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Biotechnology and Applied Biochemistry (1999) 30, (1–17) (Printed in Great Britain)

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Review

Ex vivo photodynamic purging in chronicmyelogenous leukaemia and other neoplasias with rhodaminederivatives

Luc Villeneuve*†¹

*Theratechnologies Inc., 630 boulevarde Rene-LevesquesOuest, Montreal, Québec, Canada, H3B IS6, and †Universityof Montreal, Department of Pathology and Cellular Biology, 2900Edouard Montpetit, C. P. 6128, succursale centre-ville, Montreal,Québec, Canada, H3C 1J7

Abbreviations used: PDT, photodynamic therapy; PDP, photodynamic-cell-therapy process; ROI, reactive oxygen intermediates; ROS, reactive oxygen species; AuT, autologous transplantation; MM, multiple myeloma(s); BC, breast cancer; CML, chronic myelogenous leukaemia; TX, Triton X-100; DPBS, Dulbecco PBS; PS, photosensitizer; HSC, haematopoietic stem cell; BM, bone marrow; PB, peripheral blood; HLA, human leukocyte antigen; AuPCT, autologous PB cell transplantation; (m)PBSC, (mobilized) PB stem cells; HDCT, high-dose chemotherapy; rGF, recombinant growth factor; NHL, non-Hodgkin's lymphoma; RT, reverse transcription; CFU-GM, colony forming unit-granulocyte macrophage; bcr/abl, a reciprocal translocation between the genes bcr (breakpoint cluster region) and c-abl (Abelson) gene; MPT, mitochondrial permeability transition; SCR, stem-cell rescue; mdr, multidrug resistance; PgP, P-glycoprotein; G-CSF, granulocyte colony-stimulating factor; FDA, Food and Drug Administration; FRET, fluorescence resonance energy transfer.

¹ To whom correspondence should be sent at the University of Montreal address.

Photodynamic therapy (PDT), a cancer treatment already used early in this century, has distinctive advantages over conventional chemotherapy, namely its often observed preferential accumulation in cancer cells and its low intrinsic toxicity. Aggressive therapeutic modalities using high doses of chemotherapy and/or radiation therapy are now commonplace treatments for leukaemia, lymphoma and various non-haematologic malignancies. These intensive approaches have often been used in association with haematopoietic-progenitor-cell support and have induced major responses and remissions in patients with relapsed and refractory diseases, ultimately contributing to improve the disease-free survival of patients with high risk. This has encouraged Theratechnologies, a Montreal-based pharmaceutical company, to develop photodynamic ex vivo purging procedures, including the development of new photosensitizers and irradiation devices for the safe eradication of neoplastic cells from autologous grafts. Our first specific objective, therefore, was to design, synthesize, purify and test photoactive rhodamine derivatives. We have also selected a gas and phosphorus coating characteristic of an efficient scanning fluorescent source for extra-corporeal PDT using rhodamine derivatives. 4,5-Dibromorhodamine 123 (TH9402) was selected because of its photophysical properties, low toxicity and stability. TH9402 photodynamic-cell-therapy process conditions recognized as safe for normal human haematopoietic stem cells and progenitors demonstrated the efficacy of the purging procedure on various leukaemias (including chronic-myelogenous-leukaemia as well as non-Hodgkin-leukaemias and metastatic-breast-cancer cell lines.