Dye-mediated photolysis is capable of eliminating drug-resistant (MDR+) tumor cells

Lemoli, Roberto M.; Igarashi, Tadahiko; Knizewski, Marianne; Acabá, Luis; Richter, Anna; Jain, Ashok Kumar; Mitchell, David; Levy, Julia G.; Gulati, Subhash C.

doi:10.1182/blood.v81.3.793.bloodjournal813793

Cited by 9 publications

(5 citation statements)

References 21 publications

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“…The literature reporting studies comparing and combining PDT and chemotherapy gives wide ranging results, depending on the photosensitisers and chemotherapeutic agents used. Cross‐resistance to chemotherapeutic drugs and photosensitisers like porphyrin and benzoporphyrin derivatives has been reported 26, 27, 28, 29. The failure of PDT in MDR cells was thought to be due to impaired photosensitiser accumulation due to exclusion by the aforementioned cell efflux pumps.…”

Section: Discussionmentioning

confidence: 99%

Reversal of doxorubicin resistance in breast cancer cells by photochemical internalization

Lou

Lai

Shieh

et al. 2006

Intl Journal of Cancer

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Multiple drug resistance (MDR) is a problem that seriously reduces the efficacy of many chemotherapy agents. One mechanism for MDR is increased acidification of endocytic vesicles and increased cytosol pH, so weak base chemotherapeutic agents, including doxorubicin, are trapped in endocytic vesicles and exhibit a drug resistant phenotype. Treatments that selectively reverse this accumulation may therefore reverse the MDR phenotype. Photochemical internalization (PCI) is a novel technology developed for site-specific enhancement of the therapeutic efficacy of macromolecules by selective photochemical rupture of endocytic vesicles and consequent release of endocytosed macromolecules into the cytosol. This study evaluates PCI for release of doxorubicin from endocytic vesicles in MDR cells. Two breast cancer cell lines, MCF-7 and MCF-7/ADR (the latter resistant to doxorubicin), were selected. They were found equally sensitive to photochemical treatment with the photosensitiser TPPS 2a (disulfonated meso-tetraphenylporphine) and light. On exposure to doxorubicin alone, the IC 50 (drug concentration for 50% reduction in colony formation) was 0.1 lM for MCF-7 and 1 lM for MCF-7/ADR. After PCI (photochemical treatment followed by doxorubicin), the IC 50 concentration was 0.1 lM for both cell lines. Comparable changes were seen with assay of cell viability using 3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). On fluorescence microscopy in MCF-7/ADR cells, doxorubicin localised in granules identified as lysosomes. After PCI, doxorubicin was released into the cytosol and entered cell nuclei, as was seen in MCF-7 cells without PCI. In conclusion, PCI reversed the MDR phenotype of doxorubicin resistant breast cancer cells by endolysosomal release of the drug. The technique is a promising new approach to tackling the problem of MDR. ' 2006 Wiley-Liss, Inc.Key words: photodynamic therapy; photochemical internalization; doxorubicin resistant breast cancer cells Multiple drug resistance (MDR) is a major clinical problem that seriously reduces the efficacy of many chemotherapy agents. The establishment of a MDR phenotype by cancer cells is a result of complex molecular events. The most extensively studied mechanism is the over-expression of cell surface efflux pumps (the ABCtransporter family P-glycoprotein, MDR-associated protein, etc.) that can successfully purge a wide spectrum of chemotherapeutic agents from cells, 1 thereby decreasing their intracellular accumulation. 2 Other possible mechanisms are mutation of the DNA topoisomerase, or altered intracellular distribution of anticancer drugs. 2,3 Inhibition of ABC-transporters as a method to reverse MDR in cancer patients has been studied extensively, but the results have generally been disappointing. First-generation agents (e.g. cyclosporin, verapamil) were limited by unacceptable toxicity, whereas secondgeneration agents (e.g. valspodar, biricodar) had better tolerability, but were confounded by unpredictable pharmacokinetic interactions and interactio...

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Section: Discussionmentioning

confidence: 99%

Reversal of doxorubicin resistance in breast cancer cells by photochemical internalization

Lou

Lai

Shieh

et al. 2006

Intl Journal of Cancer

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“…These data have led to an increased interest in procedures that can selectively remove breast cancer cells (BCCs) from autologous hematopoietic cells to be used for transplant, without damaging the hematopoietic reconstituting cells. Methods applied to this problem include monoclonal antibodies (MoAbs) targeted to breast cancer-associated cell surface markers, 4 breast cancer specific MoAbs conjugated to toxins, 5 in vitro incubation with cytotoxic drugs, 6 lectin agglutination, 7 phototherapy, 8 and biological modifiers. 9 Unfortunately, many of these systems for eradicating BCCs also lead to the destruction of clonogenic progenitor cells and thereby cause a prolongation of neutropenia after intensive therapy and transplantation.…”

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confidence: 99%

Cytosine Deaminase Adenoviral Vector and 5-Fluorocytosine Selectively Reduce Breast Cancer Cells 1 Million-Fold When They Contaminate Hematopoietic Cells: A Potential Purging Method for Autologous Transplantation

García‐Sánchez

Pizzorno

et al. 1998

Blood

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Ad.CMV-CD is a replication incompetent adenoviral vector carrying a cytomegalovirus (CMV)-driven transcription unit of the cytosine deaminase (CD) gene. The CD transcription unit in this vector catalyzes the deamination of the nontoxic pro-drug, 5-fluorocytosine (5-FC), thus converting it to the cytotoxic drug 5-fluorouracil (5-FU). This adenoviral vector prodrug activation system has been proposed for use in selectively sensitizing breast cancer cells, which may contaminate collections of autologous stem cells products from breast cancer patients, to the toxic effects of 5-FC, without damaging the reconstitutive capability of the normal hematopoietic cells. This system could conceivably kill even the nondividing breast cancer cells, because the levels of 5-FU generated by this system are 10 to 30 times that associated with systemic administration of 5-FU. The incorporation of 5-FU into mRNA at these high levels is sufficient to disrupt mRNA processing and protein synthesis so that even nondividing cells die of protein starvation. To test if the CD adenoviral vector sensitizes breast cancer cells to 5-FC, we exposed primary explants of normal human mammary epithelial cells (HMECs) and the established breast cancer cell (BCC) lines MCF-7 and MDA-MB-453 to the Ad.CMV-CD for 90 minutes. This produced a 100-fold sensitization of these epithelial cells to the effects of 48 hours of exposure to 5-FC. We next tested the selectivity of this system for BCC. When peripheral blood mononuclear cells (PBMCs), collected from cancer patients during the recovery phase from conventional dose chemotherapy-induced myelosuppression, were exposed to the Ad.CMV-CD for 90 minutes in serum-free conditions, little or no detectable conversion of 5-FC into 5-FU was seen even after 48 hours of exposure to high doses of 5-FC. In contrast, 70% of 5-FC was converted into the cytotoxic agent 5-FU when MCF-7 breast cancer cells (BCCs) were exposed to the same Ad.CMV-CD vector followed by 5-FC for 48 hours. All of the BCC lines tested were shown to be sensitive to infection by adenoviral vectors when exposed to a recombinant adenoviral vector containing the reporter gene betagalactosidase (Ad.CMV-βgal). In contrast, less than 1% of the CD34-selected cells and their more immature subsets, such as the CD34+CD38− or CD34+CD33− subpopulations, were positive for infection by the Ad.CMV-βgal vector, as judged by fluorescence-activated cell sorting (FACS) analysis, when exposed to the adenoviral vector under conditions that did not commit the early hematopoietic precursor cells to maturation. When artificial mixtures of hematopoietic cells and BCCs were exposed for 90 minutes to the Ad.CMV-CD vector and to 5-FC for 10 days or more, a greater than 1 million fold reduction in the number of BCCs, as measured by colony-limiting dilution assays, was observed. To test if the conditions were damaging for the hematopoietic reconstituting cells, marrow cells collected from 5-FU–treated male donor mice were incubated with the cytosine deaminase adenoviral vector and then exposed to 5-FC either for 4 days in vitro before transplantation or for 14 days immediately after transplantation in vivo. There was no significant decrease in the reconstituting capability of the male marrow cells, as measured by their persistence in female irradiated recipients for up to 6 months after transplantation. These observations suggest that adenovirus-mediated gene transfer of the Escherichia coli cytosine deaminase gene followed by exposure to the nontoxic pro-drug 5-FC may be a potential strategy to selectively reduce the level of contaminating BCCs in collections of hematopoietic cells used for autografts in breast cancer patients.

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“…Οι ουσίες αυτές προσλαµβάνονται εκλεκτικά από τα κακοήθη κύτταρα και παρουσία οξυγόνου εκτείθενται σε φως κατάλληλου µήκους κύµατος που διεγείρει τα µόρια της χρωστικής µε αποτέλεσµα την επαγωγή µιας ποικιλίας φωτοχηµικών αντιδράσεων που οδηγούν σε κυτταρική καταστροφή [191][192][193]. (multi-drug resistant) που εκφράζουν το γονίδιο της P-γλυκοπρωτεΐνης [197,198].…”

Section: φωτο∆υναμικη θεραπειαunclassified

“…Αξίζει να σηµειωθεί, ότι η Φ∆Θ φαίνεται να πλεονεκτεί έναντι των καρκινικών κυττάρων που εκφράζουν πολυφαρµακευτική αντοχή (γονίδιο MDR) [197,198]. Οργανισµό Φαρµάκων το 1996.…”

Section: εγκέφαλοςunclassified

“…Έχει χρησιµοποιηθεί για την προστασία από την καρδιοτοξικότητα από ανθρακυκλίνες [328]. [197,198,393]. Παρά την εκλεκτικότητα της µεθόδου, παρατηρείται κάποιου βαθµού τοξική επίδραση στα φυσιολογικά αιµοποιητικά προγονικά κύτταρα [298,300].…”

Section: ∆εξραζοξάνη (Icrf-187)unclassified

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Φωτοδυναμική Θεραπεία Στην Κάθαρση Νεοπλασματικών Κυττάρων Από Το Μυελό Και Το Περιφερικό Αίμα Παιδιών Με Κακοήθειες

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Dye-mediated photolysis is capable of eliminating drug-resistant (MDR+) tumor cells

Cited by 9 publications

References 21 publications

Reversal of doxorubicin resistance in breast cancer cells by photochemical internalization

Reversal of doxorubicin resistance in breast cancer cells by photochemical internalization

Cytosine Deaminase Adenoviral Vector and 5-Fluorocytosine Selectively Reduce Breast Cancer Cells 1 Million-Fold When They Contaminate Hematopoietic Cells: A Potential Purging Method for Autologous Transplantation

Φωτοδυναμική Θεραπεία Στην Κάθαρση Νεοπλασματικών Κυττάρων Από Το Μυελό Και Το Περιφερικό Αίμα Παιδιών Με Κακοήθειες

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