Efficacy of benzoporphyrin derivative, a photosensitizer, in selective destruction of leukemia cells using a murine tumor model.
The ability of a photosensitizer, benzoporphyrin derivative monoacid ring A (BPD), and light to selectively kill leukemic cells in comparison to normal hemopoietic progenitors was investigated using a murine model, the L1210 tumor of DBA/2 mice. In vitro experiments indicated that treatment of cells with BPD and light effected a 5 to 6 log reduction of clonogenic L1210 cells under conditions which caused less than a 1 log reduction of committed myeloid progenitors, determined by colony-forming cells. This apparent therapeutic window was tested in vivo using lethally irradiated DBA/2 mice hematopoietically reconstituted with 10(6) syngeneic donor splenocytes or 5 x 10(5) bone marrow cells mixed with L1210 cells and treated with BPD and light. Reconstitution with 10(6) splenocytes resulted in successful engraftment of approximately 50% of recipients, indicating that these conditions provided limiting numbers of essential stem cells. The minimum tumor-eliciting dose was determined to be between 10(1) and 10(2) L1210 cells. Experiments in which 10(6) splenocytes were mixed with 10(6) L1210 cells and treated with BPD and light demonstrated that at 100 ng/mL of BPD and a specified light dose (5.4 joules [J]/cm2), 50% of recipients underwent successful engraftment and did not develop leukemic ascites. Animals that died under this regimen died from failure to engraft rather than from tumor burden. These results establish that this approach can effectively lower tumor burden by 4 logs with virtually no loss of essential hemopoietic progenitors. Similar results were obtained when animals received bone marrow rather than splenocytes.
Department of Microbiology, University of British Columbia, Vancouver, Canada.
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Jamieson
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Richter
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Levy
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D016465:Bone Marrow Purging; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007939:Leukemia L1210 / Q000473:pathology*; D008027:Light; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D011166:Porphyrins / Q000494:pharmacology* / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013154:Spleen / Q000473:pathology; D014407:Tumor Cells, Cultured
D011166:Porphyrins; D011838:Radiation-Sensitizing Agents; C504224:benzoporphyrin D