Clinical outcomes from the CDC's Colorectal Cancer Screening Demonstration Program.

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.

Anticancer activity of novel unnatural synthetic isoprenoids.

BACKGROUND: The KRAS oncogene has a high prevalence in solid malignancies. Targeting KRAS and inappropriate activation of the MAPK pathway with novel drugs is of interest. This study developed and screened a library of compounds designed to inhibit KRAS signaling by altering prenyl function. MATERIALS AND METHODS: To screen a library of novel farnesyl analogs for their anticancer activity in human lung cancer and breast cancer cell lines. To evaluate if the designed and actual pharmacology are congruent. RESULTS: Sixty-seven novel compounds were tested and 70% of them screened positive for activity in at least one cell line. Two active compounds inhibited phosphorylation of MAP kinase consistent with KRAS inhibition. CONCLUSION: Although 47 of the 67 novel agents screened positive for activity, none of them were highly potent. However, targeting RAS with compounds that compete with farnesyl and geranylgeranyl modification of the protein remains viable and further work is already underway to create second generation molecules.

Doxorubicin and paclitaxel-loaded lipid-based nanoparticles overcome multidrug resistance by inhibiting P-glycoprotein and depleting ATP.

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.

Development of new lipid-based paclitaxel nanoparticles using sequential simplex optimization.

The objective of these studies was to develop Cremophor-free lipid-based paclitaxel (PX) nanoparticle formulations prepared from warm microemulsion precursors. To identify and optimize new nanoparticles, experimental design was performed combining Taguchi array and sequential simplex optimization. The combination of Taguchi array and sequential simplex optimization efficiently directed the design of paclitaxel nanoparticles. Two optimized paclitaxel nanoparticles (NPs) were obtained: G78 NPs composed of glyceryl tridodecanoate (GT) and polyoxyethylene 20-stearyl ether (Brij 78), and BTM NPs composed of Miglyol 812, Brij 78, and d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Both nanoparticles successfully entrapped paclitaxel at a final concentration of 150 microg/ml (over 6% drug loading) with particle sizes less than 200 nm and over 85% of entrapment efficiency. These novel paclitaxel nanoparticles were stable at 4 degrees C over five months and in PBS at 37 degrees C over 102 h as measured by physical stability. Release of paclitaxel was slow and sustained without initial burst release. Cytotoxicity studies in MDA-MB-231 cancer cells showed that both nanoparticles have similar anticancer activities compared to Taxol. Interestingly, PX BTM nanocapsules could be lyophilized without cryoprotectants. The lyophilized powder comprised only of PX BTM NPs in water could be rapidly rehydrated with a complete retention of original physicochemical properties, in vitro release properties, and cytotoxicity profile. Sequential Simplex Optimization has been utilized to identify promising new lipid-based paclitaxel nanoparticles having useful attributes.

The effect of DB-67, a lipophilic camptothecin derivative, on topoisomerase I levels in non-small-cell lung cancer cells.

PURPOSE: To determine the in vitro drug sensitivity of two non-small-cell lung cancer cell lines after treatment with the novel lipophilic camptothecin derivative, 7- tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67), to determine if topoisomerase I protein levels decrease after treatment with DB-67, and to assess the duration and extent of topoisomerase I modulation after DB-67 exposure, in order to provide information about drug resistance that may be useful in determining an appropriate dosing schedule for DB-67. METHODS: The growth inhibition of the non-small-cell lung cancer cell lines A549 and H460 after exposure to DB-67 was evaluated with the MTS assay. A549 and H460 cells were treated for various times with DB-67 and topoisomerase I levels were determined by western blot analysis. In addition, A549 and H460 cells were treated with DB-67 for 24 h and topoisomerase I levels were determined by western blot analysis daily for 1 week after drug removal. RESULTS: DB-67 inhibited the growth of both A549 and H460 cells grown in culture; the A549 cells were more resistant to the cytotoxic effects of DB-67 than H460 cells. Notably, A549 cells had approximately one-half the baseline topoisomerase I than H460 cells. Topoisomerase I protein levels significantly decreased after 8-18 h of exposure to DB-67. Both A549 and H460 cells treated with DB-67 for 24 h had only negligible amounts of topoisomerase I at the end of treatment. However, within 24 h of drug removal topoisomerase I levels returned to near baseline levels in both cell lines. CONCLUSIONS: The decrease in topoisomerase I levels caused by DB-67 may represent a mechanism of resistance to this novel camptothecin derivative. Dosing DB-67 once every 48-72 h may maximize the interaction of the drug with topoisomerase I and should be considered as a potential dosing schedule in the preclinical and clinical development of this compound.