Phase 1 study of pazopanib alone or combined with lapatinib in Japanese patients with solid tumors.

PURPOSE: A phase 1 study of pazopanib alone or in combination with lapatinib was conducted to assess the safety, tolerability, and pharmacokinetics of these oral tyrosine kinase inhibitors in Japanese patients with solid tumors. METHODS: In part A (monotherapy), 7 patients initially received pazopanib 800 mg/day, the recommended dose for non-Japanese patients. Then, 3 patients received pazopanib 400 mg/day on day 1 followed by 800 mg/day from day 2 onward. Three other patients received pazopanib 1,000 mg/day. In part B (combination therapy), 17 patients received pazopanib plus lapatinib (pazopanib/lapatinib) at once-daily doses of 400/1,000 mg (4 patients), 800/1,000 mg (3 patients), 400/1,500 mg (3 patients), and then 600/1,250 mg (7 patients). RESULTS: There was no dose-limiting toxicity during the study. In part A, most drug-related adverse events were grade 2 or lower, including neutropenia/neutrophil count decreased, thrombocytopenia/platelet count decreased, diarrhea, hypertension, aspartate aminotransferase increased, and lipase increased. In part B, rash, decreased appetite, and serum thyroid-stimulating hormone increased also occurred. In all dose groups, the plasma concentrations after multiple doses of pazopanib exceeded the target trough concentration for inhibition of vascular endothelial growth factor receptor-2 activity (20 µg/mL). CONCLUSIONS: The pharmacokinetic profiles of pazopanib and lapatinib in Japanese patients were not apparently different from those reported in non-Japanese patients. There were no consistent trends in pharmacokinetic drug interactions between pazopanib and lapatinib. Pazopanib monotherapy at 800 and 1,000 mg once daily and pazopanib plus lapatinib once daily at any doses studied were well tolerated in Japanese patients.

Group IIA secretory phospholipase A2 is a unique 12/15-lipoxygenase-regulated gene in cytokine-stimulated rat fibroblastic 3Y1 cells.

We have proposed previously that the expression of group IIA secretory phospholipase A(2) (sPLA(2)-IIA), an enzyme implicated in inflammation, is under the control of group IVA cytosolic phospholipase A(2) (cPLA(2)) and 12/15-lipoxygense (12/15-LOX) in cytokine-stimulated rat fibroblastic 3Y1 cells. Here, we show that the reduction of cytokine-stimulated sPLA(2)-IIA induction by the cPLA(2) inhibitor arachidonyl trifluoromethyl ketone (AACOCF(3)) is partially overcome by the addition of various lysophospholipids, such as lysophosphatidylcholine (LysoPC). Furthermore, this lysophospholipid effect was enhanced by further addition of 12/15-LOX products, such as 12(S)- or 15(S)-hydroxyeicosatetraenoic acid (HETE) and 13(S)-hydroxyoctadecadienoic acid (HODE), thus substantiating the hypothesis that the expression of sPLA(2)-IIA is selectively regulated by lipid products of the cPLA(2)-12/15-LOX pathway. In an attempt to identify a set of 12/15-LOX-regulated genes, the cDNA subtraction technique, followed by Northern blotting, was performed to screen particular clones, the expression of which was suppressed by the LOX inhibitor nordihydroguaiaretic acid (NDGA). NDGA-sensitive clones identified thus far included sPLA(2)-IIA, cytoplasmic signaling intermediates, several oxygenases, extracellular matrices, secretory proteins, and other cellular proteins. Of these genes, however, only the expression of sPLA(2)-IIA and 14-3-3eta was enhanced by 12/15-LOX expression. Taken together, our data suggest that sPLA(2)-IIA represents a particular group of genes, the transcription of which is up-regulated by 12/15-LOX metabolites.