Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Interaction of platinum complexes of thiazin and xanthene dyes with hyperthermia. 234 38

Complexes of the tetrachoroplatinum(II) dianion with positively charged nuclear dyes were prepared in an effort to produce agents which gain ready access into the nucleus and become very cytotoxic at clinically relevant hyperthermia temperatures. Pt(Nile blue)2 and Pt(neutral red)2 are complexes of tetrachloroplatinum(II) with two closely related p-quinonediamine dyes. Pt(Nile blue)2 and Pt(neutral red)2 were only moderately cytotoxic to exponentially growing normally oxygenated or hypoxic EMT6 cells in vitro at pH 7.40 and 37 degrees C. At pH 7.40 and 42 degrees C and especially at 43 degrees C, however, Pt(Nile blue)2 became far more cytotoxic. At pH 6.45 Pt(Nile blue)2 became more toxic toward hypoxic cells (cell kill of 3.5 logs at 500 microM, 42 degrees C for 1 h). Pt(neutral red)2 became much more cytotoxic at pH 6.45 and 42 degrees C or 43 degrees C compared to pH 7.4, and the cell kill observed was similar in both euoxic and hypoxic cells (3 logs at pH 6.45, 43 degrees C with only 100 microM). Tumor cell survival studies in the FSaIIC murine fibrosarcoma demonstrated that both drugs killed in a dose-dependent log-linear manner. Hyperthermia treatment (43 degrees C, 30 min) immediately after either drug resulted in a dose modifying effect. The tumor growth delay produced by Pt(Nile blue)2 (100 mg/kg) was 4.6 days and by Pt(neutral red)2 (100 mg/kg) was 3.8 days. Both drugs were markedly improved by hyperthermia (tumor growth delay 1.4 days for hyperthermia; tumor growth delay 10.9 days for Pt(Nile blue)2 and 8.0 days for Pt(neutral red)2. Intracellular platinum levels were approximately 200 times higher after exposure of EMT6 cells to 25 microM of Pt(Nile blue)2 or Pt(neutral red)2 for 1 h at 37 degrees C than after exposure to the same concentration of cis-diamminedichloroplatinum(II). Treatment of cells with the drugs at 42 degrees C (1 h) resulted in no change in platinum levels with cis-diamminedichloroplatinum(II), but with Pt(Nile blue)2 and Pt(neutral red)2 an increase of 2- to 3-fold was found. Since previous work has shown that both of these complexes are active radiosensitizing agents, these new drugs seem quite well suited for further development as antitumor agents for use against solid tumors alone and in conjunction with hyperthermia and/or radiation therapy.
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PMID:Interaction with hyperthermia of tetrachloroplatinum(II)(Nile blue)2 and tetrachloroplatinum(II)(neutral red)2 in EMT6 murine cells and the murine FSaIIC fibrosarcoma. 235 34

A new complex of tetrachloroplatinum(II) and the azoic diazo dye, Fast Black K, Pt(Fast Black)2, was made in an attempt to produce an uncharged molecule which could readily gain access into cells and could bring a high concentration of tetrachloroplatinum into the vicinity of the DNA. Even the lowest concentration of Pt(Fast Black)2 tested in the superhelical pBR322 plasmid DNA assay in vitro completely converted the superhelical DNA to the circular and linear forms by 24 h. When the cytotoxicity of the Pt(Fast Black)2 and Fast Black were tested in exponentially growing EMT6 cells. Pt(Fast Black)2 was slightly more toxic to normally oxygenated than to hypoxic cells at pH 7.40, but was far more toxic to cells at pH 6.45 with no difference based on cellular oxygenation. Fast Black was much less toxic than Pt(Fast Black)2 and its cytotoxicity was unaffected by pH. Pt(Fast Black)2 had a small radiosensitizing effect on hypoxic EMT6 cells with a dose-modifying factor of 1.3, but exposure to the drug entirely removed the shoulder region on the radiation survival curves for both the oxygenated and hypoxic cells. In contrast, Fast Black reduced the shoulder in hypoxic but not in oxygenated cells. When Pt(Fast Black)2 (500 mg/kg), Fast Black (300 mg/kg) (the maximally tolerated dose), or misonidazole (1 g/kg) were given intraperitoneally 15 min prior to irradiation of FSaIIC tumors with 0, 10, 20, or 30 Gy, Pt(Fast Black)2 alone caused a tumor growth delay of 6 days versus 3 days for Fast Black. With radiation, Pt(Fast Black)2 produced the greatest enhancement in tumor growth delay of the drugs tested, especially at the lowest (10 Gy) radiation dose (i.e., in the in vivo "shoulder region"). These results indicate that Pt(Fast Black)2 may be suitable for clinical development because it causes both significant direct cytotoxicity and enhancement of radiation killing. The fact that its cytotoxicity is markedly increased at an acidic pH and its radiation enhancing effects are greatest in combination with relatively low single-fraction radiation doses make it especially interesting. The cytotoxicity of Pt(Fast Black)2 may be influenced by the tumor environment, and the radiosensitizing properties appear well suited for use with radiation fraction sizes that are employed in the clinic.
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PMID:Interaction of platinum(II) tetrachlorodianion (Fast Black)2 with superhelical DNA and with radiation in vitro and in vivo. 275 4