BACKGROUND: Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. METHODS: A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. RESULTS: CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC₅₀ values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC₅₀ values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CONCLUSIONS: CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.

published_or_final_version / abstract / Clinical Oncology / Doctoral / Doctor of Philosophy

No description available.

No description available.

O resveratrol (Res), um polifenol presente no vinho tinto, é conhecido por possuir potente atividade antioxidante. O efeito do resveratrol (Res) frente à nefrotoxicidade do antineoplásico cisplatina (cDDP) foi avaliado em ratos neste estudo. Os animais foram tratados com Res (25 mg/Kg de peso copóreo, ip., dose única) 30 minutos antes da administração de cisplatina (5 mg/Kg de peso copóreo, ip., dose única) e foram sacrificados depois de 2 ou 5 dias do tratamento. Após 5 dias, o aumento da creatinina sérica, volume urinário e proteinúria, que são marcadores de alterações renais, apresentaram significativa redução (p < 0,05) com a administração de resveratrol. Os ratos tratados com cisplatina apresentaram necrose tubular aguda e maior marcação imuno-histoquímica para células ED1 e linfócitos T no córtex e medula externa renal. Estas alterações foram menos intensas nos animais tratados com resveratrol. Após 2 dias, a administração de cisplatina aos ratos induziu aumento na concentração de malonaldeído (MDA) e reduziu nos níveis de glutationa (GSH) no tecido renal, que não foram amenizadas pelo resveratrol. Os resultados desse estudo indicam que o tratamento com resveratrol atenuou as alterações renais funcionais, histológicas e imuno-histoquímicas induzidas pela cisplatina. O efeito protetor provavelmente está relacionado à diminuição de infiltrado de células inflamatórias no tecido renal / Resveratrol (Res), a polyphenolic present in red wine, is known to possess potent antioxidant properties. The ability of resveratrol to protect against the nephrotoxicity of the antineoplastic agent cisplatin (cDDP) was evaluated in rats. The animals were treated with Res (25 mg/Kg body weight, ip., single dose) 30 minutes before administration of cDDP (5 mg/Kg body weight, ip., single dose) and then, sacrificed in 2 or 5 days followed by the treatment. After 5 days with resveratrol administration, the enhanced serum creatinine levels, urinary volume and urinary protein, which are indicative of renal injury, shown a significant reduction (p < 0.05). The cisplatintreated rats presented a tubular cell necrosis and increase immunostaining for ED1 and T-lymphocytes in the renal cortex and outer medulla. Those alterations were less intense in animals treated with resveratrol. After 2 days, administration of cisplatin to rats induced a higher malondialdehyde levels (MDA), and reduction in glutathione (GSH) concentrations in kidney tissue that were not prevented by resveratrol. In this study, the results indicate that resveratrol treatment attenuated the functional, histological and immunohistochemical renal alterations induced by cisplatin. The protect effect is relatated to the decrease of cells infiltrated at kidney tissue.

Many types of chemotherapeutic agents have been developed to target specific mechanisms within the body that control the progression of cancer, though few have been able to circumvent the existing problems associated with the treatments. The current remedies entail grueling drug regimens and toxic side effects that may undermine the effectiveness of the drugs. Cisplatin, a common nitroplatinum(II) drug widely used to treat a variety of cancers, is administered intravenously and circulates systemically, affecting healthy regions of the body as well. Resistance to cisplatin is increasing and the need for new, less toxic medication must be met for future success in cancer therapy. Our lab has synthesized novel nitroplatinum(IV) cisplatin complexes (PH1-14) that may evade these problems. We examined the effects of these compounds on cell viability, as well as effects on cancer-specific mechanisms such as nitric oxide (NO) production, angiogenesis, and the STAT signaling pathways. In vitro studies demonstrated that PH1-11 and PH14 demonstrated greater efficacy at inhibiting cell proliferation with lower IC50 values that ranged from 41-58 uM (as compared with cisplatin IC50 = 66 uM). Data from NO assays were inconclusive, though there was elevated expression of inducible nitric oxide synthase in cells treated with PH3 and PH11. We also found that PH9 was able to inhibit STAT dimerization at concentrations as low as 0.3 uM. PH9 also decreased VEGF and HIF-1α expression, thereby inhibiting angiogenesis. The activity of the PH complexes was also studied in C57BL/6 mice inoculated with murine bladder MB49 tumors. The experimental group showed significantly slower tumorigenesis and smaller tumors as compared with the control group. Toxicological analyses of the blood via metabolic assays showed that no nephrotoxicity was observed in dosages of less than 7 mg drug/kg. We conclude from these results the potential for the use of novel mechanisms in the treatment of cancers. This work will guide future investigations of these drugs in further preclinical trials and also introduce an alternative to the traditional chemotherapeutic agents.

Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

Abstract Cisplatin is one of the most effective chemotherapeutic agents used in treatment of a variety of human solid tumors. The most common adverse side effect limiting the use of Cisplatin is nephrotoxicity. Recent studies indicate that inflammatory and oxidative signaling play critical role in pathogenesis of Cisplatin related nephrotoxicity. Cisplatin-induced nephrotoxicity is associated with lipid peroxidation and the superoxide anion and hydroxyl radical scavenger could prevent acute renal failure through both attenuation of tubular damage and enhanced regenerative response of the damaged tubular cells. It has been shown that green tea polyphenols with antioxidant properties inhibit inflammatory and oxidative responses in mice. However, the evidence indicating the protective effect of epigallocatechin gallate (EGCG), the major polyphenol found in green tea, on Cisplatin-induced nephrotoxicity is lacking. The present study is to evaluate the effect of EGCG injection on Cisplatin-induced nephrotoxicity in rats. The male rats were divided into four groups (n = 6 each); control group, Cisplatin group, EGCG group and Cisplatin + EGCG group. The control group received only intraperitoneal normal saline injection. Cisplatin (6 mg/kg) was given single dose intraperitoneally at day 0, EGCG (10 mg/time) was given subcutaneously at day 4, day 2 and day 0 before Cisplatin challenge and day 2 and day 4 after Cisplatin injection. Nephrotoxicity was evaluated by biochemical analysis of blood and histopathological observations of rat kidney. Nuclear factor-kappa B (NF-£eB) activation, inducible nitric oxide synthase (iNOS) expression and malonyldialdehyde (MDA) content were also determined in rat kidney. Cisplatin injection induced an increase in serum blood urea nitrogen, creatinine and tubular necrosis, and upregulation of NF-£eB and iNOS expression and MDA content in kidney. All the increases were significantly inhibited by EGCG treatment. The results suggest that EGCG may attenuate Cisplatin induced nephrotoxicity through the anti-inflammatory/oxidative effects.

No description available.

No description available.