To test the ability of nanoparticle formulations to overcome P-glycoprotein (P-gp)-mediated multidrug resistance, several different doxorubicin and paclitaxel-loaded lipid nanoparticles were prepared. Doxorubicin nanoparticles showed 6-to 8-fold lower IC 50 values in P-gp-overexpressing human cancer cells than those of free doxorubicin. The IC 50 value of paclitaxel nanoparticles was over 9-fold lower than that of Taxol in P-gp-overexpressing cells. A series of in vitro cell assays were used including quantitative studies on uptake and efflux, inhibition of calcein acetoxymethylester efflux, alteration of ATP levels, membrane integrity, mitochondrial membrane potential, apoptosis, and cytotoxicity. Enhanced uptake and prolonged retention of doxorubicin were observed with nanoparticle-based formulations in P-gp-overexpressing cells. Calcein acetoxymethylester and ATP assays confirmed that blank nanoparticles inhibited P-gp and transiently depleted ATP. I.v. injection of pegylated paclitaxel nanoparticles showed marked anticancer efficacy in nude mice bearing resistant NCI/ADR-RES tumors versus all control groups. Nanoparticles may be used to target both drug and biological mechanisms to overcome multidrug resistance via P-gp inhibition and ATP depletion. [Cancer Res 2009;69(9):3918-26]

BACKGROUND: Colorectal cancer remains the second leading cause of cancer-related deaths among US men and women. Screening rates have been slow to increase, and disparities in screening remain. METHODS: To address the disparity in screening for this high burden but largely preventable disease, the Centers for Disease Control and Prevention (CDC) designed and established a 4-year Colorectal Cancer Screening Demonstration Program (CRCSDP) in 2005 for low-income, under-insured or uninsured men and women aged 50 to 64 years in 5 participating US program sites. In this report, the authors describe the design of the CRCSDP and the overall clinical findings and screening test performance characteristics, including the positive fecal occult blood testing (FOBT) rate; the rates of polyp, adenoma, and cancer detection with FOBTs and colonoscopies; and the positive predicative value for polyps, adenomas, and cancers. RESULTS: In total, 5233 individuals at average risk and increased risk were screened for colorectal cancer across all 5 sites, including 44% who underwent screening FOBT and 56% who underwent screening colonoscopy. Overall, 77% of all individuals screened were women. The FOBT positivity rate was 10%. Results from all screening or diagnostic colonoscopies indicated that 75% had negative results and required a repeat screening colonoscopy in 10 years, 16% had low-risk adenomas and required surveillance colonoscopy in 5 to 10 years, 8% had high-risk adenomas and required surveillance colonoscopy in 3 years, and 0.6% had invasive cancers. CONCLUSIONS: This report documents the successes and challenges in implementing the CDC's CRCSDP and describes the clinical outcomes of this 4-year initiative, the patterns in program uptake and test choice, and the comparative test performance characteristics of FOBT versus colonoscopy. Patterns in final outcomes from the follow-up of positive screening tests were consistent with national registry data. KEYWORDS: colorectal cancer screening; colonoscopy; fecal occult blood testing; cancer screening programs; colorectal cancer prevention. INTRODUCTIONThe Centers for Disease Control and Prevention (CDC) designed and established a 4-year Colorectal Cancer Screening Demonstration Program (CRCSDP) in 2005 for low-income, under-insured or uninsured men and women ages 50 to 64 years in 5 participating US program sites. This report documents the successful implementation of the CRCSDP and describes the clinical outcomes of this 4-year initiative, the patterns of program uptake and test choice, the challenges of implementing fecal occult blood testing (FOBT) screening programs, and the comparative test performance characteristics of FOBT versus colonoscopy.Cancer is the second leading cause of death among US adults, and colorectal cancer is the second leading cause of US cancer-related deaths among cancers that affect both men and women. In 2007, 142,672 new cases and 53,219 deaths

Two genes from Streptomyces cyanogenous S136 that encode the reductase LanZ4 and the hydroxylase LanZ5, which are involved in landomycin A biosynthesis, were characterized by targeted gene inactivation. Analyses of the corresponding mutants as well as complementation experiments have allowed us to show that LanZ4 and LanZ5 are responsible for the unique C-11-hydroxylation that occurs during landomycin biosynthesis. Compounds accumulated by the lanZ4/Z5 mutants are the previously described landomycin F and the new landomycins M and O.

Mitochondria have recently been shown to serve a central role in programmed cell death. In addition, reactive oxygen species (ROS) have been implicated in cell death pathways upon treatment with a variety of agents; however, the specific cellular source of the ROS generation is unknown. We hypothesize that mitochondria-derived free radicals play a critical role in apoptotic cell death. To directly test this hypothesis, we treated murine fibrosarcoma cell lines, which expressed a range of mitochondrial manganese superoxide dismutase (MnSOD) activities, with respiratory chain inhibitors. Apoptosis was confirmed by DNA fragmentation analysis and electron microscopy. MnSOD overexpression specifically protected against cell death upon treatment with rotenone or antimycin. We examined bcl-x(L), p53 and poly(ADP-ribose) polymerase (PARP) to identify specific cellular pathways that might contribute to the mitochondrial-initiated ROS-mediated cell death. Cells overexpressing MnSOD contained less bcl-x(L) within the mitochondria compared to control (NEO) cells, therefore excluding the role of bcl-x(L). p53 was undetectable by Western analysis and examination of the proapoptotic protein bax, a p53 target gene, did not increase with treatment. Activation of caspase-3 (CPP-32) occurred in the NEO cells independent of cytochrome c release from the mitochondria. PARP, a target protein of CPP-32 activity, was cleaved to a 64 kDa fragment in the NEO cells prior to generation of nucleosomal fragments. Taken together, these findings suggest that mitochondrial-mediated ROS generation is a key event by which inhibition of respiration causes cell death, and identifies CPP-32 and the PARP-linked pathway as targets of mitochondrial-derived ROS-induced cell death.