Skin inflammation exacerbates food allergy symptoms in epicutaneously sensitized mice.

BACKGROUND: Cutaneous exposure to food antigen through impaired skin barrier has been shown to induce epicutaneous sensitization, thereby causing IgE-mediated food allergies. OBJECTIVE: We examined whether skin barrier impairment following epicutaneous sensitization exacerbates food allergies. METHODS: BALB/c mice were epicutaneously sensitized by repeated application of ovalbumin (OVA) to MC903-pretreated ear skin for 48 hours weekly and then intragastrically challenged with OVA. After the first oral challenge, the skin barrier was disrupted with topical application of MC903 or by tape-stripping. Mice were monitored for changes in body temperature and the occurrence of diarrhea after undergoing the second oral challenge. Serum levels of mouse mast cell protease-1 (mmcp1) and OVA-specific IgE, IgG1, IgG2a antibodies and OVA-specific IgA levels in intestinal lavage fluid were measured by ELISA. Tissue accumulation of eosinophils was determined histologically. RESULTS: Epicutaneously sensitized mice developed anaphylaxis after intragastric challenge, as evidenced by diarrhea, decreased body temperature, and increased serum mmcp1 levels. Skin barrier disruption by MC903 treatment or tape-stripping exacerbated allergic reactions induced by oral challenge. MC903 treatment increased serum baseline and postchallenge mmcp1 levels. Topical pretreatment with dexamethasone alleviated allergic reactions that were exacerbated by MC903 treatment. CONCLUSION: Even after eliminating exposure to the antigen, inflammation from skin barrier disruption can exacerbate the severity of food allergy symptoms. Serum baseline mmcp1 levels might be an effective marker for predicting the severity of antigen-induced allergic symptoms.

The Biomarker Salivary SP-D May Indicate Small Airway Inflammation and Asthma Exacerbation.

BACKGROUND: Noninvasive and child-friendly biomarkers are important tools for understanding the various phenotypes of childhood asthma. Objective: The aim of this study was to examine the usefulness of salivary surfactant protein (SP) D in assessing the pathophysiology of childhood asthma. METHODS: We measured salivary concentrations of SP-D and forced oscillation technique (FOT) indexes in 19 healthy controls and 21 asthmatic children. Regression equations for the predictive values of FOT indexes were generated from healthy controls. We analyzed the correlations between salivary SP-D concentration and percentages of the predictive values of FOT indexes, as well as the severity of exacerbation. RESULTS: We found that salivary SP-D levels were higher in asthmatic children than in healthy controls. In the asthmatic children, salivary SP-D levels correlated with the percentages of predicted differences in resistance between 5 Hz and 20 Hz (%R5-R20), which represented the resistance of peripheral airways, and with the severity of asthma exacerbation. CONCLUSIONS: Salivary SP-D may reflect asthmatic inflammation in peripheral small airways and may be a useful marker for monitoring the degree of exacerbation in childhood asthma.

A self-consistent Ornstein-Zernike approximation for a fluid with a screened power series interaction.

We present a thermodynamically self-consistent Ornstein-Zernike approximation (SCOZA) for a fluid of spherical particles with a pair potential given by a hard-core repulsion and screened power series (SPS) tails. We take advantage of the known analytic properties of the solution of the Ornstein-Zernike equation for the case in which the direct correlation function outside the repulsive core is given by the SPS tails [M. Yasutomi, J. Phys.: Condens. Matter 13, L255 (2001)]: c(r)=∑(n=1) (N)exp(-z(n)r)∑(τ=-1) (L(n) )K((n,τ))z(n) (τ+1)r(τ) r>1. The analytic properties are rewritten so as to be optimally suited to the numerical computations. The SCOZA is known to provide very good overall thermodynamics, remarkably accurate critical point, and coexistence curve. In this paper, we present some numerical results for parameters in c(r) which are chosen to fit the Lennard-Jones potential. We show that both the energy and the compressibility paths lead to the same thermodynamics with high accuracy due to the thermodynamic consistency condition that has been enforced. The present method will be applicable to fluids with a large variety of smooth, realistic isotropic potentials where the pair potentials can be fitted by the SPS tails. The fitting procedure is superior to that by multi-Yukawa tails which is the only method presented so far.

A modified version of a self-consistent Ornstein-Zernike approximation for a fluid with a one-Yukawa pair potential.

We present a modified version of a thermodynamically self-consistent Ornstein-Zernike approximation (SCOZA) for a fluid of spherical particles with a pair potential given by a hard core repulsion and a Yukawa tail [Formula: see text]. We take advantage of the known analytical properties of the solution of the Ornstein-Zernike equation for the case in which the direct correlation function outside the repulsive core is given by the multi-screened Coulomb plus power series (multi-SCPPS) tails [Formula: see text] and the radial distribution function g(r) satisfies the exact core condition g(r) = 0 for r<1. The SCOZA is known to provide very good overall thermodynamics and a remarkably accurate critical point and coexistence curve. However, the SCOZA presented so far for continuum fluids has the deficiency that the solution behaves singularly at a density ρ where the screening length z(1)(ρ) of the hard sphere fluid nearly coincides with the Yukawa-tail screening length z(2) (>3.8). This is by no means a rare case in the studies of real fluids and colloidal suspensions. We show that the deficiency is resolved in the modified version of the SCOZA with multi-SCPPS tails. As a demonstration, we present some numerical results for z(2) = 8.0.

Alterations of the double-strand break repair gene MRE11 in cancer.

MRE11 plays a role in DNA double-strand break repair. Hypomorphic mutations of MRE11 have been demonstrated in ataxia-telangiectasia (AT)-like disorder. ATM mutations play a causal role in AT and have been demonstrated in lymphoid malignancies in patients without AT histories. By analogy with the relationship of ATM to lymphoid malignancies, it is probable that alterations of MRE11 are associated with tumor formation. We performed a mutation analysis of MRE11 in 159 unselected primary tumors. Three missense mutations at conserved positions were found in breast and lymphoid tumors. Additionally, an aberrant transcript without genomic mutation was found in a breast tumor. These findings suggest an occasional role for MRE11 alterations in the development of primary tumors.

Mutations in the RAD54 recombination gene in primary cancers.

Association of a recombinational repair protein RAD51 with tumor suppressors BRCA1 and BRCA2 suggests that defects in homologous recombination are responsible for tumor formation. Also recent findings that a protein associated with the MRE11/RAD50 repair complex is mutated in Nijmegen breakage syndrome characterized by increased cancer incidence and ionizing radiation sensitivity strongly support this idea. However, the direct roles of BRCA proteins and the protein responsible for NBS in recombinational repair are not clear though they are associated with the recombinational repair complexes. Since RAD51 forms a complex with other members of the RAD52 epistasis group and with BRCA proteins, it is reasonable to ask if alterations of members of the RAD52 epistasis group lead to tumor development. Here we describe missense mutations at functional regions of RAD54 and the absence of the wild-type RAD54 expression resulting from aberrant splicing in primary cancers. Since RAD54 is a recombinational protein associated with RAD51, this is the first genetic evidence that cancer arises from a defect in repair processes involving homologous recombination.

Mutations of a novel human RAD54 homologue, RAD54B, in primary cancer.

Association of breast tumor susceptibility gene products BRCA1 and BRCA2 with the RAD51 recombination protein suggested that cancer could arise through defects in recombination. The identification of NBS1, responsible for Nijmegen breakage syndrome, from the MRE11/RAD50 recombination protein complex also supports this hypothesis. However, our mutation analysis revealed that known members of the RAD52 epistasis group are rarely mutated in human primary cancer. Here we describe the isolation of a novel member of the SNF2 superfamily, characterized with sequence motifs similar to those in DNA and RNA helicases. The gene, designated RAD54B, is significantly homologous to the RAD54 recombination gene. The expression of RAD54B was high in testis and spleen, which are active in meiotic and mitotic recombination. These findings suggest that RAD54B may play an active role in recombination processes in concert with other members of the RAD52 epistasis group. RAD54B maps to human chromosome 8q21.3-q22 in a region associated with cancer-related chromosomal abnormalities. Homozygous mutations at highly conserved positions of RAD54B were observed in human primary lymphoma and colon cancer. These findings suggest that some cancers arise through alterations of the RAD54B function.

Human lung adenocarcinoma cell lines with different lung colonization potential (LCP), and a correlation between expression of sialosyl dimeric Le(x) (defined by MAb FH6) and LCP.

Human lung adenocarcinoma sub-cell lines HAL-8, HAL-24 and HAL-33, showing different lung colonization potential (LCP), were established from human lung adenocarcinoma cell line KUM-LK-2 using repeated cloning with limiting dilution technique. Cell lines HAL-8 and -33 were characterized by high and low LCP, respectively, while HAL-24 did not give rise to lung colonies. The cell surface protein and carbohydrate profiles were determined by cell surface labeling (with lactoperoxidase-dependent 125I-iodination and galactose oxidase-NaB3H4, respectively) followed by SDS-gel electrophoresis. Various carbohydrate epitopes expressed at the cell surface were analysed by cytofluorometry using various monoclonal antibodies (MAbs) directed to Le(x), sialosyl-Le(x), sialosyl dimeric Le(x), T, Tn and sialosyl-Tn structures, which are often reported as being highly expressed in a variety of human cancers, particularly adenocarcinoma. Expression of sialosyl dimeric Le(x) (defined by MAb FH6) was high on HAL-8, moderate on HAL-33, and relatively low on HAL-24. In contrast, each of the three lines showed essentially equal expression (as determined by MAb reactivity) of sialosyl-Tn (defined by MAb TKH2), Le(x) (defined by MAb SH1), and Tn (defined by MAb 1E3). The cell lines showed extremely weak expression of T (defined by MAb HH8). LCP of HAL-8 and -33 was completely inhibited by sialidase treatment of cells. It is suggested that higher expression of sialosyl dimeric Le(x) (defined by MAb FH6) in HAL-8 cells may play an important role in higher potential of blood-borne lung colonization.

Living donor liver transplantation for fulminant hepatic failure.

BACKGROUND: Living donor liver transplantation (LDLT) was originally indicated only for elective cases of pediatric patients with end-stage liver disease. In Japan, however, where liver transplantation from brain-dead donor is performed very rarely, this indication has been expanded to emergency cases such as fulminant hepatic failure (FHF). METHODS: Thirty-eight patients with FHF were treated between May 1992 and April 1999. Causes of acute liver failure were non-A, non-B hepatitis in 27 patients, hepatitis B virus in seven, and hepatitis A virus, Epstein-Barr virus, herpes simplex virus, and chrome poisoning in one each. RESULTS: Four patients did not undergo LDLT because of severe brain damage or combined multiple organ failure. The remaining 34 patients underwent a total of 36 LDLTs, including two retransplantations; 16 children received transplants of 17 lateral segments, three children and eight adults transplants of 11 left lobes, and seven adults transplants of eight right lobes. A total of 15 recipients died, four of primary graft dysfunction, three of refractory acute rejection, two of pneumonia, and one each of ductopenic rejection, sepsis, aplastic anemis, recurrence of Epstein-Barr virus hepatitis, multiple organ failure by chrome poisoning, and unknown hepatic failure. Primary graft dysfunction developed in adult recipients with small-for-size graft transplants, whereas refractory acute rejection and ductopenic rejection occurred in six grafts each of children with non-A, non-B FHF. CONCLUSIONS: LDLT can be safely expanded to cases of FHF in adult patients. Primary graft dysfunction in adult recipients with small-for-size left lobe grafts can be overcome by using right lobes. However, refractory acute rejection and ductopenic rejection in children remain a major problem.

Enhanced inhibitory effect of polymeric star burst formed yigsr Peptide on newly established nude-mouse spontaneous adenocarcinoma metastatic model.

A highly metastatic nude mouse adenocarcinoma cell line, XK-4, was established, and the inhibitory effect of the polymeric star burst YIGSR peptide on XK-4 metastasis was examined. XK-4 adenocarcinoma arose spontaneously in a nude mouse after the subucutaneous transplantation of a human colon cancer. XK-4 cells were first cultured in February, 1990 after serial transplantation of the tumor in nude mice since October, 1985. The XK-4 cell line produces blood borne lung or liver metastasis 2 weeks after injection into the tail vein or anterior mesenteric vein, respectively. Chromosomal analysis of the XK-4 cell line revealed only murine chromosomes, and isozyme analysis showed a murine pattern. Transplantation of XK-4 cells into a thymus-intact litter mate was rejected. These results suggest that the XK-4 adenocarcinoma grew spontaneously in the nude mouse due to some kind of human cancer stimulation. A peptide consisting of the active domain of laminin, YIGSR, was chemically synthesized as a polymer with a star burst pattern. The inhibitory effect of polymeric star burst YIGSR on XK-4 metastasis was enhanced, compared with monomeric YIGSR. These effects appear to be due to the prolonged half-life of polymeric star burst YIGSR in vivo, and increased binding of polymeric star burst YIGSR to the YIGSR receptor. In this study we established a new metastatic model, and confirmed the enhanced metastatic inhibitory effect of a polymeric form of the star burst YIGSR peptide.

Drug sensitivity test for primary culture of human cancer-cells using collagen gel embedded culture and image-analysis.

A new drug sensitivity assay method using the collagen gel embedded culture and image analysis was developed. Human cancer cells cultured in collagen gels showed extremely high cloning efficiency and in vivo-like drug response. In addition, image analysis was used successfully for the first time to automatically discriminate cancer colonies from contaminating fibroblastic cells by taking advantage of the difference in shape between them after cultivation to determine the drug response of cultured cancer cells accurately and easily. A new approach for the practical use of the drug sensitivity test on human cancer cells is suggested.

Involvement of galectin-3 expression in colorectal cancer progression and metastasis.

Galectin-3 is a beta-galactoside-specific lectin that binds to laminin sugar-sites and is involved in tumor malignancy. Galectin-3 expression in relation to primary tumor and liver metastasis of colorectal cancer was examined to determined its involvement in cancer progression and metastasis. Immunohistochemical staining of galectin-3 was performed on 117 primary lesions and 15 liver metastases of colorectal cancer using TIB166 monoclonal antibody. The expression of galectin-3 was evaluated by grading the intensity of the staining as either negative, weakly positive, or strongly positive. Normal mucosa of all patients were strongly positive for galectin-3, but the staining in these tissues was still significantly less than in the primary lesions of the cancer (31.6%). Galectin-3 expression in the primary lesions was significantly increased, correlating with the progression of clinical stage (p=0. 0224), liver metastasis (p<0.0001), venous invasion (p=0.0048), and lymph node metastasis (p=0.0289). Liver metastatic lesions also showed up-regulated levels of galectin-3 compared to the primary lesions (p=0.0030). The group showing strongly positive galectin-3 had a significantly poorer prognosis than the negative/weakly positive group in terms of disease-free survival (p=0.0224). The strong expression of galectin-3 in colorectal cancer correlates with cancer progression, liver metastasis, and poor prognosis for patients.

Correlation of prognosis of breast cancer patients and expression of Ley which acts as a cofactor of tumor procoagulant.

Association between Ley expression and prognosis of breast cancer was investigated using monoclonal antibody (MoAb) FS01, which recognizes Ley as an epitope, inhibits the procoagulant activity of cancer cell-derived coagulating activity 1 (CCA-1). Expression intensity and procoagulant activity of CCA-1, tissue factor and HLA-DR on breast cancer cell lines were also examined. Immunohistochemical staining of Ley was performed on primary lesions of 223 breast cancer patients who received absolute curative operation. Flow cytometric analysis and clot timer was used to detect expression and activity of each procoagulant on cancer cell lines. The Ley expression was 73.5%, and no significant relation was observed between clinicopathological factors and intensity of Ley expression. The group showing strong Ley positivity had a significantly poorer prognosis than the Ley-negative group in 5-year disease-free survival (p=0.019). Multivariate analysis using the Cox's proportional hazards' regression model showed that Ley expression is an independent prognostic factor (p=0.018), following tumor size and lymph node metastasis. Ley expression on cancer cell surface is higher than tissue factor and HLA-DR. FS01 and anti-tissue factor MoAb inhibited the coagulating activity of tissue factor-expressing lines, but no cells were inhibited by staphylococcal enterotoxin A, which is known to inhibit the coagulating activity of HLA-DR. CCA-1 and tissue factor plays a important role in the blood coagulating activity of breast cancer cell lines. Breast cancer patients are thought to have a poor prognosis because Ley expression on the surface of the cancer cell induces blood coagulation via CCA-1.

Role of galectin-3 in adenocarcinoma liver metastasis.

Galectin-3 is a lactosamine-specific lectin that binds to laminin sugar-sites, and up-regulated expression of galectin-3 in primary colorectal cancer is involved in cancer progression and metastasis. Inhibitory effects of cell adhesion and liver metastasis of adenocarcinoma via portal vein by lectin-binding sugar and anti-galectin-3 antibody was examined to determine the role of galectin-laminin binding in cancer liver metastasis. Highly metastatic adenocarcinoma cell lines XK4-A3 and RPMI4788 were used in in vitro cell attachment and nude mice liver metastatic experiments, and inhibitory effects of anti-galectin-3 antibody or lectin-binding sugars were examined. The in vitro adhesion assay demonstrated that the anti-galectin-3 antibody and alpha-lactose inhibited XK4-A3 and RPMI4788 cell adhesion to laminin in a dose-dependent manner. The liver metastasis of XK4-A3 and RPMI4788 was reduced 50 and 60%, respectively (P<0.001) by alpha-lactose treatment. Anti-galectin-3 antibody also inhibited liver metastasis in a dose-dependent manner, and maximum inhibition rate was 66% for XK4-A3 and 90% for RPMI4788. Galectin-3 plays an important role in liver metastasis of adenocarcinoma by the mechanisms of galectin-3 binding to laminin. Inhibition of galectin-3 on cancer cell surface induces reduced cell attachment to laminin and liver metastasis.

An in vitro chemosensitivity test for solid human tumors using collagen gel droplet embedded cultures.

In vitro chemosensitivity testing using a collagen gel droplet embedded culture drug sensitivity test (CD-DST), was conducted with several types of solid cancer. The overall evaluable rate was 80% (443/554), including 76% for lung (n=243), 78% for breast (n=110), 87% for gastric (n=62), 83% for colorectal (n=107) cancers and 88% for 32 metastatic brain tumors. The in vitro sensitivity of breast, gastric and colorectal cancers to mitomycin C (MMC), cisplatin (CDDP), 5-fluorouracil (5-FU) and doxorubicin (DXR) was similar to the efficacy rates reported for each drug. This was also observed with lung cancer, the sensitivity of which to MMC, CDDP, vindesine (VDS) and etoposide (VP-16) was similar to the clinical efficacy. The clinical response to chemotherapy was compared with the results of in vitro chemosensitivity testing in Il patients: the clinical correlation was 91%, with a 80% true positive and 100% true negative rate. These results suggest that the CD-DST may be clinically useful by allowing the prediction of clinical response in various solid cancers.

Ley glycolipid-recognizing monoclonal antibody inhibits procoagulant activity and metastasis of human adenocarcinoma.

Tumor procoagulant is associated with cancer at advanced stages of malignancy such as infiltration and metastasis. In the present study, we investigated the role of Ley glycolipid in the mechanism of cancer metastasis. Ley glycolipid acts as an important cofactor in the expression of the blood-coagulating activity of cancer cell-derived coagulating activity 1 (CCA-1), which is one of the known tumor procoagulants. Monoclonal antibody (MoAb) FS01, which serves as the Ley-recognizing epitope, inhibits the procoagulant activity of CCA-1 was found to dose-dependently inhibit the procoagulant activity of normal plasma induced by the human lung adenocarcinoma cell line, HAL8, which shows a high level of Ley expression. It did not, however, inhibit the procoagulant activity of the human colon cancer cell line, RPMI4788, which does not express Ley. Administration of FS01 MoAb inhibited lung metastasis of HAL8 cells, but not that of RPMI4788. The absence of antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity of FS01 MoAb against the HAL8 cell line suggests that the inhibition of HAL8 metastasis by FS01 MoAb derives from the inhibition of blood-coagulating activity of the latter. These findings indicate that Ley glycolipid plays an important role in the mechanism of cancer metastasis via the procoagulant activity of CCA-1.

Evidence that donor pretreatment with FK506 has a synergistic effect on graft prolongation in hamster-to-rat heart xenotransplantation.

BACKGROUND: Concordant xenografts are rejected in a different fashion than are discordant xenografts or allografts. We tested the effect of donor pretreatment with the use of FK506 combined with posttransplantation FK506 treatment and splenectomy and analyzed the mechanism of rejection in hamster-to-rat heart xenotransplantation. METHODS: Heart xenotransplantation from hamster to rat was carried out under immunosuppression with the use of donor pretreatment with FK506, posttransplantation FK506 treatment and splenectomy, followed by complement-dependent cytotoxicity assay, delayed type hypersensitivity test, and histologic analysis. RESULTS: The cardiac graft survived 3 days without donor pretreatment, whereas it survived 4.8 days with donor pretreatment with FK506 (5 mg/kg for 3 days). The graft survival was synergistically enhanced by donor pretreatment, posttransplantation FK506 therapy, and splenectomy, and the longest survival was 43.6 +/- 7.7 days in the group with donor pretreatment, posttransplantation FK506 therapy for 4 weeks, and splenectomy. Delayed-type hypersensitivity response was suppressed significantly in the donor pretreatment group. The antibody typed by immunoglobulin M was mainly detected in the rat serum with the rejected grafts by complement-dependent cytotoxicity assay. Correlating with this complement-dependent cytotoxicity titer, neutrophil infiltration and vasculitis of the coronary vessels were recognized in the rejected grafts, and the marginal zone of the white pulp expanded in the spleen. CONCLUSIONS: Donor pretreatment with FK506 combined with posttransplantation FK506 therapy and splenectomy suppresses the outlet antigen, immunoglobulin M production, and lymphocyte activation, thereby prolonging the graft survival in hamster-to-rat heart xenotransplantation.

Establishment of a concordant xenogeneic splenocyte injection model for the dynamic study of the marginal zone in the spleen.

BACKGROUND: This study was undertaken to establish a simple technique with which we could investigate the relationship between the marginal zone (MZ) in the spleen and antispecies antibody production, as well as to estimate the efficacy of various immunosuppressive treatments in xenotransplantation. METHODS: With a concordant xenogeneic combination (hamster-to-rat), the early phase reaction of the MZ was studied by use of quantitative histologic analysis, and complement-dependent cytotoxic antibody titers were determined in both a heart transplantation model and the splenocyte injection model. Furthermore, changes in the MZ were examined with isogeneic and allogeneic combinations with the splenocyte injection model. Next, the effect of cyclophosphamide, a promising immunosuppressant for concordant xenotransplantation, was examined by use of the splenocyte injection model. RESULTS: With a concordant xenogeneic combination, the MZ enlarged, and antihamster immunoglobulin M antibody synthesis increased after immunization in both models. On the other hand, with an isogeneic combination, the MZ did not expand, and with an allogeneic combination the MZ enlargement was not as great as that with a concordant xenogeneic combination. Cyclophosphamide suppressed the MZ expansion in a dose-dependent manner and effectively diminished antibody production in the splenocyte injection model. CONCLUSION: Dynamic studies of the MZ in the spleen with the splenocyte injection model are useful for the elucidation of the mechanisms of reaction and for estimating the efficacy of various immunosuppressive treatments in concordant xenotransplantation.

Evaluation of tetrahydropyranyladriamycin as an immunosuppressant in concordant xenotransplantation.

BACKGROUND: Tetrahydropyranyladriamycin (THP), a derivative of anthracycline, exhibits a stronger antiproliferative activity and a lower cardiotoxicity than the other anthracyclines. The value of THP as an immunosuppressant has not been examined yet, whereas cyclophosphamide, which is another antiproliferative drug, has shown promise as an immunosuppressant in concordant xenotransplantation. METHODS: The effect of THP on the marginal zone in the spleen and anti-species antibody production was evaluated and was compared with that of cyclophosphamide in a concordant xenogeneic splenocyte injection model (hamster-to-rat). Next, THP was used as monotherapy for hamster-to-rat heart transplantation to substantiate the potency of its immunosuppressive activity in concordant xenotransplantation. Finally, combination therapy with THP plus FK506 was tried. RESULTS: THP (5 mg/kg) suppressed the expansion of the marginal zone more than did cyclophosphamide (40 mg/kg) and inhibited the production of antispecies antibody as much as did cyclophosphamide (40 mg/kg) in the splenocyte injection model. THP monotherapy could prolong the survival of hamster-to-rat heart grafts up to 14.5 +/- 3.2 days (n = 21). The rejected grafts in the THP-treated animals did not show any histologic evidence of vascular endothelial damage but did exhibit a mononuclear cell infiltration. Combination therapy with THP plus FK506 provided excellent graft survival. CONCLUSIONS: THP can prevent early phase humoral rejection in concordant xenotransplantation.

Antitumor and endocrine effects of an aromatase inhibitor (CGS 16949A) on DMBA-induced rat mammary tumor.

The antitumor and endocrine effects of a new nonsteroidal aromatase inhibitor were studied using DMBA-induced rat mammary carcinomas. CGS 16949A (CGS) was administered orally once daily for 3 weeks. A marked antitumor effect was noted at doses of more than 1 mg/kg, and weight gain was dose dependent. Histologic examination showed atrophic changes of the tumors and decreased expression of estrogen receptor levels. To investigate the mechanism of the antitumor effect of CGS, we studied the changes in endocrine function in rats given this agent. In the groups receiving more than 1 mg/kg of CGS, the serum estradiol and prolactin levels were lower and the serum luteinizing hormone level was higher than in the control group. In rats treated with CGS, ovary weight was increased, while uterus and pituitary weights were decreased. These changes were dose dependent. In contrast, the serum corticosterone level and adrenal weight remained unchanged. We conclude that CGS inhibits the growth of hormone-dependent tumors by changing the hormonal environment.