Primary malignant pulmonary hemangiopericytoma.

A primary malignant pulmonary hemangiopericytoma was diagnosed in a 45-year-old woman who complained of 10 months of cough and exertional dyspnea. One year after resection of the mass, a metastatic lesion was removed from the contralateral lung. The literature on this unusual pulmonary lesion is reviewed.

Organ-specific biotransformation of ormaplatin in the Fischer 344 rat.

We examined the intracellular biotransformation products of ormaplatin [(d,l-trans)1,2-diaminocyclohexanetetrachloroplatinum(IV)] (formerly called tetraplatin) in liver, kidney, spleen, small intestine, and plasma of the adult male Fischer 344 rat. Previous studies have established that the rank order of ormaplatin toxicity in Fischer 344 rats is spleen approximately gastrointestinal tract > kidney >> liver. Animals were given tritium-labelled drug i.v. at 12.5 mg/kg, and tissues were harvested 30 min later. The kidney was found to concentrate total and cytosolic platinum to a greater extent than any of the other tissues. The absolute amount of cytosolic platinum, in micrograms per gram tissue, that was irreversibly bound to protein and/or other macromolecules was also greatest in the kidney. However, when the amount bound was expressed as a percentage of the total cytosolic platinum, the kidney was significantly lower than any other tissue. Of the various low molecular mass platinum biotransformation species characterized, by far the most abundant were complexes of platinum with the sulfur-containing molecules cysteine, methionine, and glutathione (GSH). There was more of the methionine complex in the blood plasma than in any of the tissues except for the spleen. No significant differences among the tissues were detected for the dichloro, cysteine, methionine, or the GSH complexes. The tritium-labelled diaminocyclohexane (DACH) carrier ligand appeared to remain stably bound to the platinum while in the plasma, as there was less free DACH ligand detected in plasma ultrafiltrate than in any tissue ultrafiltrate. Among the tissues, the free DACH levels were in the range of 20% of the radioactivity recovered from the HPLC column and were not significantly different. Consequently, neither biodistribution nor tissue-specific biotransformation of ormaplatin provides a ready explanation for the tissue specificity of ormaplatin toxicity in Fischer 344 rats. However, in kidney there was much less of the reactive PtCl2(DACH) species than has previously been reported for the corresponding Pt(NH3)2Cl2 species in cisplatin-treated rats. Thus, these data suggest a possible explanation for differences in nephrotoxicity induced by cisplatin versus that by ormaplatin.

In vitro interaction of liposomal valinomycin and platinum analogs: cytotoxic and cytokinetic effects.

Cisplatin is the most active agent in the chemotherapy of ovarian cancer and this activity can be enhanced by liposomal valinomycin (MLV-VM) in vitro. To test whether MLV-VM is capable of augmenting the cytotoxic and cytokinetic effects of other platinum analogs, drug combinations of MLV-VM and platinum drugs were tested against two human ovarian cancer cell lines (OVCAR-3 and CaOV-3) and on Chinese hamster ovary (CHO) cells in vitro. MLV-VM enhanced the sensitivity to cisplatin, ormaplatin and carboplatin on human ovarian carcinoma cells that show various degrees of drug sensitivity. This interaction was shown to be truly synergistic by median-effect analysis up to 90% cell kill. The combination index at 50% cell kill (Cl50) was also used to quantitate the extent of drug synergy. In the OVCAR-3 cell line, for example, the Cl50s were 0.62, 0.85 and 0.8 for cisplatin, ormaplatin and carboplatin, respectively. DNA histograms obtained by flow cytometry showed that CHO cells treated with cisplatin alone accumulated in the S-G2 segment, with a partial G2 block. The addition of 2 microM VM with cisplatin, significantly enhanced the accumulation of cells at the G2/M phase. Our results further demonstrate that in vitro treatment with VM, cisplatin and/or combination is associated with an increase in protein kinase C (PKC) activity. These findings suggest that accumulation of cells at G2/M phases and modulation of PKC activity could be among the basis for the cytotoxic synergism observed between cisplatin and VM.