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Defining the therapeutic window of vertebral photodynamic therapy in a murine pre-clinical model of breast cancer metastasis using the photosensitizer BPD-MA (Verteporfin)

  • Margarete K. AkensEmail author
  • Michael R. Hardisty
  • Brian C. Wilson
  • Joerg Schwock
  • Cari M. Whyne
  • Shane Burch
  • Albert J. M. Yee
Preclinical Study

Abstract

Breast cancer is known to cause metastatic lesions in the bone, which can lead to skeletal-related events. Currently, radiation therapy and surgery are the treatment of choice, but the success rate varies and additional adjuncts are desirable. Photodynamic therapy (PDT) has been applied successfully as a non-radiative treatment for numerous cancers. Earlier work has shown that the athymic rat model is suitable to investigate the effect of PDT on bone metastasis and benzoporphyrin-derivative monoacid ring A (BPD-MA; verteporfin) has been shown to be a selective photosensitizer. The aim of this study was to define the therapeutic window of photosensitizer with regard to drug and light dose. Human breast carcinoma cells (MT-1)—stable transfected with the luciferase gene—were injected intra-cardiacally into athymic rats. At 14 days, the largest vertebral lesion by bioluminescence imaging was targeted for single treatment PDT. A drug escalating-de-escalating scheme was used (starting drug dose and light energy of 0.2 mg/kg and 50 J, respectively). Outcomes included 48 h post-treatment bioluminescence of remaining viable tumour, histomorphometric assessment of tumour burden, and neurologic evaluation. The region of effect by bioluminescence and histology increased with increasing drug dose and light energy. A safe and effective drug-light dose combination in this model appears to be 0.5 mg/kg BPD-MA and applied light energy of less than 50 J for the thoracic spine and 1.0 mg/kg and 75 J for the lumbar spine. For translation to clinical use, it is an advantage that BPD-MA (verteporfin), a second-generation photosensitizer, is already approved to treat age-related macular degeneration. Overall, PDT represents an exciting potential new minimally-invasive local, safe and effective therapy in the management of patients with spinal metastases.

Keywords

Spine Breast cancer Bone metastasis Photodynamic therapy 

Notes

Acknowledgment

Funding for this study was generously provided by the Canadian Breast Cancer Foundation, Ontario Chapter through a grant from the National Cancer Institute of Canada. The human breast cancer MT-1 cells were kindly provided by Dr. O. Engebraaten, Norwegian Radium Hospital, Oslo, Norway.

References

  1. 1.
    Lipton A (2003) Bone metastases in breast cancer. Curr Treat Options Oncol 4:151–158. doi: 10.1007/s11864-003-0016-9 CrossRefPubMedGoogle Scholar
  2. 2.
    Ecker RD, Endo T, Wetjen NM, Krauss WE (2005) Diagnosis and treatment of vertebral column metastases. Mayo Clin Proc 80:1177–1186CrossRefPubMedGoogle Scholar
  3. 3.
    Clemons M, Dranitsaris G, Cole D, Gainford MC (2006) Too much, too little, too late to start again? Assessing the efficacy of bisphosphonates in patients with bone metastases from breast cancer. Oncologist 11:227–233. doi: 10.1634/theoncologist.11-3-227 CrossRefPubMedGoogle Scholar
  4. 4.
    Tatsui H, Onomura T, Morishita S, Oketa M, Inoue T (1996) Survival rates of patients with metastatic spinal cancer after scintigraphic detection of abnormal radioactive accumulation. Spine 21:2143–2148. doi: 10.1097/00007632-199609150-00017 CrossRefPubMedGoogle Scholar
  5. 5.
    Katagiri H, Takahashi M, Inagaki J, Kobayashi H, Sugiura H, Yamamura S, Iwata H (1998) Clinical results of nonsurgical treatment for spinal metastases. Int J Radiat Oncol Biol Phys 42:1127–1132. doi: 10.1016/S0360-3016(98)00288-0 PubMedGoogle Scholar
  6. 6.
    Wai EK, Finkelstein JA, Tangente RP, Holden L, Chow E, Ford M, Yee A (2003) Quality of life in surgical treatment of metastatic spine disease. Spine 28:508–512. doi: 10.1097/00007632-200303010-00018 CrossRefPubMedGoogle Scholar
  7. 7.
    Powers SK, Cush SS, Walstad DL, Kwock L (1991) Stereotactic intratumoral photodynamic therapy for recurrent malignant brain tumors. Neurosurgery 29:688–695. doi: 10.1097/00006123-199111000-00008 (discussion 695–696)CrossRefPubMedGoogle Scholar
  8. 8.
    Marcon NE (1994) Photodynamic therapy and cancer of the esophagus. Semin Oncol 21:20–23PubMedGoogle Scholar
  9. 9.
    Lam S (1994) Photodynamic therapy of lung cancer. Semin Oncol 21:15–19PubMedGoogle Scholar
  10. 10.
    Allison R, Mang T, Hewson G, Snider W, Dougherty D (2001) Photodynamic therapy for chest wall progression from breast carcinoma is an underutilized treatment modality. Cancer 91:1–8. doi: 10.1002/1097-0142(20010101)91:1<1::AID-CNCR1>3.0.CO;2-P CrossRefPubMedGoogle Scholar
  11. 11.
    Biel MA (2007) Photodynamic therapy treatment of early oral and laryngeal cancers. Photochem Photobiol 83:1063–1068. doi: 10.1111/j.1751-1097.2007.00153.x CrossRefPubMedGoogle Scholar
  12. 12.
    Buytaert E, Dewaele M, Agostinis P (2007) Molecular effectors of multiple cell death pathways initiated by photodynamic therapy. Biochim Biophys Acta 1776:86–107PubMedGoogle Scholar
  13. 13.
    Niedre M, Patterson MS, Wilson BC (2002) Direct near-infrared luminescence detection of singlet oxygen generated by photodynamic therapy in cells in vitro and tissues in vivo. Photochem Photobiol 75:382–391. doi: 10.1562/0031-8655(2002)075<0382:DNILDO>2.0.CO;2 CrossRefPubMedGoogle Scholar
  14. 14.
    Verma S, Watt GM, Mai Z, Hasan T (2007) Strategies for enhanced photodynamic therapy effects. Photochem Photobiol 83:996–1005. doi: 10.1111/j.1751-1097.2007.00166.x CrossRefPubMedGoogle Scholar
  15. 15.
    Burch S, Bisland SK, Bogaards A, Yee AJ, Whyne CM, Finkelstein JA, Wilson BC (2005) Photodynamic therapy for the treatment of vertebral metastases in a rat model of human breast carcinoma. J Orthop Res 23:995–1003. doi: 10.1016/j.orthres.2004.12.014 CrossRefPubMedGoogle Scholar
  16. 16.
    Akens MK, Yee AJM, Wilson BC, Burch S, Johnson CL, Lilge L, Bisland SK (2007) Photodynamic therapy of vertebral metastases: evaluating tumor-to-neural tissue uptake of BPD-MA and ALA-PpIX in a murine model of metastatic human breast carcinoma. Photochem Photobiol 83:1034–1039. doi: 10.1111/j.1751-1097.2007.00172.x CrossRefPubMedGoogle Scholar
  17. 17.
    Richter AM, Cerruti-Sola S, Sternberg ED, Dolphin D, Levy JG (1990) Biodistribution of tritiated benzoporphyrin derivative (3H-BPD-MA), a new potent photosensitizer, in normal and tumor-bearing mice. J Photochem Photobiol B 5:231–244. doi: 10.1016/1011-1344(90)80008-L CrossRefPubMedGoogle Scholar
  18. 18.
    Parekh SG, Trauner KB, Zarins B, Foster TE, Anderson RR (1999) Photodynamic modulation of wound healing with BPD-MA and CASP. Lasers Surg Med 24:375–381. doi: 10.1002/(SICI)1096-9101(1999)24:5<375::AID-LSM8>3.0.CO;2-B CrossRefPubMedGoogle Scholar
  19. 19.
    Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12:1–21CrossRefPubMedGoogle Scholar
  20. 20.
    Fingar VH, Potter WR, Henderson BW (1987) Drug and light dose dependence of photodynamic therapy: a study of tumor cell clonogenicity and histologic changes. Photochem Photobiol 45:643–650. doi: 10.1111/j.1751-1097.1987.tb07392.x CrossRefPubMedGoogle Scholar
  21. 21.
    Burch S, Bogaards A, Siewerdsen J, Moseley D, Yee A, Finkelstein J, Weersink R, Wilson BC, Bisland SK (2005) Photodynamic therapy for the treatment of metastatic lesions in bone: studies in rat and porcine models. J Biomed Opt 10:34011. doi: 10.1117/1.1921887 CrossRefGoogle Scholar
  22. 22.
    Dole KC, Chen Q, Hetzel FW, Whalen LR, Blanc D, Huang Z (2005) Effects of photodynamic therapy on peripheral nerve: in situ compound-action potentials study in a canine model. Photomed Laser Surg 23:172–176. doi: 10.1089/pho.2005.23.172 CrossRefPubMedGoogle Scholar
  23. 23.
    Hausmann ON (2003) Post-traumatic inflammation following spinal cord injury. Spinal Cord 41:369–378. doi: 10.1038/sj.sc.3101483 CrossRefPubMedGoogle Scholar
  24. 24.
    Bendszus M, Ladewig G, Jestaedt L, Misselwitz B, Solymosi L, Toyka K, Stoll G (2008) Gadofluorine M enhancement allows more sensitive detection of inflammatory CNS lesions than T2-w imaging: a quantitative MRI study. Brain 131:2341–2352. doi: 10.1093/brain/awn156 CrossRefPubMedGoogle Scholar
  25. 25.
    Hebel R, Stromberg MW (1986) Anatomy and embryology of the laboratory rat. BioMed Verlag, WoerthseeGoogle Scholar
  26. 26.
    Burch S, Yee AJM (2005) Role of photodynamic therapy for bone metastasis. In: Singh G, Rabbani SA (eds) Bone metastasis. Humana Press Inc, Totowa, pp 243–253Google Scholar
  27. 27.
    Bisland SK, Lilge L, Lin A, Rusnov R, Wilson BC (2004) Metronomic photodynamic therapy as a new paradigm for photodynamic therapy: rationale and preclinical evaluation of technical feasibility for treating malignant brain tumors. Photochem Photobiol 80:22–30. doi: 10.1562/2004-03-05-RA-100.1 CrossRefPubMedGoogle Scholar
  28. 28.
    Henderson BW, Gollnick SO, Snyder JW, Busch TM, Kousis PC, Cheney RT, Morgan J (2004) Choice of oxygen-conserving treatment regimen determines the inflammatory response and outcome of photodynamic therapy of tumors. Cancer Res 64:2120–2126. doi: 10.1158/0008-5472.CAN-03-3513 CrossRefPubMedGoogle Scholar
  29. 29.
    Henderson BW, Busch TM, Snyder JW (2006) Fluence rate as a modulator of PDT mechanisms. Lasers Surg Med 38:489–493. doi: 10.1002/lsm.20327 CrossRefPubMedGoogle Scholar
  30. 30.
    Grossweiner LI (1997) PDT light dosimetry revisited. J Photochem Photobiol B 38:258–268. doi: 10.1016/S1011-1344(96)07469-6 CrossRefPubMedGoogle Scholar
  31. 31.
    Li J, Zhu TC (2008) Determination of in vivo light fluence distribution in a heterogeneous prostate during photodynamic therapy. Phys Med Biol 53:2103–2114. doi: 10.1088/0031-9155/53/8/007 CrossRefPubMedGoogle Scholar
  32. 32.
    Zhou X, Pogue BW, Chen B, Hasan T (2004) Analysis of effective molecular diffusion rates for verteporfin in subcutaneous versus orthotopic dunning prostate tumors. Photochem Photobiol 79:323–331. doi: 10.1562/MU-03-31.1 CrossRefPubMedGoogle Scholar
  33. 33.
    Cruess AF, Zlateva G, Pleil AM, Wirostko B (2008) Photodynamic therapy with verteporfin in age-related macular degeneration: a systematic review of efficacy, safety, treatment modifications and pharmacoeconomic properties. Acta Ophthalmol (Copenh). doi: 10.1111/j.1755-3768.2008.01218.x

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Margarete K. Akens
    • 1
    Email author
  • Michael R. Hardisty
    • 1
  • Brian C. Wilson
    • 2
  • Joerg Schwock
    • 2
  • Cari M. Whyne
    • 1
  • Shane Burch
    • 3
  • Albert J. M. Yee
    • 1
  1. 1.Division of Orthopaedic SurgerySunnybrook Health Science CentreTorontoCanada
  2. 2.Ontario Cancer InstituteTorontoCanada
  3. 3.Department of Orthopaedic SurgeryUniversity of CaliforniaSan FranciscoUSA

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