Single-Arm Study of Etanercept in Adult Patients with Moderate to Severe Rheumatoid Arthritis Who Failed Adalimumab Treatment.

INTRODUCTION: To evaluate the efficacy and safety of etanercept treatment in adult patients with moderate to severe rheumatoid arthritis (RA) who failed to respond (primary failure) or lost a satisfactory response (secondary failure) to adalimumab. METHODS: All patients discontinued prior adalimumab treatment and continued methotrexate with etanercept 50 mg once weekly for 24 weeks. The primary study endpoint was American College of Rheumatology 20% improvement criteria (ACR20) at week 12. RESULTS: Eighty-five patients (mean age 56.6 years; female 80.0%) were evaluated for safety and 84 for efficacy. Thirty (35.7%) patients achieved ACR20 at week 12; the lower bound of the 95% confidence interval (CI; 25.6, 46.9) was greater than the prespecified goal of 24% based on previous research. Improvements from baseline in clinical outcomes and patient-reported outcomes were observed at each study visit. In planned subgroup analyses, patients with anti-adalimumab antibodies and secondary adalimumab failure had the highest ACR20 response to etanercept at week 12 (11/17 patients; 64.7%). Among the patients with secondary adalimumab failure, those with anti-adalimumab antibodies were fivefold more likely to have an ACR20 response to etanercept than those without anti-adalimumab antibodies (odds ratio 5.2; 95% CI 2.0, 13.5; P < 0.001). Adverse events were reported for 62 (72.9%) patients and were consistent with previous studies of etanercept. Most adverse events were mild or moderate in severity. CONCLUSION: Switching to etanercept is a therapeutic option in patients with RA who fail adalimumab treatment. The presence of anti-adalimumab antibodies may provide additional support for switching to etanercept, particularly in patients with secondary adalimumab failure. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01927757.

Penetration of anticancer drugs through tumour tissue as a function of cellular packing density and interstitial fluid pressure and its modification by bortezomib.

BACKGROUND: Limited penetration of anticancer drugs in solid tumours is a probable cause of drug resistance. Our previous results indicate that drug penetration depends on cellular packing density and adhesion between cancer cells. METHODS: We used epithelioid and round cell variants of the HCT-8 human colon carcinoma cell lines to generate tightly and loosely packed xenografts in nude mice. We measured packing density and interstitial fluid pressure (IFP) and studied the penetration of anti-cancer drugs through multilayered cell cultures (MCC) derived from epithelioid HCT-8 variants, and the distribution of doxorubicin in xenografts with and without pre-treatment with bortezomib. RESULTS: We show lower packing density in xenografts established from round cell than epithelioid cell lines, with lower IFP in xenografts. There was better distribution of doxorubicin in xenografts grown from round cell variants, consistent with previous data in MCC. Bortezomib pre-treatment reduced cellular packing density, improved penetration, and enhanced cytotoxcity of several anticancer drugs in MCC derived from epithelioid cell lines. Pre-treatment of xenografts with bortezomib enhanced the distribution of doxorubicin within them. CONCLUSIONS: Our results provide a rationale for further investigation of agents that enhance the distribution of chemotherapeutic drugs in combination with conventional chemotherapy in solid tumours.

[Can tumor hypoxia be turned into a chemotherapeutic advantage?]. / L'hypoxie tumorale peut-elle devenir un avantage pour la chimiothérapie ?

The heterogeneous vascular distribution and blood flow in solid tumors create areas of low oxygen partial pressure or hypoxic areas. Hypoxia acts as a stressor that perpetuates the malignant phenotype by increasing genomic instability, altering gene expression, and the tumor's metabolic microenvironment. The heterodimeric transcription factor, hypoxia inducible factor, HIF-1 (Hypoxia-Inducible Factor-1), allows tumor cells to adapt to their microenvironment by stimulating the expression of a large number of hypoxia-related genes. Hypoxia has been shown to reduce chemotherapeutic efficacy by causing cells within hypoxic regions to cycle more slowly, and by providing a selection mechanism for cells with reduced susceptibility for apoptosis. Due to limited drug penetration within solid tumors, hypoxic regions (especially those located furthest from blood vessels) are often protected from the cytotoxic effects of chemotherapeutic agents further reducing drug efficacy. Given the contribution of tumor hypoxia to tumor progression and drug resistance, a number of hypoxia-targeted therapeutics are under development. These therapeutics ranges from hypoxic cytotoxins, such as tirapazamine and the pro-drug AQ4N, to the use of obligate anaerobic bacterial spores. Development of methodologies to characterize causes of drug resistance related to the tumor microenvironment has considerable potential to improve the outcome following systemic treatment of solid tumors.

The penetration of anticancer drugs through tumor tissue as a function of cellular adhesion and packing density of tumor cells.

To reach cancer cells in optimal quantities, therapeutic agents must be delivered to tumors through their imperfect blood vascular system, cross vessel walls into the interstitium, and penetrate multiple layers of tissue. Strategies to enhance drug penetration have potential to improve therapeutic outcome. The development of multicellular layers (MCLs), in which tumor cells are grown on a semipermeable Teflon support membrane, has facilitated quantification of drug penetration through solid tissue. The goals of the present study were to quantify the penetration of anticancer drugs as a function of cellular adhesion and packing density and to determine the effects of variable penetration on therapeutic efficacy in this model system. We compared the properties of MCLs grown from two epithelioid and round subclones of a colon carcinoma cell line. One pair of epithelioid and round sublines differed in expression of alpha-E-catenin, and both pairs generated MCLs with different packing density. The penetration of commonly used anticancer agents (paclitaxel, doxorubicin, methotrexate, and 5-fluorouracil) through MCLs derived from these cell lines was significantly greater through the round (loosely packed) than through the epithelioid (tightly packed) sublines. In MCLs treated with doxorubicin, we observed greater survival in the tightly packed cell lines than in the loosely packed cell lines. Impaired penetration of anticancer agents through MCLs derived from the tightly packed cell lines and relative resistance to killing of cells within them by doxorubicin treatment strengthen the role of tumor cell adhesion and packing density as contributing to drug resistance.