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.

The Selective Uptake of Benzoporphyrin Derivative Mono‐Acid Ring A Results in Differential Cell Kill of Multiple Myeloma Cells in vitro

“…As shown, BPD-MA ha5 relatively little effect upon stem cells in vitm. However, the efficacy of BPD-MA against multidrug-resistant cells is low when compared to Photofrin@ (51). At the concentration of BPD-MA that killed 100% OCI-MY7, over 90% of stem cells (CD34') cells survived.…”

Selective elimination of malignant stem cells using photosensitizers followed by light treatment

“…One potential advantage of photodynamic purging of hemopoietic cell: with PHOTOFRIN@ was pointed out by Lemoli et al [20]. They showed that the presence of the multidrug resistance marker (MDR') on two human leukemic cell lines (HL-60/RV and CEM/VBL) did not increase their resistance to PDT with PHOTOFRIN@.…”

“…Similar selectivity with B P D was noted in experiments comparing normal progenitor survival with survival of leukemic blast progenitors from patients with AML. In these studies, in which medium contained 1% fetal calf serum (FCS) at all times, a 3 log reduction (limit of detection) was seen under conditions in which fewer than 50% of normal progenitors were eliminated [20].…”