Treatment of advanced gastric cancer with etoposide,folinic acid,and fluorouracil in the clinical setting: efficacy of therapy and value of serum tumor markers

The combination of etoposide, folinic acid, and 5-fluorouracil (5-FU) (ELF regimen) has been proved to be an active chemotherapy in patients with advanced gastric cancer. The aim of this study was to confirm the efficacy in the clinical setting and to correlate response with different parameters like serum tumor markers. We treated 60 patients with advanced gastric cancer with 120 mg/m² etoposide, 300 mg/m² folinic acid, and 500 mg/m² 5-FU, on d 1–3. The cycle was repeated on d 21. Objective response was obtained in 23% of all patients with measurable disease. Stable disease was obtained in 37%. The tumor-growth-control rate in patients with proximal carcinoma was significantly higher than in those with distal carcinoma (85% vs 48%, p=0.04). Median survival for all patients was 8.0 mo (95% confidence interval [CI] 7.0–8.5). In responsive patients, survival was more than two-fold longer than in patients with progressive disease. The administration of ELF could be performed safely on an outpatient basis. Toxicity was rather mild. The most frequently elevated serum tumor marker was CA 72-4 (55% of the patients). An elevated level of carcinoembryonic antigen before treatment was significantly correlated with progressive disease. A more than two-fold elevation of at least one marker under treatment was significantly correlated to progressive disease (p<0.002). A reduction of at least one marker under treatment was significantly correlated to tumor growth control (p<0.00015). The results of the present trial confirm the efficacy and low toxicity of the ELF regimen in advanced gastric carcinoma. Serum tumor markers proved suitable parameters for assessing response to treatment.     

Cytoplasmic localization of wild-type p53 in glioblastomas correlates with expression of vimentin and glial fibrillary acidic protein

Cytoplasmic accumulation of wild-type p53 in tumor cells indicates that the tumor suppressor is inactive with regard to growth suppressive functions. Whether this occurs randomly during tumor development or characterizes a certain tumor cell subset is not known. Here we assayed primary glioblastomas for expression and subcellular localization of p53 and determined a correlation with expression of intermediate filament proteins characterizing glial cell development. Sixty-nine percent of the tumors were p53 positive in immunohistochemistry. A significant number of tumors (23%) accumulated wild-type p53 in the cytoplasm, which correlated with the presence of vimentin and glial fibrillary acidic protein, except for 1 case. Tumors with exclusive nuclear p53 contained none or only one of these intermediate filament proteins. In an alternative approach, tumors positive for glial fibrillary acidic protein were screened for expression of p53 and vimentin. Thirty-eight percent of these tumors showed cytoplasmic p53, and all of those also expressed vimentin. Tumors with only nuclear p53 were vimentin negative, except for 1 case. No mutation was detected in p53 exons 5 to 8 in tumors with cytoplasmic p53, suggesting that they express wild-type p53. The data indicate that a cytoplasmic accumulation of wild-type p53 in human primary glioblastomas correlates with a certain intermediate filament protein expression, suggesting that it identifies a certain subset of tumors.     

Polysaccharides isolated from Echinacea purpurea herba cell cultures to counteract undesired effects of chemotherapy--a pilot study

In an open prospective study with matched historical controls we aimed to evaluate whether a polysaccharide fraction isolated from the herb Echinacea purpurea could counteract the undesired effects of chemotherapy. Fifteen patients with advanced gastric cancer undergoing palliative chemotherapy with etoposide, leucovorin and 5-fluorouracil (ELF) received for 10 days (beginning 3 days before chemotherapy) daily i.v. injections of 2 mg of a polysaccharide fraction isolated from Echinacea purpurea herb cell cultures (EPS-EPO VIIa). The median number of leukocytes 14-16 days after chemotherapy was 3630/microL (range 1470-5770) in the patients receiving EPS-EPO VIIa compared with 2370/microL (870-3950) in the patients of the historical control group (p = 0.015). EPS-EPO VIIa had no clinically relevant effects on phagocytic activity of granulocytes or on lymphocyte subpopulations. Sixty-eight adverse events including two deaths were observed, most likely due to chemotherapy and the general condition of the patients. However, an association with the test intervention cannot be ruled out completely. The results of this pilot study suggest that EPS-EPO VIIa might be effective in reducing chemotherapy-induced leukopenia. The efficacy and safety should be investigated in further studies.     

An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole,letrozole, and exemestane

BACKGROUND: The newer generation, nonsteroidal aromatase inhibitors (AIs) anastrozole and letrozole have shown superior efficacy compared with tamoxifen as first-line treatments and compared with megestrol acetate as second-line therapy in postmenopausal women with advanced breast carcinoma. In an open-label, Phase II trial, it was reported that exemestane showed numerical superiority compared with tamoxifen for objective response and clinical benefit. Because these agents ultimately may be administered for periods of up to 5 years in the adjuvant setting, it is of increasing importance to assess their tolerability and pharmacologic profiles. METHODS: In the absence of data from direct clinical comparisons, the published literature was reviewed for the clinical pharmacology, pharmacokinetic characteristics, and selectivity profiles of anastrozole, letrozole, and exemestane. RESULTS: At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) were 41-48 hours, 2-4 days, and 27 hours, respectively. The time to steady-state plasma levels was 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have been reported only with exemestane. Anastrozole treatment had no impact on plasma lipid levels, whereas both letrozole and exemestane had an unfavorable effect on plasma lipid levels. In indirect comparisons, anastrozole showed the highest degree of selectivity compared with letrozole and exemestane in terms of a lack of effect on adrenosteroidogenesis. CONCLUSIONS: All three AIs demonstrated clinical efficacy over preexisting treatments. However, there were differences in terms of pharmacokinetics and effects on lipid levels and adrenosteroidogenesis. The long-term clinical significance of these differences remains to be elucidated.     

Expression of a "self-"antigen by human tumor cells enhances tumor antigen-specific CD4(+) T-cell function

CD4(+) T cells can recognize "self" tumor antigens, but the impact of tumor cell expression of self-antigens on CD4(+) T-cell function in humans is unknown. Here, we identify a new epitope (ISPNSVFSQWRVVCDSLEDYD) derived from tyrosinase-related protein-1 (TRP-1) using a predictive algorithm and mice transgenic for a chimeric HLA-DRB1*0401 molecule. We then compared the functions of TRP-1-epitope-specific, CD4(+) T-cell responses in normal healthy individuals to those found in patients with metastatic malignant melanoma. Surprisingly, we found that tumor-bearing patients had significantly higher levels of TRP-1-specific, CD4(+) T-cell function than healthy volunteers as measured ex vivo. Thus, the net effect of "self" antigen expression by tumor cells was the enhancement of tumor antigen-specific CD4(+) T-cell function, rather than immunosuppression. These findings indicate that antigens expressed by malignant melanoma cells can partially activate CD4(+) T lymphocytes.     

CD40-expressing carcinoma cells induce down-regulation of CD40 ligand (CD154) and impair T-cell functions

The interaction of CD40 expressed by immunocompetent cells with its ligand CD154 on the surface of T-helper cells plays a crucial role in the immune response. Recently, the presence of CD40 was also demonstrated on a variety of carcinomas. Whereas the critical relevance of CD40 in cytotoxic T-cell priming via dendritic cells is already established, the biological role of CD40/CD154 interactions in nonhematopoetic cells is still unclear. In the present study we demonstrate that CD154 expression density is down-regulated on activated T cells on interaction with CD40+ tumor cells. Naive T cells cocultured with CD40+carcinoma showed impaired functionality as indicated by a reduced frequency of IFN-gamma secreting cells, reduced interleukin 2 secretion, impaired proliferation, and a lack of CD154 re-expression on restimulation. In distinction, T-cell effector lysing capacity was not impaired by CD40-expressing tumor cell targets. The present results suggest that in marked contrast to antigen-presenting cells, CD40 expression on carcinoma cells suppresses T-cell activation. Our findings support the statement that CD40 functions are context dependent and imply a new function for CD40 expressed on nonantigen-presenting cells.     

Vaccination with poly-L-arginine as immunostimulant for peptide vaccines: induction of potent and long-lasting T-cell responses against cancer antigens

Vaccines that induce high numbers of sustained T cell responses are urgently needed for the treatment of numerous diseases including cancer. Antigen-presenting cells (APCs), the most important of which are dendritic cells, orchestrate antigen-dependent T cell responses in that they present antigens to T cells in an appropriate environment. Here we present evidence that after vaccination with a simple mixture of the cationic poly-amino acid poly-L-arginine and tumor antigen-derived peptide antigens, large numbers of antigen-specific T cells are induced and APCs mediate the generation of T lymphocytes. We observe that after s.c. injection, MHC class II(+) cells infiltrate injection sites and are loaded with large amounts of antigen in vivo under the influence of poly-L-arginine. Consequently, numerous antigen-charged APCs can be detected in draining lymph nodes of vaccinated animals. Antigen-specific T cell responses induced are systemic and were readily detected more than 4 months after the last vaccination, the latest time point we measured. By contrast, even after repeat injections, we were consistently unable to detect antibody responses against poly-L-arginine, allowing this compound to be used for numerous booster injections. Clinical trials in cancer patients using poly-L-arginine as immunostimulant will be carried out in the near future.     

Eradication of glioblastoma,and breast and colon carcinoma xenografts by Hsp70 depletion

Heat shock protein 70 (Hsp70) is an antiapoptotic chaperone protein highly expressed in human tumors. Here we demonstrate that locoregional application of adenovirus expressing antisense Hsp70 cDNA (Ad.asHsp70) eradicates orthotopic xenografts of glioblastoma and breast carcinoma, as well as s.c. xenografts of colon carcinoma in immunodeficient mice. Ad.asHsp70-treated tumors showed massive apoptosis-like cell death and recruitment of macrophages. Human monocyte-derived macrophages effectively removed the corpses of Ad.asHsp70-treated tumor cells in vitro. Interestingly, both tumor cell death and phagocytosis were caspase-independent. Thus, Hsp70 appears as a promising target for the treatment of cancers resistant to classic caspase-mediated apoptosis.     

Radiotherapy for chordomas and low-grade chondrosarcomas of the skull base with carbon ions

PURPOSE: Compared to photon irradiation, carbon ions provide physical and biologic advantages that may be exploited in chordomas and chondrosarcomas. METHODS AND MATERIALS: Between August 1998 and December 2000, 37 patients with chordomas (n = 24) and chondrosarcomas (n = 13) were treated with carbon ion radiotherapy within a Phase I/II trial. Tumor conformal application of carbon ion beams was realized by intensity-controlled raster scanning with pulse-to-pulse energy variation. Three-dimensional treatment planning included biologic plan optimization. The median tumor dose was 60 GyE (GyE = Gy x relative biologic effectiveness). RESULTS: The mean follow-up was 13 months. The local control rate after 1 and 2 years was 96% and 90%, respectively. We observed 2 recurrences outside the gross tumor volume in patients with chordomas. Progression-free survival was 100% for chondrosarcomas and 83% for chordomas at 2 years. Partial remission after carbon ion radiotherapy was observed in 6 patients. Treatment toxicity was mild. CONCLUSION: These are the first data demonstrating the clinical feasibility, safety, and effectiveness of scanning beam delivery of ion beams in patients with skull base tumors. The preliminary results in patients with skull base chordomas and low-grade chondrosarcomas are encouraging, although the follow-up was too short to draw definite conclusions concerning outcome. In the absence of major toxicity, dose escalation might be considered.