ABSTRACT
The efficacy of single-allergen-specific immunotherapy in polysensitized subjects is a matter of debate. We therefore performed a post hoc analysis of pooled data from six randomized, double-blind, placebo-controlled trials (N = 1871) comparing the efficacy and safety of the SQ-standardized grass allergy immunotherapy tablet (AIT), Grazax (Phleum pratense 75 000 SQ-T/2800 BAU, ALK, Denmark), in mono- and polysensitized subjects. A statistically significant reduction in the mean total combined symptom/medication score (TCS) of 27% was demonstrated in actively treated subjects compared with placebo (P < 0.0001). This was not dependent on sensitization status (P = 0.5772), suggesting a similar treatment effect in mono- and polysensitized subjects (i.e. reductions of the TCSs of 28% and 26%, respectively, both P < 0.0001). Finally, a comparable and favourable safety profile of grass AIT was demonstrated in the two subgroups. Thus, no difference in efficacy and safety of single-allergen grass AIT was observed between mono- and polysensitized subjects.
Subject(s)
Desensitization, Immunologic/methods , Plant Extracts/therapeutic use , Poaceae/immunology , Rhinitis, Allergic, Seasonal/drug therapy , Administration, Sublingual , Adult , Antigens, Plant/immunology , Child , Child, Preschool , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Patient Safety , Phytotherapy/methods , Randomized Controlled Trials as Topic , Rhinitis, Allergic, Seasonal/immunology , Rhinitis, Allergic, Seasonal/physiopathology , Risk Assessment , Severity of Illness Index , Tablets/administration & dosage , Treatment OutcomeABSTRACT
A number of studies have demonstrated that high tumor tissue levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) are associated with a poor prognosis in breast cancer, suggesting that TIMP-1 could be a valid prognostic marker in this disease. Recently, our laboratories have presented results showing that TIMP-1 also carries prognostic information when measured in serum. This is an important finding, since serum is a much more preferable material compared with tumor tissue extracts. The aim of the present study was to validate the previous results concerning the prognostic value of TIMP-1 in serum obtained preoperatively from 68 patients with primary breast cancer. This was done by measuring the same serum samples as in the previous study but in a different laboratory using a different ELISA assay. We confirmed that patients with the highest serum levels of TIMP-1 (> 197.7 ng/ml) had significantly shorter disease-specific survival compared with patients with low serum TIMP-1 levels. In the group of node-negative patients, 53% of the patients with high levels of TIMP-1 survived after 10 years of follow-up compared to 92% of the patients with low levels. This study thus confirms the reproducibility across laboratories of the results concerning the prognostic value of TIMP-1 in serum. We also investigated whether measurements of the specific fraction of uncomplexed TIMP-1 improved the prognostic value of TIMP-1 in serum, as has been shown to be the case for tumor tissue extracts. However, including information of the level of uncomplexed TIMP-1 did not seem to provide additional prognostic information to that already provided by total TIMP-1.
Subject(s)
Biomarkers, Tumor/blood , Breast Neoplasms/blood , Tissue Inhibitor of Metalloproteinase-1/blood , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunohistochemistry , Middle Aged , PrognosisABSTRACT
Tissue inhibitor of metalloproteinases-1 (TIMP-1) is one of four inhibitors of the matrix metalloproteinases, which are capable of degrading most components of the extracellular matrix. However, in recent years, TIMP-1 has been recognised as a multifunctional protein, playing a complex role in cancer. In this regard, several studies have demonstrated an antiapoptotic effect of TIMP-1 in a number of different cell types. Since chemotherapy works by inducing apoptosis in cancer cells, we raised the hypothesis that TIMP-1 promotes resistance against chemotherapeutic drugs. In order to investigate this hypothesis, we have established TIMP-1 gene-deficient and TIMP-1 wild-type fibrosarcoma cells from mouse lung tissue. We have characterised these cells with regard to TIMP-1 genotype, TIMP-1 expression, malignant transformation and sensitivity to chemotherapy-induced apoptosis. We show that TIMP-1 gene deficiency increases the response to chemotherapy considerably, confirming that TIMP-1 protects the cells from apoptosis. This is to our knowledge the first study investigating TIMP-1 and chemotherapy-induced apoptosis employing a powerful model system comprising TIMP-1 gene-deficient cells and their genetically identical wild-type controls. For future studies, this cell system can be used to uncover the mechanisms and signalling pathways involved in the TIMP-1-mediated inhibition of apoptosis as well as to investigate the possibility of using TIMP-1 inhibitors to optimise the effect of conventional chemotherapy.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Tissue Inhibitor of Metalloproteinase-1/genetics , Animals , Apoptosis/genetics , Cell Division/drug effects , Cell Division/genetics , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Cell Transformation, Neoplastic/genetics , Cells, Cultured , Cytarabine/pharmacology , DNA Fragmentation/drug effects , Dose-Response Relationship, Drug , Etoposide/pharmacology , Female , Gene Expression/genetics , Genotype , Male , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, Transgenic , Time Factors , Tissue Inhibitor of Metalloproteinase-1/deficiency , Vincristine/pharmacologyABSTRACT
Whether patients diagnosed with primary breast cancer are offered adjuvant systemic therapy following surgical removal of the tumor is based on prognosis. Prognosis is estimated in every patient using established prognostic variables. Unfortunately, when using the currently available prognostic parameters a significant proportion of patients are over-treated. Thus, in order to improve stratification of breast cancer patients, additional prognostic factors need to be identified. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is one of the promising candidates for new prognostic markers in breast cancer, as a number of studies have demonstrated an association between high tumor-tissue levels of TIMP-1 mRNA as well as TIMP-1 protein and a poor prognosis of breast cancer patients. TIMP-1 is a member of the TIMP family, currently comprising four members (TIMP-1-4), and its main function is inhibition of the activity of various matrix metalloproteinases (MMPs). The association between high levels of protease inhibitor and poor prognosis may be somewhat surprising, as proteolytic activity plays a pivotal role in cancer cell invasion and metastasis. However, the recent discovery of other biological functions of TIMP-1 such as growth-stimulating functions, as well as anti-apoptotic and pro-angiogenetic effects, may in part explain this paradox. The purpose of this review is to give an update on the current status of TIMP-1 in breast cancer, emphasizing the prognostic utility of the inhibitor. In addition, the suggested tumor-stimulatory roles of TIMP-1 will be outlined.
