414.
S. Cao, F. A. Durrani and Y. M. Rustum, “Selective Modulation of the Therapeutic Efficacy of Anticancer Drugs by Selenium Containing Compounds against Human Tumor Xenografts,” Clinical Cancer Research, Vol. 10, 2004, pp. 2561-2569.
M. Lopez-Lazaro, E. Willmore, S. L. Elliott and C. A. Austin, “Selenite Induces Topoisomerase I and II Dna Complexes in K562 Leukemia Cells,” International Journal Cancer, Vol. 123, 2008, pp. 2217-2221. doi:10.1002/ijc.23783
G. M. Pighetti, M. L. Eskew, C. C. Reddy and L. M. Sordillo, “Selenium and Vitamin E Deficiency Impair Transferrin Receptor Internalization but Not Il-2, Il-2 Receptor, or Transferrin Receptor Expression,” Journal of Leukocyte Biology, Vol. 63, 1998, pp. 131-137.
T. Kaneko, D. Willner, J. O. Knipe, G. R. Braslawsky, R. S. Greenfield and D. M. Vyas, “New Hydrazone Derivatives of Adriamycin and Their Immunoconjugates – A Correlation between Acid Stability and Cytotoxicity,” Bioconjugate Chemistry, Vol. 2, 1991, pp. 133-141. doi:10.1021/bc00009a001