Effect of molecular structure on the performance of triarylmethane dyes as therapeutic agents for photochemical purging of autologous bone marrow grafts from residual tumor cells.
Extensively conjugated cationic molecules with appropriate structural features naturally accumulate into the mitochondria of living cells, a phenomenon typically more prominent in tumor than in normal cells. Because a variety of tumor cells also retain pertinent cationic structures for longer periods of time compared with normal cells, mitochondrial targeting has been proposed as a selective therapeutic strategy of relevance for both chemotherapy and photochemotherapy of neoplastic diseases. Here we report that the triarylmethane dye crystal violet stains cell mitochondria with efficiency and selectivity, and is a promising candidate for photochemotherapy applications. Crystal violet exhibits pronounced phototoxicity toward L1210 leukemia cells but comparatively small toxic effects toward normal hematopoietic cells (murine granulocyte-macrophage progenitors, CFU-GM). On the basis of a comparative examination of chemical, photochemical, and phototoxic properties of crystal violet and other triarylmethane dyes, we have identified interdependencies between molecular structure, and selective phototoxicity toward tumor cells. These structure-activity relationships represent useful guidelines for the development of novel purging protocols to promote selective elimination of residual tumor cells from autologous bone marrow grafts with minimum toxicity to normal hematopoietic stem cells.
Indig
G L
GL
School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin, Madison, WI 53706, USA. glindig@facstaff.wisc.edu
Anderson
G S
GS
Nichols
M G
MG
Bartlett
J A
JA
Mellon
W S
WS
Sieber
F
F
D000818:Animals; D016465:Bone Marrow Purging / Q000379:methods*; D004396:Coloring Agents / Q000493:pharmacokinetics / Q000633:toxicity; D005840:Gentian Violet / Q000493:pharmacokinetics / Q000633:toxicity; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007939:Leukemia L1210; D015471:Leukemia, Basophilic, Acute; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018365:Neoplasm, Residual; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000633:toxicity; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D012394:Rosaniline Dyes / Q000493:pharmacokinetics / Q000633:toxicity; D014407:Tumor Cells, Cultured
D004396:Coloring Agents; D017319:Photosensitizing Agents; D000644:Quaternary Ammonium Compounds; D012394:Rosaniline Dyes; C084160:Victoria blue BO; C034887:ethyl violet; D005840:Gentian Violet