title: Dye-mediated photolysis is capable of eliminating drug-resistant (MDR+) tumor cells.
abstract: We evaluated the potential role of photoradiation therapy with a benzoporphyrin derivative, monoacid ring A (BPD-MA), and dihematoporphyrin ether (DHE), for the ex vivo purging of residual tumor cells from autologous bone marrow (BM) grafts. BPD-MA and DHE photosensitizing activity was tested against two human large-cell lymphoma cell lines and colony-forming unit-leukemia (CFU-L) derived from patients with acute myelogenous leukemia (AML). In mixing experiments, 4-log elimination of tumor cell lines was observed after 1 hour of incubation with 75 ng/mL of BPD-MA or 30 minutes of treatment with 12.5 micrograms/mL of DHE followed by white light exposure. By comparison, using the same concentration of BPD-MA, the mean recovery of normal BM progenitors was 4% +/- 0.8% (mean +/- SD) for granulocyte-macrophage colony-forming unit (CFU-GM) and 5% +/- 0.8% for burst-forming unit-erythroid (BFU-E). Similarly, DHE treatment resulted in the recovery of 5.2% +/- 2% and 9.8% +/- 3% of CFU-GM and BFU-E, respectively. Furthermore, equivalently cytotoxic concentrations of both DHE and BPD-MA and light were found not to kill normal pluripotent stem cells in BM, as demonstrated by their survival in two-step long-term marrow culture at levels equal to untreated controls. The T-lymphoblastic leukemia cell line CEM and its vinblastine (VBL)-resistant subline CEM/VBL, along with the acute promyelocyte leukemia cell line HL-60 and its vincristine (VCR)-resistant subline HL-60/VCR, were also tested. BPD-MA at 75 ng/mL was able to provide a greater than 4-log elimination of the drug-sensitive cell lines, but only a 34% and 55% decrease of the drug-resistant HL-60/VCR and CEM/VBL cell lines, respectively. On the contrary, 12.5 micrograms/mL of DHE reduced the clonogenic growth of all the cell lines by more than 4 logs. Further experiments demonstrated decreased uptake of both BPD-MA and DHE by the resistant cell lines. However, all the cell lines took up more DHE than BPD-MA under similar experimental conditions. Our results demonstrate the preferential cytotoxicity of BPD-MA and DHE toward neoplastic cell lines and CFU-L from AML patients. In addition, DHE was slightly more effective in purging tumor cells expressing the p-170 glycoprotein. These results suggest that photoradiation with DHE would be useful for in vitro purging of residual drug-resistant leukemia and lymphoma cells.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
authors.forename: R M
authors.initials: RM
authors.lastname: Lemoli
authors.forename: T
authors.initials: T
authors.lastname: Igarashi
authors.forename: M
authors.initials: M
authors.lastname: Knizewski
authors.forename: L
authors.initials: L
authors.lastname: Acaba
authors.forename: A
authors.initials: A
authors.lastname: Richter
authors.forename: A
authors.initials: A
authors.lastname: Jain
authors.forename: D
authors.initials: D
authors.lastname: Mitchell
authors.forename: J
authors.initials: J
authors.lastname: Levy
authors.forename: S C
authors.initials: SC
authors.lastname: Gulati
mesh_terms: D001853:Bone Marrow / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects*; D017323:Dihematoporphyrin Ether / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006801:Humans; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D015473:Leukemia, Promyelocytic, Acute; D016393:Lymphoma, B-Cell; D016403:Lymphoma, Large B-Cell, Diffuse; D010782:Photolysis; D011166:Porphyrins / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D011166:Porphyrins; D011838:Radiation-Sensitizing Agents; C504224:benzoporphyrin D; D017323:Dihematoporphyrin Ether