Interaction with hyperthermia of platinum complexes of triaminotriphenylmethane dyes.
Complexes of the tetrachloroplatinum(II) dianion PtCl4 with positively charged nuclear dyes have been designed in an effort to create new anticancer drugs for use with hyperthermia and/or radiation. The PtCl4 complexes with the monocationic triaminotriphenylmethane dye basic fuchsin [Pt(basic fuchsin)2] and the dicatrionic triaminotriphenylmethane dye methyl green [Pt(methyl green)], as well as the free dyes, were tested in exponentially growing EMT6 cells in vitro. Both the platinum complexes and free dyes were only moderately cytotoxic at pH 7.40 and 37 degrees C in normally oxygenated and hypoxic cells where cell killing by these drugs ranged from 0.5 to 1.5 logs at 500 microM. Each agent, however, became more cytotoxic at hyperthermic temperatures and pH 7.40. Pt(methyl green) and Pt(basic fuchsin)2 were slightly more cytotoxic to euoxic as opposed to hypoxic cells. Both platinum complexes became even more cytotoxic at pH 6.45 and 43 degrees C. Under these conditions, Pt(basic fuchsin)2 killed more hypoxic than euoxic cells (4.5 versus 2.5 logs at 500 microM), but Pt(methyl green) killed more euoxic than hypoxic cells (4.5 versus 2.5 logs at 100 microM). Methyl green was less cytotoxic than Pt(methyl green) at pH 6.45 and 43 degrees C, but basic fuchsin was the most cytotoxic drug under these conditions (cell kill of 3.5 logs in both euoxic and hypoxic cells at 100 microM). Intracellular platinum levels measured after 1 h exposure to 25 microM cisplatin, K2PtCl4, PT(methyl green), and PT(basic fuchsin)2 showed that approximately 1 ng of platinum per 10(6) cells was present after treatment with CDDP at pH 7.40 and pH 6.45 and at 37 degrees C and 42 degrees C; and approximately 0.2 ng was present after exposure to K2PtCl4 under each of these conditions. After exposure to Pt(methyl green), approximately 2.5 ng of platinum per 10(6) cells at pH 7.40, 37 degrees C, and 42 degrees C were present but increased to about 6.5 ng at pH 6.45 and 42 degrees C. With Pt(basic fuchsin)K, 726 ng of platinum were present at 37 degrees C, pH 7.40; 920 ng at 42 degrees C, pH 7.40; 313 ng at 37 degrees C, pH 6.45; and 413 ng at 42 degrees C, pH 6.45. Since Pt(methyl green) was more cytotoxic to cells at pH 6.45 and 42 degrees C, some of this effect could be attributed to increased uptake under these conditions.(ABSTRACT TRUNCATED AT 400 WORDS)
Herman
T S
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Dana-Farber Cancer Institute, Boston, MA 02115.
Teicher
B A
BA
Pfeffer
M R
MR
Khandekar
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VS
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D006358:Hot Temperature / Q000627:therapeutic use*; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000378:metabolism; D008739:Methyl Green / Q000627:therapeutic use*; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D010984:Platinum / Q000378:metabolism; D012394:Rosaniline Dyes / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D012394:Rosaniline Dyes; C065097:platinum basic fuchsin complex; C065098:platinum methyl green complex; D010984:Platinum; D008739:Methyl Green