Anti-cancer drugs
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15-Deoxy-Delta-prostaglandin J2 is a naturally occurring endogenous ligand for peroxisome proliferator-activated receptor-gamma. The current study was aimed to determine the mechanism of anti-proliferative effect of 15-deoxy-Delta-prostaglandin J2+docetaxel against A549 and H460 non-small-cell lung cancer cell lines and xenograft tumors. In-vitro cytotoxicity of 15-deoxy-Delta-prostaglandin J2 alone and in combination with docetaxel was studied against A549 and H460 cell lines. ⋯ Isobolographic analysis demonstrated synergistic interaction (combination index <1.0) between 15-deoxy-Delta-prostaglandin J2 and docetaxel against A549 and H460 cells in vitro. 15-Deoxy-Delta-prostaglandin J2+docetaxel significantly reduced the tumor volume compared with control (P<0.05), 15-deoxy-Delta-prostaglandin J2 (P<0.05) and docetaxel (P<0.05, P<0.01) in both A549 and H460 tumors. 15-Deoxy-Delta-prostaglandin J2+docetaxel showed a significant increase in apoptosis associated with inhibition of the Bcl2 and cyclin D1 expression and overexpression of caspase and p53 pathway genes. Further, enhanced expression of caspase 3 and inhibition of cyclin D1 by 15-deoxy-Delta-prostaglandin J2+docetaxel was not reversed by GW9662, thus suggesting a possible peroxisome proliferator-activated receptor-gamma-independent mechanism. In conclusion, 15-deoxy-Delta-prostaglandin J2 enhanced the anti-tumor action of docetaxel by peroxisome proliferator-activated receptor-gamma-dependent and -independent mechanisms mediated by induction of apoptosis.
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We studied the pharmacokinetics and clinical outcome of a new once-daily intravenous area under the curve-targeted dosing scheme for busulfan based on body surface area. Eighteen children undergoing busulfan-based conditioning for allogeneic stem cell transplantation were enrolled. The age of the children ranged from 0.5 to 16 years. ⋯ We conclude that intravenous busulfan in children administered once daily is safe, convenient and feasible, and can be dosed surface-based, independent of age. There was very limited (liver) toxicity, but the rejection rate was relative high, which can be probably overcome by a higher exposure to busulfan. Future investigations should be aimed at further optimizing the target area under the curve of intravenous busulfan for specific patient groups.
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Aromatase inhibitors have become well established for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and for adjuvant hormonal therapy for primary breast cancer. Benefit of aromatase inhibition has not yet been extended to premenopausal women. Ovarian ablation by oophorectomy, ovarian radiation or hormonal suppression is the initial recommended treatment for hormone receptor-positive metastatic breast cancer in premenopausal women. ⋯ One patient remained free of progression for 4 years, while the other two remained free of progression for more than 5 and 3 years, respectively. We also note that monthly zoledronic acid for 4 years produced sclerosis of vertebral body metastasis. We conclude that combined ovarian ablation and aromatase inhibition is a feasible treatment modality that deserves more attention and further investigation for hormone receptor-positive metastatic breast cancer in premenopausal women.
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Oxaliplatin (OXA) and irinotecan (IRI) are active drugs for metastatic colorectal cancer, their toxicity profiles are not overlapping, and both drugs have shown at least additivity with folinic acid-modulated 5-fluorouracil (5FU). We carried out this phase II study to assess the activity and toxicity of a biweekly regimen including OXA plus IRI on day 1, and levo-folinic acid (LFA) plus 5FU on day 2 (OXIRIFAFU) in pretreated patients with metastatic colorectal cancer. Forty-one patients, all previously treated with adjuvant and/or palliative 5FU-based chemotherapy (16 of them already exposed to IRI, OXA or both), were enrolled into this trial. ⋯ Median overall survival was 14.4 (95% CI, 10.4-18.4) months from the start of OXIRIFAFU and 25.3 (95% CI, 18.1-32.5) months from the diagnosis of metastatic disease. This OXIRIFAFU triplet regimen was highly effective in resistant/refractory colorectal cancer patients. A slight dose reduction of all cytotoxic drugs could be advisable in order to improve the tolerability of this regimen without jeopardizing its activity.
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Cantharidin is a natural toxin that possesses potent anti-tumor properties. Its clinical application, however, is limited due to severe side-effects. Its cytotoxicity is believed to be mediated by the inhibition of serine/threonine protein phosphatase 2A. ⋯ Accordingly, analogue 13 exhibited potent inhibitory activity on protein phosphatase 2A, and analogues 9, 11 and 12 showed weak inhibitory activity, while other analogues did not show any inhibitory activity. The findings indicate that the cytotoxicity of synthetic cantharidin analogues is likely to be associated with their protein phosphatase 2A inhibitory activity. The mode of inhibition of cantharidin and analogue 13 on protein phosphatase 2A is identified as noncompetitive inhibition by the Lineweaver-Burk plot.