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. 1999 Oct;81(4):600–608. doi: 10.1038/sj.bjc.6690736

Effective treatment of liver metastases with photodynamic therapy, using the second-generation photosensitizer meta-tetra(hydroxyphenyl)chlorin (mTHPC), in a rat model

J P Rovers 1, A E Saarnak 3, A Molina 1, J J Schuitmaker 2, H J C M Sterenborg 3, O T Terpstra 1
PMCID: PMC2362893  PMID: 10574244

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. © 1999 Cancer Research Campaign

Keywords: photodynamic therapy, photosensitizer, colon cancer, liver metastasis, fluorescence, extraction, tumour response

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Selected References

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  1. Alian W., Andersson-Engels S., Svanberg K., Svanberg S. Laser-induced fluorescence studies of meso-tetra(hydroxyphenyl)chlorin in malignant and normal tissues in rats. Br J Cancer. 1994 Nov;70(5):880–885. doi: 10.1038/bjc.1994.414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Amin Z., Donald J. J., Masters A., Kant R., Steger A. C., Bown S. G., Lees W. R. Hepatic metastases: interstitial laser photocoagulation with real-time US monitoring and dynamic CT evaluation of treatment. Radiology. 1993 May;187(2):339–347. doi: 10.1148/radiology.187.2.8475270. [DOI] [PubMed] [Google Scholar]
  3. Ballantyne G. H., Quin J. Surgical treatment of liver metastases in patients with colorectal cancer. Cancer. 1993 Jun 15;71(12 Suppl):4252–4266. doi: 10.1002/1097-0142(19930615)71:12+<4252::aid-cncr2820711815>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  4. Bellnier D. A., Ho Y. K., Pandey R. K., Missert J. R., Dougherty T. J. Distribution and elimination of Photofrin II in mice. Photochem Photobiol. 1989 Aug;50(2):221–228. doi: 10.1111/j.1751-1097.1989.tb04152.x. [DOI] [PubMed] [Google Scholar]
  5. Berenbaum M. C., Akande S. L., Bonnett R., Kaur H., Ioannou S., White R. D., Winfield U. J. meso-Tetra(hydroxyphenyl)porphyrins, a new class of potent tumour photosensitisers with favourable selectivity. Br J Cancer. 1986 Nov;54(5):717–725. doi: 10.1038/bjc.1986.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bown S. G., Tralau C. J., Smith P. D., Akdemir D., Wieman T. J. Photodynamic therapy with porphyrin and phthalocyanine sensitisation: quantitative studies in normal rat liver. Br J Cancer. 1986 Jul;54(1):43–52. doi: 10.1038/bjc.1986.150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Braichotte D. R., Wagnières G. A., Bays R., Monnier P., van den Bergh H. E. Clinical pharmacokinetic studies of photofrin by fluorescence spectroscopy in the oral cavity, the esophagus, and the bronchi. Cancer. 1995 Jun 1;75(11):2768–2778. doi: 10.1002/1097-0142(19950601)75:11<2768::aid-cncr2820751122>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  8. Braichotte D., Savary J. F., Glanzmann T., Westermann P., Folli S., Wagnieres G., Monnier P., Van den Bergh H. Clinical pharmacokinetic studies of tetra(meta-hydroxyphenyl)chlorin in squamous cell carcinoma by fluorescence spectroscopy at 2 wavelengths. Int J Cancer. 1995 Oct 9;63(2):198–204. doi: 10.1002/ijc.2910630209. [DOI] [PubMed] [Google Scholar]
  9. Busch E., Kemeny M. M. Colorectal cancer: hepatic-directed therapy--the role of surgery, regional chemotherapy, and novel modalities. Semin Oncol. 1995 Oct;22(5):494–508. [PubMed] [Google Scholar]
  10. Cady B. Natural history of primary and secondary tumors of the liver. Semin Oncol. 1983 Jun;10(2):127–134. [PubMed] [Google Scholar]
  11. Fingar V. H., Wieman T. J., Doak K. W. Role of thromboxane and prostacyclin release on photodynamic therapy-induced tumor destruction. Cancer Res. 1990 May 1;50(9):2599–2603. [PubMed] [Google Scholar]
  12. Henderson B. W., Dougherty T. J. How does photodynamic therapy work? Photochem Photobiol. 1992 Jan;55(1):145–157. doi: 10.1111/j.1751-1097.1992.tb04222.x. [DOI] [PubMed] [Google Scholar]
  13. Holt S., Tulip J., Hamilton D., Cummins J., Fields A., Dick C. Experimental laser phototherapy of the Morris 7777 hepatoma in the rat. Hepatology. 1985 Mar-Apr;5(2):175–180. doi: 10.1002/hep.1840050203. [DOI] [PubMed] [Google Scholar]
  14. Korbelik M., Krosl G. Enhanced macrophage cytotoxicity against tumor cells treated with photodynamic therapy. Photochem Photobiol. 1994 Nov;60(5):497–502. doi: 10.1111/j.1751-1097.1994.tb05140.x. [DOI] [PubMed] [Google Scholar]
  15. Lilge L., O'Carroll C., Wilson B. C. A solubilization technique for photosensitizer quantification in ex vivo tissue samples. J Photochem Photobiol B. 1997 Jul;39(3):229–235. doi: 10.1016/s1011-1344(97)00010-9. [DOI] [PubMed] [Google Scholar]
  16. Lofgren L. A., Ronn A. M., Abramson A. L., Shikowitz M. J., Nouri M., Lee C. J., Batti J., Steinberg B. M. Photodynamic therapy using m-tetra(hydroxyphenyl) chlorin. An animal model. Arch Otolaryngol Head Neck Surg. 1994 Dec;120(12):1355–1362. doi: 10.1001/archotol.1994.01880360051010. [DOI] [PubMed] [Google Scholar]
  17. Marijnissen J. P., Versteeg J. A., Star W. M., van Putten W. L. Tumor and normal tissue response to interstitial photodynamic therapy of the rat R-1 rhabdomyosarcoma. Int J Radiat Oncol Biol Phys. 1992;22(5):963–972. doi: 10.1016/0360-3016(92)90795-j. [DOI] [PubMed] [Google Scholar]
  18. Marquet R. L., Westbroek D. L., Jeekel J. Interferon treatment of a transplantable rat colon adenocarcinoma: importance of tumor site. Int J Cancer. 1984 May 15;33(5):689–692. doi: 10.1002/ijc.2910330521. [DOI] [PubMed] [Google Scholar]
  19. Mikvy P., Messman H., MacRobert A. J., Pauer M., Sams V. R., Davies C. L., Stewart J. C., Bown S. G. Photodynamic therapy of a transplanted pancreatic cancer model using meta-tetrahydroxyphenylchlorin (mTHPC). Br J Cancer. 1997;76(6):713–718. doi: 10.1038/bjc.1997.451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mizeret J. C., van den Bergh H. E. Cylindrical fiberoptic light diffuser for medical applications. Lasers Surg Med. 1996;19(2):159–167. doi: 10.1002/(SICI)1096-9101(1996)19:2<159::AID-LSM6>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
  21. Nishiwaki Y., Nakamura S., Sakaguchi S. New method of photosensitizer accumulation for photodynamic therapy in an experimental liver tumor. Lasers Surg Med. 1989;9(3):254–263. doi: 10.1002/lsm.1900090308. [DOI] [PubMed] [Google Scholar]
  22. Peng Q., Moan J., Ma L. W., Nesland J. M. Uptake, localization, and photodynamic effect of meso-tetra(hydroxyphenyl)porphine and its corresponding chlorin in normal and tumor tissues of mice bearing mammary carcinoma. Cancer Res. 1995 Jun 15;55(12):2620–2626. [PubMed] [Google Scholar]
  23. Potter W. R., Mang T. S., Dougherty T. J. The theory of photodynamic therapy dosimetry: consequences of photo-destruction of sensitizer. Photochem Photobiol. 1987 Jul;46(1):97–101. doi: 10.1111/j.1751-1097.1987.tb04741.x. [DOI] [PubMed] [Google Scholar]
  24. Ris H. B., Altermatt H. J., Inderbitzi R., Hess R., Nachbur B., Stewart J. C., Wang Q., Lim C. K., Bonnett R., Berenbaum M. C. Photodynamic therapy with chlorins for diffuse malignant mesothelioma: initial clinical results. Br J Cancer. 1991 Dec;64(6):1116–1120. doi: 10.1038/bjc.1991.474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rovers J. P., Schuitmaker J. J., Vahrmeijer A. L., van Dierendonck J. H., Terpstra O. T. Interstitial photodynamic therapy with the second-generation photosensitizer bacteriochlorin a in a rat model for liver metastases. Br J Cancer. 1998 Jun;77(12):2098–2103. doi: 10.1038/bjc.1998.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schuitmaker J. J., Baas P., van Leengoed H. L., van der Meulen F. W., Star W. M., van Zandwijk N. Photodynamic therapy: a promising new modality for the treatment of cancer. J Photochem Photobiol B. 1996 Jun;34(1):3–12. doi: 10.1016/1011-1344(96)07342-3. [DOI] [PubMed] [Google Scholar]
  27. Star W. M., Marijnissen H. P., van den Berg-Blok A. E., Versteeg J. A., Franken K. A., Reinhold H. S. Destruction of rat mammary tumor and normal tissue microcirculation by hematoporphyrin derivative photoradiation observed in vivo in sandwich observation chambers. Cancer Res. 1986 May;46(5):2532–2540. [PubMed] [Google Scholar]
  28. Sterenborg H. J., Saarnak A. E., Frank R., Motamedi M. Evaluation of spectral correction techniques for fluorescence measurements on pigmented lesions in vivo. J Photochem Photobiol B. 1996 Sep;35(3):159–165. doi: 10.1016/s1011-1344(96)07320-4. [DOI] [PubMed] [Google Scholar]
  29. Svanberg K., Liu D. L., Wang I., Andersson-Engels S., Stenram U., Svanberg S. Photodynamic therapy using intravenous delta-aminolaevulinic acid-induced protoporphyrin IX sensitisation in experimental hepatic tumours in rats. Br J Cancer. 1996 Nov;74(10):1526–1533. doi: 10.1038/bjc.1996.584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Van Hillegersberg R., Van den Berg J. W., Kort W. J., Terpstra O. T., Wilson J. H. Selective accumulation of endogenously produced porphyrins in a liver metastasis model in rats. Gastroenterology. 1992 Aug;103(2):647–651. doi: 10.1016/0016-5085(92)90860-2. [DOI] [PubMed] [Google Scholar]
  31. Welch J. P., Donaldson G. A. The clinical correlation of an autopsy study of recurrent colorectal cancer. Ann Surg. 1979 Apr;189(4):496–502. doi: 10.1097/00000658-197904000-00027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Whelpton R., Michael-Titus A. T., Basra S. S., Grahn M. Distribution of temoporfin, a new photosensitizer for the photodynamic therapy of cancer, in a murine tumor model. Photochem Photobiol. 1995 Apr;61(4):397–401. doi: 10.1111/j.1751-1097.1995.tb08629.x. [DOI] [PubMed] [Google Scholar]
  33. Whelpton R., Michael-Titus A. T., Jamdar R. P., Abdillahi K., Grahn M. F. Distribution and excretion of radiolabeled temoporfin in a murine tumor model. Photochem Photobiol. 1996 Jun;63(6):885–891. doi: 10.1111/j.1751-1097.1996.tb09646.x. [DOI] [PubMed] [Google Scholar]
  34. de Vree W. J., Essers M. C., de Bruijn H. S., Star W. M., Koster J. F., Sluiter W. Evidence for an important role of neutrophils in the efficacy of photodynamic therapy in vivo. Cancer Res. 1996 Jul 1;56(13):2908–2911. [PubMed] [Google Scholar]
  35. van Hillegersberg R., Marijnissen J. P., Kort W. J., Zondervan P. E., Terpstra O. T., Star W. M. Interstitial photodynamic therapy in a rat liver metastasis model. Br J Cancer. 1992 Dec;66(6):1005–1014. doi: 10.1038/bjc.1992.402. [DOI] [PMC free article] [PubMed] [Google Scholar]

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