Abstract
The only curative treatment for patients with liver metastases to date is surgery, but few patients are suitable candidates for hepatic resection. The majority of patients will have to rely on other treatment modalities for palliation. Photodynamic therapy (PDT) could be a selective, minimally invasive treatment for patients with liver metastases. We studied PDT in an implanted colon carcinoma in the liver of Wag/Rij rats, using the photosensitizer meta-tetra(hydroxyphenyl)chlorin (mTHPC). mTHPC tissue kinetics were studied using ex vivo extractions and in vivo fluorescence measurements. Both methods showed that mTHPC kinetics were different for liver and tumour tissue. After initial high levels at 4 h after administration (0.1 and 0.3 mg kg–1) mTHPC in liver tissue decreased rapidly in time. In tumour tissue no decrease in photosensitizer levels occurred, with mTHPC remaining high up to 48 h after administration. Both concentration data and fluorescence data showed an increase in tumour to liver ratios of up to 6.3 and 5.0 respectively. Illumination with 652 nm (15 J) resulted in extensive damage to tumour tissue, with necrosis of up to 13 mm in diameter. Damage to normal liver tissue was mild and transient as serum aspartate aminotransferase and alanine aminotransferase levels normalized within a week after PDT treatment. Long-term effects of mTHPC-PDT were studied on day 28 after treatment. Regardless of drug dose and drug–light interval, PDT with mTHPC resulted in complete tumour remission in 27 out of 31 treated animals (87%), with only four animals in which tumour regrowth was observed. Non-responding tumours proved to be significantly larger (P < 0.001) in size before PDT treatment. This study demonstrates that mTHPC is retained in an intrahepatic tumour and that mTHPC-PDT is capable of inducing complete tumour remission of liver tumours.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Alian, W, Andersson-Engels, S, Svanberg, K & Svanberg, S (1994) Laser-induced fluorescence studies of meso-tetra(hydroxyphenyl)chlorin in malignant and normal tissue in rats. Br J Cancer 70: 880–885
Amin, Z, Donald, JJ, Masters, A, Kantr, R, Steger, AC, Bown, SG & Lees, WR (1993) Hepatic metastases interstitial laser photocoagulation with real-time US-monitoring and dynamic CT evaluation of treatment. Radiology 187: 339–347
Ballantyne, GH & Quin, J (1993) Surgical treatment of liver metastases in patients with colorectal cancer. Cancer 71: 4252–4266
Bellnier, DA, Ho, YK, Pandey, RK, Missert, JR & Dougherty, TJ (1989) Distribution and elimination of Photofrin II in mice. Photochem Photobiol 50: 221–228
Berenbaum, MC, Akande, SL, Bonnet, R, Kaur, H, Ioannou, S, White, RD & Winfield, UJ (1986) meso-Tetra-(hydroxyphenyl) porphyrins, a new class of potent tumour photosensitizers with favourable selectivity. Br J Cancer 54: 717–725
Bown, SG, Tralau, CJ, Coleridge-Smith, PD, Akdemir, D & Wieman, TJ (1986) Photodynamic therapy with porphyrin and phthalocyanine sensitization: quantitative studies in normal rat liver. Br J Cancer 54: 43–52
Braichotte, D, Savary, JF & Glanzman, T et al 1995a) Clinical pharmacokinetic studies of tetra(meta-hydroxyphenyl)chlorin in squamous cell carcinoma by fluorescence spectroscopy at 2 wavelengths. Int J Cancer 63: 198–204
Braichotte, D, Wagnieres, GA, Bays, R, Monnier, P & van den Bergh, HE (1995b) Clinical pharmacokinetic studies of photofrin by fluorescence spectroscopy in the oral cavity, the esophagus, and the bronchi. Cancer 75: 2768–2778
Bush, E & Kemeny, MM (1995) Colorectal cancer: hepatic-directed therapy – role of surgery, regional chemotherapy, and novel modalities. Semin Oncol 22: 494–508
Cady, B (1983) Natural history of primary and secondary tumors of the liver. Semin Oncol 10: 127–133
de Vree, WJA, Esser, MC, De Bruijn, HS, Star, WM, Koster, JF & Sluiter, W (1996) Evidence for an important role of neutrophils in the efficacy of photodynamic therapy in vivo. Cancer Res 56: 2908–2911
Dilkes, MG, Dejode, ML, Rowntree-Taylor, A, McGilligan, JA, Kenyon, GS & McKelvie, P (1996) m-THPC photodynamic therapy for head and neck cancer. Lasers Med Sci 11: 23–29
Fingar, VH, Wieman, TJ & Doak, KW (1990) Role of thromboxane and prostacyclin release on photodynamic therapy-induced tumor destruction. Cancer Res 50: 2599–2603
Grosjean, P, Savary, JF, Wagnieres, G & Mizeret, J et al (1996) Tetra(m-hydroxyphenyl)chlorin clinical photodynamic therapy of early bronchial and oesophageal cancers. Lasers Med Sci 11: 227–235
Henderson, BW Dougherty (1992) How does photodynamic therapy work? Photochem Photobiol 55: 145–157
Holt, S, Tulip, J, Hamilton, D, Cummins, J, Fields, A & Dick, C (1985) Experimental laser phototherapy of the morris 7777 hepatoma in the rat. Hepatology 5: 175–180
Korbelik, M & Krosl, G (1994) Enhanced macrophage cytotoxicity against tumor cells treated with photodynamic therapy. Photochem Photobiol 60: 497–502
Lilge, L, O’Carroll, C & Wilson, BC (1997) A solubilization technique for photosensitizer quantification in ex vivo tissue samples. J Photochem Photobiol B 39: 229–235
Lofgren, LA, Ronn, AM, Abramson, AL, Shikowitz, MJ, Nouri, M, Lee, CJ, Batti, J & Steinberg, BM (1994) Photodynamic therapy using m-tetra(hydroxyphenyl)-chlorin. An animal model. Arch Otolaryngol Head Neck Surg 120: 1355–1362
Marijnissen, JP, Versteeg, JA, Star, WM & van Putten, WL (1992) Tumor and normal tissue response to interstitial photodynamic therapy of the rat R-1 rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 22: 963–972
Marquet, RL, Westbroek, DL & Jeekel, J (1984) Interferon treatment of a transplantable rat colon adenocarcinoma: importance of tumor site. Int J Cancer 33: 689–692
Mizeret, JC & van den Bergh, HE (1996) Cylindrical fiberoptic light diffuser for medical applications. Lasers Surg Med 19: 159–167
Mlkvy, P, Messman, H, MacRobert, AJ, Pauer, M, Sams, VR, Davies, CL, Stewart, JCM & Bown, SG (1997) Photodynamic therapy of a transplanted pancreatic cancer model using meta-tetrahydroxyphenylchlorin (mTHPC). Br J Cancer 76: 713–718
Nishiwaki, Y, Nakamura, S & Sakaguchi, S (1989) New method of photosensitizer accumulation for photodynamic therapy in an experimental liver tumour. Lasers Surg Med 9: 254–263
Peng, Q, Moan, J, Ma, LW & Nesland, JM (1995) Uptake, localization, and photodynamic effect of meso-tetra(hydroxyphenyl)porphyrin and its corresponding chlorin in normal and tumour tissue of mice bearing mammary carcinoma. Cancer Res 55: 2620–2626
Potter, WR, Mang, TS & Dougherty, TJ (1987) The theory of photodynamic therapy dosimetry: consequences of photodestruction of sensitizers. Photochem Photobiol 46: 97–101
Purkiss, SF, Grahn, MF, Abulafi, AM, Dean, JT, Allardice, JT & Williams, NS (1994) Multiple fibre interstitial photodynamic therapy of patients with colorectal liver metastases. Lasers Med Sci 9: 27–35
Ris, HB, Altermatt, HJ, Inderbitzi, R & Hess, R et al (1991) Photodynamic therapy with chlorins for diffuse malignant mesothelioma: initial clinical results. Br J Cancer 64: 1116–1120
Rovers, JP, Schuitmaker, JJ, Vahrmeijer, AL, Van Dierendonck, JH & Terpstra, OT (1998) Interstitial photodynamic therapy with the second generation photosensitizer bacteriochlorin in a rat model for liver metastases. Br J Cancer 77: 2098–2103
Schuitmaker, JJ, Baas, P, van Leengoed, HLLM, van der Meulen, FW, Star, WM & van Zandwijk, N (1996) Photodynamic therapy: a promising new modality for treatment of cancer. J Photochem Photobiol B: Biology 34: 3–12
Star, WM, Marijnissen, HP, van den Berg-Blok, AE, Versteeg, JA, Franken, FA & Reinhold, HS (1986) Destruction of rat mammary tumor and normal tissue microcirculation by hematoporphyrin derivative photoradiation observed in vivo in sandwich observation chambers. Cancer Res 46: 2532–2540
Sterenborg, HJ, Saarnak, AE, Frank, R & Motamedi, M (1996) Evaluation of spectral correction techniques for fluorescence measurements on pigmented lesions in vivo. J Photochem Photobiol B: Biology 35: 159–165
Svanberg, K, Liu, DL, Wang, I, Andersson-Engels, S, Stenram, U & Svanberg, S (1996) Photodynamic therapy using intravenous d-aminolaevulinic acid-induced protoporphyrin IX sensitisation in experimental hepatic tumours in rats. Br J Cancer 74: 1526–1533
van Hillegersberg, R, Marijnissen, JPA, Kort, WJ, Zondervan, PE, Terpstra, OT & Star, WM (1992a) Interstitial photodynamic therapy in a rat liver metastases model. Br J Cancer 66: 1005–1014
van Hillegersberg, R, van den Berg, JW, Kort, WJ, Terpstra, OT & Wilson, JH (1992b) Selective accumulation of endogenously produced porphyrins in a liver metastasis model in rats. Gastroenterology 103: 647–651
Welch, JP & Donaldson, GA (1979) The clinical correlation of an autopsy study of recurrent colorectal cancer. Ann Surg 89: 496–502
Whelpton, R, Michael-Titus, AT, Basra, SS & Grahn, MF (1995) Distribution of temoporfin, a new photosensitizer for the photodynamic therapy of cancer, in a murine tumor model. Photochem Photobiol 61: 397–401
Whelpton, R, Michael-Titus, AT, Jamdar, RP, Abdillah, K & Grahn, MF (1996) Distribution and excretion of radiolabelled temoporphin in a murine tumour model. Photochem Photobiol 63: 885–891
Wilson, BC, Patterson, MS & Lilge, L (1997) Implicit and explicit dosimetry in photodynamic therapy: a new paradigm. Lasers Med Sci 12: 182–199
Author information
Authors and Affiliations
Additional information
Correspondence to: OT Terpstra
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Rovers, J., Saarnak, A., Molina, A. et al. Effective treatment of liver metastases with photodynamic therapy, using the second-generation photosensitizer meta-tetra(hydroxyphenyl)chlorin (mTHPC), in a rat model. Br J Cancer 81, 600–608 (1999). https://doi.org/10.1038/sj.bjc.6690736
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690736
Keywords
This article is cited by
-
Lipid nanoemulsions and liposomes improve photodynamic treatment efficacy and tolerance in CAL-33 tumor bearing nude mice
Journal of Nanobiotechnology (2016)
-
Schedule-dependent interaction between Doxorubicin and mTHPC-mediated photodynamic therapy in murine hepatoma in vitro and in vivo
Cancer Chemotherapy and Pharmacology (2006)
-
Locoregional Therapies of Liver Metastases in a Rat CC531 Coloncarcinoma Model Results in Increased Resistance to Tumour Rechallenge
Clinical & Experimental Metastasis (2005)