In an attempt to develop
platinum-containing drugs for use with
hyperthermia that would be relatively nontoxic at 37 degrees C but would become very cytotoxic at 42 degrees or 43 degrees C, several nuclear
dyes were complexed to the tetrachloroplatinum(II) dianion (
PtCl4) at a ratio of 2:1. The cytotoxicity of
PtCl4 complexes of three thiazin
dyes (
thionin,
azure B, and
methylene blue), the
xanthene dye pyronin Y, and the
thiazole dye thioflavin was examined in exponentially growing euoxic and hypoxic EMT6 cells in vitro at 37 degrees, 42 degrees, and 43 degrees C and at pH 7.40 and 6.45. Of the thiazin
dye complexes, the cytotoxicity of Pt(
methylene blue)2 was most enhanced at hyperthermic temperatures. Both Pt(
pyronin Y)2 and Pt(thioflavin)2 also became markedly more cytotoxic at 42 degrees and 43 degrees C at pH 6.45 vs pH 7.40. In vivo
tumor excision assays in the FSaIIC
fibrosarcoma showed that with each of the thiazin
dye-
platinum complexes,
hyperthermia enhanced cell kill [most effectively on Pt(
methylene blue)2] but was not dose-modifying. For both Pt(
pyronin Y)2 and Pt(thioflavin)2, however, administration of 43 degrees C, 30-min
hyperthermia to the
tumor immediately after i.p.
drug injection was dose-modifying.
Tumor growth delay studies in the FSaIIC
tumor system demonstrated that, as with the in vitro studies, Pt(
pyronin Y)2 and Pt(
methylene blue)2 were most enhanced by
hyperthermia [
tumor growth delay increased by 4.8- and 3.0-fold, respectively, vs only 1.3-fold for
cisplatin (CDDP)]. Examination of intracellular
platinum levels after exposure of EMT6 cells to 25 microM of
drug for 1 h at 37 degrees and 42 degrees C and at pH 7.40 and 6.45 showed that each
platinum-
dye complex achieved
platinum levels that were 100-600 times higher at 37 degrees C and pH 7.40 than those obtained using CDDP. The
platinum levels for each
drug dropped markedly when exposure took place at pH 6.45. Exposure at 42 degrees C only moderately increased
platinum levels in cells exposed to these drugs. Thus, for several of these drugs the level of cytotoxicity observed was in great part independent of the intracellular
platinum levels achieved. Pt(
pyronin Y)2 is an effective
drug for use with
hyperthermia, and further studies using this combination with and without radiation are under way.