This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Teicher, B. A. Articles by Khandekar, V. S. Search for Related Content PubMed PubMed Citation Articles by Teicher, B. A. Articles by Khandekar, V. S.

Interaction of PtCl₄(Fast Black)₂ with Hyperthermia¹

Dana-Farber Cancer Institute [B. A. T., T. S. H., M. R. P., E. A. S., V. S. K.] and Joint Center for Radiation Therapy [T. S. H., M. R. P.], Boston, Massachusetts 02115

We are developing complexes of negatively charged PtCl₄ with positively charged nuclear dyes as new antitumor agents for use alone and in conjunction with hyperthermia and/or radiation. Elemental analysis has shown that the complex PtCl₄(Fast Black)₂ is a tight ion pair. In experimentally growing EMT6 cells in vitro, PtCl₄(Fast Black)₂ killed cells in a log-linear manner which increased as the temperature of the exposures was increased from 37 to 42°C or 43°C. In addition, cell kill was also increased under conditions of low pH (6.45), especially in hypoxic cells treated at elevated temperature. Measurement of intracellular platinum levels after exposure to 25 µM cisplatin or PtCl₄(Fast Black)₂ demonstrated that platinum levels were between 170- and 200-fold higher after exposure to PtCl₄(Fast Black)₂. In vivo studies in the FSaIIC murine fibrosarcoma showed, again, that PtCl₄(Fast Black)₂ killed in a log-linear manner. Treatment of tumors placed in the thigh with 43°C, 30-min hyperthermia immediately following i.p. injection of PtCl₄(Fast Black)₂ was dose modifying. One hundred mg/kg of PtCl₄(Fast Black)₂ produced a 4.6-day tumor growth delay which increased to 6.4 days with 43°C, 30-min hyperthermia (growth delay for hyperthermia alone was 1.4 days), and 500 mg/kg produced a 5.6-day delay which increased to 11.0 days with hyperthermia. In contrast, cisplatin (5 mg/kg) produced a 4.4-day delay which increased to 5.9 days with hyperthermia. PtCl₄(Fast Black)₂ was well tolerated by animals, and the maximally tolerated dose was approximately 650 mg/kg. This new complex appears quite active as an antitumor agent alone and in conjunction with hyperthermia, and, since other studies have shown it to interact positively with radiation, this agent seems a very appropriate candidate for further development as a clinical anticancer drug.

¹ This work was supported by NIH Grants RO1-36508 (B. A. T.) and RO1-CA47379 (T. S. H.).

² To whom requests for reprints should be addressed.

Received 4/20/89. Revised 8/11/89. Accepted 8/18/89.