Pomegranate juice derived ellagitannins and their intestinal bacterial metabolites, urolithins, inhibited TCDD-induced CYP1-mediated EROD activity in vitro with IC(50) values ranging from 56.7 microM for urolithin A to 74.8 microM for urolithin C. These compounds exhibited dose- and time-dependent decreases in cell proliferation and clonogenic efficiency of HT-29 cells. Inhibition of cell proliferation was mediated through cell cycle arrest in the G(0)/G(1) and G(2)/M stages of the cell cycle followed by induction of apoptosis. These results indicate that the ellagitannins and urolithins released in the colon upon consumption of pomegranate juice in considerable amounts could potentially curtail the risk of colon cancer development, by inhibiting cell proliferation and inducing apoptosis.

Derivatives of podophyllotoxin were prepared by coupling 10 FA with the C4-alpha-hydroxy function of podophyllotoxin. The coupling reactions between FA and podophyllotoxin were carried out by dicyclohexylcarbodiimide in the presence of a catalytic amount of dimethylaminopyridine to produce quantitative yields of desired products. FA incorporated were the following: 10-hydroxydecanoic, 12-hydroxydodecanoic, 15-hydroxypentadecanoic, 16-hydroxyhexadecanoic, 12-hydroxyoctadec-Z-9-enoic, eicosa-Z-5,8,11,14-tetraenoic, eicosa-Z-8,11, 14-trienoic, eicosa-Z-11,14-dienoic, eicosa-Z-11-enoic, and eicosanoic acids. Spectroscopic studies confirmed the formation of the desired products. New molecules were investigated for their in vitro anticancer activity against a panel of human cancer cell lines including SK-MEL, KB, BT-549, SK-OV-3 (solid tumors), and HL-60 (human leukemia) cells. Most of the analogs were cytotoxic against cancerous cells, whereas no effect was observed against normal cells, unlike the parent compound podophyllotoxin, the use of which is limited due to its severe side effects.

Hypocrellins A and B were evaluated for in vitro antimicrobial and antileishmanial activities. Hypocrellin A exhibited promising activity against Candida albicans and moderate activity against Staphylococcus aureus, methicillin-resistant S. aureus, Pseudomonas aeruginosa, and Mycobacterium intracellulare. Hypocrellin B showed weak antimicrobial activities. Hypocrellin A exhibited potent antileishmanial activity, while hypocrellin B was only moderately active. These results of promising antifungal and antileishmanial activity of hypocrellin A may be useful for further structure-activity relationship and in vivo studies.Antifungal drugs, such as amphotericin B, ketoconazole (and other azoles), and griseofulvin, have been widely used in the treatment of patients with various fungal infections. However, their clinical use is limited, due either to lack of efficacy or their toxicity and resistance (8,17). Therefore, there is a need for new antifungal agents that are more effective and less toxic. For leishmanial infections, only a few drugs, which are highly toxic, are available (4), and their use has further been compromised due to development of drug resistance. Thus, there is a continuous interest in developing new antileishmanial compounds with different modes of action and low toxicities to satisfy clinical use.Hypocrellins A and B ( Fig. 1) are two main pigments isolated from the parasitic fungus Hypocrella bambusae (Berk. et Broome) Sacc., which grows abundantly in the northwest region of Yunnan Province, People's Republic of China, and the southeastern region of Xizang (Tibet), an autonomous region of the People's Republic of China. These pigments have a long history of use as traditional medicinal agents and were commonly used to treat rheumatoid arthritis, gastric diseases (20), and skin diseases related to fungal infections (18,19). Previous studies showed that hypocrellins exhibited photodynamic anticancer (2, 5, 12, 21) and antiviral (9, 10) activities. These activities were related to their ability to generate active oxygen•Ϫ , and • OH) (1, 16) and inhibit protein kinase C activity (6). However, no antifungal or antileishmanial activity has been reported. In this study, hypocrellins A and B were evaluated for activities against a panel of fungi and bacteria and for activity against Leishmania donovani, the causative agent of visceral leishmaniasis.Hypocrellins A and B were isolated from H. bambusae as described previously (3) at the Experimental Center of Yunnan University, Yunnan, People's Republic of China. Purity was determined to be 99.2%. Samples were dissolved in dimethyl sulfoxide (DMSO). The final concentration of DMSO in all assays was less than 0.2%, which has no effect on the tested organisms.Activity against a panel of microorganisms, including Candida albicans, Cryptococcus neoformans, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa, and Mycobacterium intracellulare, was evaluated in vitro. All organisms were obtained from the American Type Culture Col...

A modeling framework relating exposure, biomarkers (vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor (sVEGFR)-2, -3, soluble stem cell factor receptor (sKIT)), and tumor growth to overall survival (OS) was extended to include adverse effects (myelosuppression, hypertension, fatigue, and hand–foot syndrome (HFS)). Longitudinal pharmacokinetic–pharmacodynamic models of sunitinib were developed based on data from 303 patients with gastrointestinal stromal tumor. Myelosuppression was characterized by a semiphysiological model and hypertension with an indirect response model. Proportional odds models with a first-order Markov model described the incidence and severity of fatigue and HFS. Relative change in sVEGFR-3 was the most effective predictor of the occurrence and severity of myelosuppression, fatigue, and HFS. Hypertension was correlated best with sunitinib exposure. Baseline tumor size, time courses of neutropenia, and relative increase of diastolic blood pressure were identified as predictors of OS. The framework has potential to be used for early monitoring of adverse effects and clinical response, thereby facilitating dose individualization to maximize OS.