ABC  Vol.6 No.6 , December 2016
Evaluation of Silicon Phthalocyanine 4 Photodynamic Therapy against Human Cervical Cancer Cells in Vitro and in Mice
Abstract: Background: Cervical cancer is the second most common cancer in women worldwide [1]. Photodynamic therapy has been used for cervical intraepithelial neoplasia with good responses, but few studies have used newer phototherapeutics. We evaluated the effectiveness of photodynamic therapy using Pc 4 in vitro and in vivo against human cervical cancer cells. Methods: CaSki and ME-180 cancer cells were grown as monolayers and spheroids. Cell growth and cytotoxicity were measured using a methylthiazol tetrazolium assay. Pc 4 cellular uptake and intracellular distribution were determined. For in vitro Pc 4 photodynamic therapy, cells were irradiated at 667 nm at a fluence of 2.5 J/cm2 at 48 h. SCID mice were implanted with CaSki and ME-180 cells both subcutaneously and intracervically. Forty-eight hours after Pc 4 photodynamic therapy was administered at 75 and 150 J/cm2. Results: The IC50s for Pc 4 and Pc 4 photodynamic therapy for CaSki and ME-180 cells as monolayers were, 7.6 μM and 0.016 μM and >10 μM and 0.026 μM; as spheroids, IC50s of Pc 4 photodynamic therapy were, 0.26 μM and 0.01 μM. Pc 4 was taken up within cells and widely distributed in tumors and tissues. Intracervical photodynamic therapy resulted in tumor death, however mice died due to gastrointestinal toxicity. Photodynamic therapy resulted in subcutaneous tumor death and growth delay. Conclusions: Pc 4 photodynamic therapy caused death within cervical cancer cells and xenografts, supporting development of Pc 4 photodynamic therapy for treatment of cervical cancer. Support: P30-CA47904, CTSI BaCCoR Pilot Program.
Cite this paper: Gadzinski, J. , Guo, J. , Philips, B. , Basse, P. , Craig, E. , Bailey, L. , Latoche, J. , Comerci, J. and Eiseman, J. (2016) Evaluation of Silicon Phthalocyanine 4 Photodynamic Therapy against Human Cervical Cancer Cells in Vitro and in Mice. Advances in Biological Chemistry, 6, 193-215. doi: 10.4236/abc.2016.66017.

[1]   Ferlay, J., Soerjomataram, I., Ervik, M., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D. and Bray, F. (2013) GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. International Agency for Research on Cancer, Lyon.

[2]   World Health Organization and Regional Office Africa (2015) Cervical Cancer.

[3]   American Cancer Society (2015) Cancer Facts and Figures.

[4]   Minig, L., Patrono, M.G., Romero, N., Moreno, J.F.R. and Garcia-Donas, J. (2014) Different Strategies of Treatment for Uterine Cervical Carcinoma Stage 1B2-IIB. World Journal of Clinical Oncology, 5, 86-92.

[5]   Hequet, D., Marchand, E., Place, V., Fourchotte, V., De La Rochefordière, A., Dridi, S., Coutant, C., Lecuru, F., Bats, A.S., Koskas, M., Bretel, J.J., Bricou, A., Delpech, Y. and Barranger, E. (2013) Evaluation and Impact of Residual Disease in Locally Advanced Cervical Cancer after Concurrent Chemoradiation Therapy: Results of a Multicenter Study. European Journal of Surgical Oncology, 39, 1428-1434.

[6]   Jancar, N., Rakar, S., Poljak, M., Fujs, K., Kocja, B.J. and Vrtacnik-Bokal, E. (2006) Efficiency of Three Surgical Procedures in Eliminating High-Risk Human Papilloma Virus Infection in Woman with Precancerous Cervical Lesions. European Journal of Gynaecological Oncology, 27, 239-242.

[7]   Wilkinson, E.J. (2009) Women with Cervical Intraepithelial Neoplasia: Requirement for Active Long-Term Surveillance after Therapy. Journal of the National Cancer Institute, 101, 696-697.

[8]   Shishkova, N., Kuznetsova, O. and Berezov, T. (2012) Photodynamic Therapy for Gynecological Diseases and Breast Cancer. Cancer Biology and Medicine, 9, 9-17.

[9]   Jakobsson, M. and Norwitz, E.R. (2015) Cervical Intraepithelial Neoplasia: Reproductive Effects of Treatment.

[10]   Telmer, C.A., Verma, R., Teng, H., Andreko, S., Law, L. and Bruchez, M.P. (2015) Rapid, Specific, No-Wash, Far-Red Fluorogen Activation in Subcellular Compartments by Targeted Fluorogen Activating Proteins. ACS Chemical Biology, 10, 1239-1246.

[11]   Egorin, M.J., Zuhowski, E.G., Sentz, D.L., Dobson, J.M., Callery, P.S. and Eiseman, J.L. (1999) Plasma Pharmacokinetics and Tissue Distribution in CD2F1 Mice of Pc 4 (NSC 676418), a Silicone Phthalocyanine Photodynamic Sensitizing Agent. Cancer Chemotherapy and Pharmacology, 44, 283-294.

[12]   Lam, M., Hsia, A.H., Liu, Y., Guo, M., Swick, A.R., Berlin, J.C., McCormick, T.S., Kenney M.E., Oleinick, N.L., Cooper, K.D. and Baron, E.D. (2011) Successful Cutaneous Delivery of the Photosensitizer Silicon Phthalocyanine 4 for Photodynamic Therapy. Clinical and Experimental Dermatology, 36, 645-651.

[13]   Oleinick, N., Morris, R.L. and Belichenko, I. (2002) The Role of Apoptosis in Response to Photodynamic Therapy: What, Where, Why, and How. Photochemical & Photobiolological Sciences, 1, 1-21.

[14]   Master, A., Malamas, A., Solanki, R., Clausen, D.M., Eiseman, J.L. and Sen Gupta, A. (2013) A Cell-Targeted Photodynamic Nanomedicine Strategy for Head and Neck Cancers. Molecular Pharmaceutics, 10, 1988-1997.

[15]   Bai, L., Guo, J., Bontempo, F.A. and Eiseman, J.L. (2009) The Relationship of Phthalocyanine 4 (Pc 4) Concentrations Measured Noninvasively to Outcome of Pc 4 Photodynamic Therapy in Mice. Photochemistry and Photobiology, 85, 1011-1019.

[16]   Baron, E.D., Malbasa, C.L., Santo-Domingo, D., Fu, P., Miller, J.D., Hanneman, K.K., Hsia, A.H., Oleinick, N.L., Colussi, V.C. and Cooper, K.D. (2010) Silicion Phthalocyanin (Pc 4) Photodynamic Therapy Is a Safe Modality for Cutaneous Neoplasms: Results of a Phase 1 Clinical Trial. Lasers in Surgery and Medicine, 42, 728-735.

[17]   Muñoz, N., Bosch, F.X., de Sanjosé, S., Herrero, R., Castellsagué, X., Shah, K.V., Snijders, P.J. and Meijer, C.J. (2003) Epidemiologic Classification of Human Papillomavirus Types Associated with Cervical Cancer. New England Journal of Medicine, 348, 518-527.

[18]   Hirschhaeuser, F., Menne, H., Dittfeld, C.C., West, J., Mueller-Klieser, W. and Kunz-Schughart, L.A. (2010) Multicellular Tumor Spheroids: An Underestimated Tool Is Catching up Again. Journal of Biotechnology, 148, 3-15.

[19]   3D Biomatrix, Inc. (2013) 5 Reasons Cancer Researchers Adopt 3D Cell Culture: A Review of Recent Literature.

[20]   Mroz, P., Yaroslavsky, A., Kharkwal, G.B. and Hamblin, M.R. (2011) Cell Death Pathways in Photodynamic Therapy of Cancer. Cancers, 3, 2516-2539.

[21]   Kanbour, A.I. and Stock, R.J. (1978) Squamous Cell Carcinoma in Situ of the Endometrium and Fallopian Tube as Superficial Extension of Invasive Cervical Carcinoma. Cancer, 42, 570-580.<570::AID-CNCR2820420225>3.0.CO;2-N

[22]   Motoyama, T. and Wantanabe, H. (1988) Squamous Cell Carcinoma of the Cervix with Extensive Superficial Spreading to almost Whole Genital Tract and Associated with Endometrial Stromal Sarcoma. Acta Pathologica Japonica, 38, 1445-1452.

[23]   Maniar, K.P. and Wei, J. (2009) Pathology of Cervical Carcinoma.

[24]   Padmanabhan, P., Grosse, J., Asad A.B., Radda, G.K. and Golay, X. (2013) Gastrointestinal Transit Measurements in Mice with 99mTc-DTPA-Labeled Activated Charcoal Using Nano-SPECT-CT. EJNMMI Research, 3, 60.

[25]   Huang, Z. (2005) A Review of Progress in Clinical Photodynamic Therapy. Technology in Cancer Research and Treatment, 4, 283-293.

[26]   Bae, S.M., Kim, Y.W., Lee J.M., Namkoong, S.E, Han, S.J., Kim, J.K., Lee, C.H., Chun, H.J., Jin, H.S. and Ahn, W.S. (2004) Photodynamic Effects of Radachlorin® on Cervical Cancer Cells. Cancer Research and Treatment, 36, 389-394.

[27]   Kim, Y.W., Bae, S.M., Battogtokh, G., Bang, H.J. and Ahn, W.S. (2012) Synergistic Anti-Tumor Effects of Combination of Photodynamic Therapy and Arsenic Compound in Cervical Cancer Cells: In Vivo and in Vitro Studies. PLoS ONE, 7, e38583.

[28]   Bellnier, D.A., Greco, W.R., Goewen, G.M., Nava, H., Oseroff, A.R. and Dougherty, T.J. (2006) Clinical Pharmacokinetics of the PDT Photosensitizers Porfimer Sodium (Photofrin), 2-[1-Hexyloxyethyl]-2-devinyl pyropheophorbide-a (Photochlor) and 5-ALA-Induced Protoporphyrin IX. Lasers in Surgery and Medicine, 38, 439-444.

[29]   Choi, M.C., Jung, S.G., Park, H., Lee, S.Y., Lee, C., Hwang, Y.Y. and Kim S.J. (2013) Photodynamic Therapy for Management of Cervical Intraepithelial Neoplasia II and III in Young Patients and Obstetric Outcomes. Lasers in Surgery and Medicine, 45, 564-572.