Interaction of platinum complexes of thiazin and xanthene dyes with hyperthermia

Terence S. Herman, Beverly A. Teicher, M. Raphael Pfeffer, Vrinda S. Khandekar, Enrique Alvarez Sotomayor

Resultado de la investigación: Articlerevisión exhaustiva

6 Citas (Scopus)

Resumen

In an attempt to develop platinum-containing drugs for use with hyperthermia that would be relatively nontoxic at 37° C but would become very cytotoxic at 42° or 43° 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°, 42°, and 43° 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° and 43° 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° 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 μM of drug for 1 h at 37° and 42° 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° 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°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.

Idioma originalEnglish (US)
Páginas (desde-hasta)127-134
Número de páginas8
PublicaciónCancer chemotherapy and pharmacology
Volumen26
N.º2
DOI
EstadoPublished - may. 1990
Publicado de forma externa

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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