Photochemically generated elemental selenium forms conjugates with serum proteins that are preferentially cytotoxic to leukemia and selected solid tumor cells.
The objective of this study was to determine if and how photoproducts contribute to the antitumor effect of merocyanine-mediated PDT. A panel of barbituric, thiobarbituric and selenobarbituric acid analogues of Merocyanine 540 was photobleached, and the resulting photoproducts were characterized by absorption, fluorescence emission, mass, energy dispersive X-ray, and X-ray photoelectron spectroscopy and tested for cytotoxic activity against tumor cell lines and freshly explanted bone marrow cells. While all dyes were readily photobleached, only photoproducts of selone dyes showed cytotoxic activity. One-hour incubations with micromolar concentrations of selone-derived photoproducts were sufficient to reduce leukemia/lymphoma cells ≥10 000 fold, whereas preserving virtually all normal CD34-positive bone marrow cells. Of six multidrug-resistant tumor cell lines tested, five were as sensitive or more sensitive to photoproducts than the corresponding wild-type lines. Physicochemical characterizations of the cytotoxic activity indicated that it consisted of conjugates of subnano particles of elemental selenium and (lipo)proteins. The discovery of cytotoxic Se-protein conjugates provides a rare example of photoproducts contributing substantially to the antitumor effect of PDT and challenges the long-held view that Se in oxidation state zero is biologically inert. Agents modeled after our Se-protein conjugates may prove useful for the treatment of leukemia.
Department of Pediatrics, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA.
Jean-Pierre
JP
Daziano
Wolfgang H H
WH
Günther
Marianne
M
Krieg
Ichiro
I
Tsujino
Kiyoko
K
Miyagi
Gregory S
GS
Anderson
Reynée W
RW
Sampson
Martin D
MD
Ostrowski
Sarah A
SA
Muir
Raymond J
RJ
Bula
Fritz
F
Sieber
D001463:Barbiturates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008027:Light; D008074:Lipoproteins / Q000737:chemistry / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D055668:Photochemical Processes; D010778:Photochemotherapy; D056951:Photoelectron Spectroscopy; D017319:Photosensitizing Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D018036:Selenium Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D001463:Barbiturates; D008074:Lipoproteins; D017319:Photosensitizing Agents; D011744:Pyrimidinones; D018036:Selenium Compounds; C003954:merocyanine dye