Asbestos Cancer Update 2008

Lexington Medical Center, Lexington, South Carolina, USA.

3-HMG-CoA reductase inhibitors (statins) block the growth of malignant cells in vitro. A meta-analysis of randomized controlled trials failed to show reduced risk of cancers in statin users. Case-control studies, however, have the advantage of examining remote exposures. This study determined the association between statins and breast cancer, colon cancer, lung cancer, prostate cancer, or any cancer in case-control studies. A comprehensive search for studies published through November 2006 was performed. Twenty case-control studies (100 129 incident cancer cases) were combined to obtain a pooled odds ratio using an inverse variance method. A funnel plot did not suggest a significant absence of unpublished data. The studies were significantly heterogeneous (P<0.01), thus a random effects model was used. The pooled OR and 95% confidence intervals for statin users and cancer were as follows: any cancer 0.71 (0.56-0.89), breast cancer 0.86 (0.60-1.23), colon cancer 0.89 (0.82-0.97), lung cancer 0.75 (0.50-1.11), and prostate cancer 0.74 (0.45-1.20). In this meta-analysis of case-control studies, we found a significant association between statin usage and any cancer, but when stratified by cancer type, only the association with colon cancer remained. On the basis of these results, randomized control trials with longer follow-up times than previously used are warranted.

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University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, 600 Highland Avenue K4/6 CSC, Madison, WI, 53792, USA, hhbailey@facstaff.wisc.edu.

PURPOSE: Perillyl alcohol (POH) is a naturally occurring lipid with preclinical activity against mammary carcinomas. We conducted a phase II multi-institutional study of oral POH administered four times daily in women with advanced treatment-refractory breast cancer. METHODS: Eligible women were treated with POH four times daily at 1,200-1,500 mg m(-2) dose(-1) on a 28-day cycle. Patients tolerating 1,200 mg m(-2) day(-1) four times daily after one cycle were dose-escalated to 1,500 mg/m(2). The primary endpoint was 1-year freedom-from-progression (FFP) rate. Secondary endpoints were response rate, tolerability and correlative evaluations. RESULTS: Twenty-nine cycles of POH were administered to 14 women. Three patients were dose-escalated to 1,500 mg/m(2). Grade 1 and grade 2 gastrointestinal effects and fatigue were predominant toxicities. Of seven patients receiving up to one cycle, three stopped therapy due to intolerance. Only two patients received more than two cycles, with disease stabilization of 3 and 8 months. Thirteen patients were evaluable for response. One-year FFP rate was zero. No objective responses were seen. The median time to progression was 35 days (95% CI, 29-123 days). Median overall survival was 389 days (95% CI, 202-776 days). Pharmacokinetic parameters were similar to previous investigations. The ability to correlate plasma TGF-beta1 levels with outcome was limited by lack of clinical benefit and inter- and intra-patient variability. CONCLUSIONS: Enrollment was suspended short of planned accrual because of lack of response and poor tolerance to POH. This regimen does not appear to provide benefit in advanced treatment-refractory breast carcinoma.

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Department of Chemical & Biomolecular Engineering, National University of Singapore, Block E5, 02-11, 4 Engineering Drive 4, Singapore 117576, Singapore.

We synthesized nanoparticles (NPs) of the blend of two-component copolymers for targeted chemotherapy with paclitaxel used as model drug. One component is poly(lactide)-d-alpha-tocopheryl polyethylene glycol succinate (PLA-TPGS), which is of desired hydrophobic-lipophilic balance, and another is TPGS-COOH, which facilitates the folate conjugation for targeting. The nanoparticles of the two-copolymer blend at various component ratio were prepared by the solvent extraction/evaporation single emulsion method and then decorated by folate, which were characterized by laser light scattering (LLS) for particles’ size and size distribution, zeta potential analyzer for surface charge, and X-ray photoelectron spectroscopy (XPS) for surface chemistry. The drug encapsulation efficiency (EE) and in vitro drug release were measured by high performance liquid chromatography (HPLC). The targeting effect was investigated in vitro by cancer cell uptake of coumarin-6-loaded NPs and further confirmed by cytotoxicity of cancer cells treated with the drug formulated in the NPs. We showed that the NP formulation has great advantages vs the pristine drug in achieving better therapeutic effect, which increased 8.68% for MCF-7 breast cancer cells, and that the folate-decoration can significantly promote targeted delivery of the drug into the corresponding cancer cells and thus enhance its therapeutic effect, which increased 24.4% for the NP formulation of 16.7% TPGS-COOH component and 31.1% for the NP formulation of 33.3% TPGS-COOH component after 24h treatment at the same 25mug/ml paclitaxel concentration. The experiments on C6 glioma cells further confirmed these advantages.

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Medical Oncology, Yale University School of Medicine, Section of Medical Oncology, New Haven, Connecticut, USA bOncology Unit, Third Department of Medicine, Athens Medical School, Sotiria General Hospital, Athens, Greece.

Xeloda (capecitabine), a thymidine phosphorylase activated fluoropyrimidine carbamate, is currently the only universally approved orally administered 5-fluorouracil (5-FU) prodrug. It belongs to a newer generation of orally administered fluoropyrimidines. It has been developed because of the clinical need for efficient, tolerable and convenient agents, which do not require continuous infusion. Capecitabine is not a cytotoxic drug in itself, but via a three-step enzymatic cascade, it is converted to 5-FU mainly within human cancer cells. While the drug compares favorably with 5-FU in patients with advanced or metastatic colorectal cancer and pretreated breast cancer, it also has an improved toxicity profile, mainly of gastrointestinal and dermatologic effects with a significantly lower incidence of grade 3/4 myelotoxicity compared with infusional 5-FU-based chemotherapy. Capecitabine’s selective activation within the tumor allows for less systemic toxicity events. A gradient of fluoropyrimidine toxicity is observed: high in the US and low in East Asia. In addition, there is a discrepancy in tolerance of dose among patients treated in the US vs. Europe. Although patients can take the drug orally in the convenience of their own home, the key to successful management of capecitabine is the clinician’s awareness of its severe, but low in incidence, adverse effects, and the patients’ education, emphasizing compliance with the treatment plan, prevention and timely recognition of its toxicities.

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Department of Genetics, Peking Union Medical College bReproductive and Genetic Center of National Research Institute for Family Planning cWHO Collaborative Center for Research in Human Reproduction dDepartment of Laboratory Animal Science, Peking University, Beijing eNorth China Coal Medical College, Tangshan, China.

In our study we use nordihydroguaiaretic acid (NDGA), the naturally occurring lignan, to investigate whether it plays a role in the prevention and treatment of cancer by epigenetic modifications. The growth inhibitory effect of NDGA on human breast cancer cell lines was determined using the MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay). It substantially inhibited the growth of human breast cancer cell lines SKBR3 and MDA-MB-435 with an estimated IC50 of 31.09+/-1.6 and 38.8+/-2.1 mumol/l respectively, after 4 days incubation with different NDGA concentrations. The in-vivo anticancer activity of NDGA was evaluated by calculating the tumor growth inhibition value. NDGA substantially inhibited the growth of human breast carcinoma cells in both animal and cell-based models. We also found that a single treatment with NDGA reactivates methylation-silenced E-cadherin gene in vitro and in vivo, suggesting an intriguing concept that lignans may act as natural effective epigenetic modifiers in the prevention and treatment of cancer.

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