Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monoclonal antibodies to the transferrin receptor or to the T cell antigen, CD5, were chemically linked to mammalian RNase A and found to specifically inhibit protein synthesis in antigen-positive cells. Antibody-mediated specificity of these cytotoxic ribonuclease chimeras (CRCs) was demonstrated in three ways. 1) Toxicity was due to the chemical linkage of RNase to antibody, as the individual components added separately or in combination did not inhibit protein synthesis; 2) the anti-transferrin receptor CRCs inhibited protein synthesis in those cells expressing the human transferrin receptor (K562, U251, Jurkat cells) but had no detectable toxicity to cells lacking the human transferrin receptor (Vero or NIH 3T3 cells); 3) free antibody to either the human transferrin receptor (454A12 or 5E-9) or to the T cell antigen, CD5 (T101), blocked the cytotoxicity of the respective CRC. Two CRC species, designated P1 and P2, that differed in size and stoichiometry of RNase A to antibody, were purified by size-exclusion high performance liquid chromatography. The higher molecular weight P1 conjugate had an IC50 of 20-30 nM, whereas the P2 conjugate had a higher IC50 of 300-500 nM. Bioactivity could be reversibly increased more than 10-fold by freezing. The cytotoxicity of the CRCs was examined in vivo in a solid tumor animal model. Intratumoral injections of an anti-transferrin receptor CRC into established U251 human glioblastoma tumors grown in the flanks of nude mice prevented tumor growth, whereas RNase A mixed with antibody was ineffective. CRCs, therefore, express cytotoxicity in vitro and in vivo. Mammalian nucleases coupled to antibodies may be utilized as cell type-selective cytotoxins and have potential as pharmacologic reagents. The systemic toxicity and immunogenicity observed with mammalian derived cytotoxins may be significantly less than that of the currently employed plant- and bacterial-derived immunotoxins.
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PMID:Cytotoxic ribonuclease chimeras. Targeted tumoricidal activity in vitro and in vivo. 152 74

The expression of HLA-DR and of the receptors for transferrin and interleukin-2 was histochemically analyzed for 27 human lung carcinomas, 3 mesotheliomas, and 3 thymomas by use of the monoclonal antibodies CLONAB Tf-R, Il-2R, and LN3. In addition, a pan B-cell antibody (CD-19) and a pan T-cell antibody (CD3) were applied. The transferrin receptor was found to be expressed in all cases of adenocarcinoma, in 12/17 cases of epidermoid carcinoma, and in a similar percentage of the thymoma cases (2/3). The interleukin-2 receptor specific antibody stained positively only for 3 cases (1 mesothelioma, 1 adenocarcinoma, and 1 epidermoid carcinoma). The expression of HLA-DR could be demonstrated in a similar small percentage of adenocarcinoma and of epidermoid carcinoma, however in 2/3 cases of mesothelioma and thymoma, respectively. The CD-19 antibody stained negatively for all tumor cases, the pan T-antibody positive in 2/10 adenocarcinoma and in 1/3 thymoma. The data suggest that the transferrin receptor may play an important role in human lung tumor growth. In addition, it may be used as diagnostic aid for distinguishing mesothelioma from metastatic adenocarcinoma of lung into the pleura.
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PMID:Expression of transferrin- and interleukin-2-receptors, and HLA-DR in human lung carcinoma. 202 54

Expression of the product of the c-erbB-2 gene, a proto-oncogene related to, but distinct from c-erbB-1 encoding the epidermal growth factor receptor (EGF-R), was investigated in human urinary bladder carcinomas. In addition, levels of EGF-R and transferrin receptor were also analyzed using an immunohistochemical approach, and the results compared with histological pattern and grading, and tumor staging. Increased expression of c-erb B-2 product was found in 32% of cases (7/22), a positive reaction being observed in 60% of transitional cell carcinoma (TCC) Grade 3 lesions (3/5), 20% of Grade 2 TCCs (2/10) and 100% of adenocarcinomas (AC) (2/2), but in none of the cases of squamous cell carcinoma (SCC). Although no statistical correlation with staging was evident, TCCs or SCCs of high grade and stage often showed EGF-R-positive staining, whereas other well differentiated lesions and normal bladder epithelium were generally negative. Most cases of urinary bladder carcinoma were positive for the transferrin receptor, which was not detected in normal bladder. The results thus suggested that a positive reaction for c-erbB-2 product is correlated with TCC histological grading or AC morphology. A high intensity of EGF-R staining in human bladder carcinomas may be associated with poor differentiation and invasion, whereas transferrin receptor expression might reflect tumor growth.
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PMID:Immunohistochemical analysis of c-erbB-2 oncogene product and epidermal growth factor receptor expression in human urinary bladder carcinomas. 220 26

Data are presented indicating that the growth of 5 out of 5 murine lymphoid tumors can be inhibited in a synergistic fashion in vitro by combined treatment with the iron chelator deferoxamine (DFO) and an immunoglobulin G (IgG) monoclonal anti-transferrin receptor antibody (ATRA). A two-way dose/response analysis shows that the ATRA becomes more efficient as an inhibitor with increasing doses of DFO. Flow cytometric studies further support the view that IgG ATRAS impair transferrin receptor (TR) function by causing TR down-modulation and degradation, even when the presence of DFO acts to promote increased cell surface TR expression. It is also shown that an IgG ATRA is nearly as effective as an IgM ATRA in inhibiting tumor cell growth when used in combination with DFO. Finally, studies with the iron chelator picolinic acid show that it produces only additive, or very slightly supra-additive, effects when used in combination with the ATRA. Therefore, these studies not only continue to suggest that combination chelator/ATRA therapy warrants further investigation as a tool in the therapy of hematopoietic malignancies, but also make the following new points: (1) the clinically familiar iron chelator deferoxamine, but not all iron chelators, produces synergistic inhibition of tumor growth in vitro with ATRAS; and (2) IgG ATRAS, which may be clinically more attractive reagents than IgA or IgM ATRAS because of better access to extra vascular tissue spaces, have unexpectedly been found to function as powerful growth inhibitors when used in combination with DFO.
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PMID:Synergistic inhibition of lymphoid tumor growth in vitro by combined treatment with the iron chelator deferoxamine and an immunoglobulin G monoclonal antibody against the transferrin receptor. 239 21

Soluble transferrin receptor (sTfR) in serum of cancer patients was measured by a sandwich enzyme-linked immunosorbent assay, and the effect of sTfR for natural killer cytotoxicity was also studied. The statistical values of sTfR levels in sera were found to be 250 +/- 77 U (Mean +/- SD) in healthy individuals, while 288 +/- 162 U in chronic liver disease, 402 +/- 290 U in hepatocellular carcinoma, 429 +/- 261 U in gastric cancer, 347 +/- 207 U in acute leukemia and malignant lymphoma, and 251 +/- 100 U in other cancer. No significant difference in the sTfR levels among the patients was observed, although the difference between the healthy individuals and the patient groups was shown to be statistically significant at p less than 0.01 level. The effect of sTfR isolated from serum of a patient with iron-deficiency anemia by means of Sephadex G-200 column for natural killer activity was carried out. Cytotoxicity of natural killer cell in healthy individuals was inhibited by sTfR as the dose dependent manner, and the inhibitory rate was found to be 23.1 +/- 12.8% (Mean +/- SD) when the concentration of the sTfR was 1,250 U added in the cytotoxicity test. Furthermore, the inhibitory activity of serum in cancer patients was correlated with the sTfR level. These results suggest that sTfR is one of the inhibitory factors for the natural killer cell activity in vivo, and the factor could be facilitated for tumor growth and metastasis. Therefore, the measurement of sTfR in serum may be useful for monitoring immunological competency in cancer patients.
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PMID:[Elevation of soluble transferrin receptor substance in serum of cancer patients with suppressed natural killer activity]. 261 80

The percentages of activated lymphocytes in colon cancers were compared to clinical features of the tumors and to functional characteristics of the tumor-infiltrating lymphocytes (TIL) in order to evaluate the role of activated TIL in controlling tumor growth. The TIL isolated from colon cancers contained 80 +/- 6% T cells [cluster designation (CD) 2+], 42 +/- 9% CD4+ cells, 27 +/- 9% CD8+ cells, 17 +/- 5% cells (surface immunoglobulin or SIg+), 6 +/- 2% null cells (CD2-, SIg-), 6 +/- 4% Leu 7+ cells, 1 +/- 0% macrophages (CDw 14+), and no plasma cells (PCA+). The lamina propria lymphocytes (LPL) isolated from adjacent colonic mucosa contained a similar distribution but with fewer CD8+ (10 +/- 5%) and Leu 7+ (0.6 +/- 0.3%) lymphocytes (P less than 0.05). More TIL than LPL expressed the interleukin-2 (IL-2) receptor (9 +/- 8% vs 1 +/- 0.8% CD25+ cells; P less than 0.05) and the transferrin receptor (4 +/- 5% vs 0.3 +/- 0.6% T9+ cells; P less than 0.05). Those TIL expressing activation antigens were CD2+, SIg-. The percentage of TIL that were CD25+ did not correlate with the extent of tumor spread, with the degree of tumor differentiation, nor with the percentage of HLA-DR+ tumor cells. However, there were significantly more CD25+ TIL from tumors located in the left colon, particularly small lesions, than from tumors located in the right colon (P less than 0.05). The proliferation of TIL preparations cultured with medium alone, with mitogens, or with IL-2 did not vary according to the percentage of CD25+ lymphocytes in the TIL. T cells may be activated by foreign surface determinants on tumor cells, particularly in small, left-sided lesions.
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PMID:Characterization of activated lymphocytes in colon cancer. 278 2

Previous studies have shown that the ganglioside GD3 is expressed in high concentrations on melanoma cells and that monoclonal antibodies (MAbs) against GD3 may induce partial remissions in tumor growth in patients with melanoma. The present studies indicated that incubation of interleukin 2 (IL2) dependent murine natural killer cells with several MAbs against the ganglioside GD3 potentiated the proliferative response to IL2. There was no effect on cell division in the absence of added IL2. Similarly the mitogenic response of human blood lymphocytes to phytohemagglutinin (PHA) or the T3 antigen was enhanced by coculture with these MAbs. This was noted when the MAbs to GD3 were added either before or up to 48 h after addition of PHA or MAb to T3. Kinetic analysis revealed that the potentiation of the PHA induced mitogenic response followed the expected response to PHA suggesting that the MAbs amplified normal activation pathways. These effects were also seen wih MAb to GD3 and the T10 structure on T-cells but not with MAbs to the transferrin receptor or isotype MAb controls. Studies on T-cell subsets suggested that the enhanced PHA responses were confined mainly to the T8 subset and responses of the T4 subset were not enhanced. Flow cytometric analysis revealed low levels of GD3 expression on blood lymphocytes which increased during culture with PHA. IL2 receptor (Tac epitope) expression did not show close correlation with the enhanced lymphocyte responses and the mechanism of the potentiation remains uncertain. These studies raise questions concerning the role of gangliosides in T-cell activation and whether these in vitro effects of MAbs to GD3 may account in part for their antitumor effects in patients with melanoma.
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PMID:Potentiation of lymphocyte responses by monoclonal antibodies to the ganglioside GD3. 302 15

Epidermal growth factor receptor (EGFR) expression was determined on 88 primary breast carcinomas immunohistochemically. These results were compared with growth fractions (Ki-67 immunoreactivity and Transferrin receptor (TrfR) expression), histologic tumor type, tumor grading, axillary lymph node status and estrogen receptor (ER) status. 60.2% were EGFR positive. Cytomorphology predominantly revealed a fine granular staining pattern. Sometimes a concentrated immunoreaction on the intercellular and basal oriented cell poles could be observed. EGFR expression in relation to growth fractions, grading, tumor diameter and lymph node status showed no correlation, suggesting that EGFR status seems to be independent to tumor growth and morphological prognostic parameters. ER status revealed an inverse correlation to EGFR expression (Kendall's tau: -0.22804, p = 0.012). In this context, it stands to reason to investigate further how far determination of EGFR expression justifies the existence of different subpopulations of breast cancer cells with respect to prognostic value.
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PMID:Expression of epidermal growth factor receptors (EGFR) on breast carcinomas in relation to growth fractions, estrogen receptor status and morphological criteria. An immunohistochemical study. 336 49

An immunotoxin composed of an antibody to the human transferrin receptor (454A12) and ricin A chain (RTA) was shown to inhibit the growth of NIH:OVCAR-3 tumors in a nude mouse model of human ovarian cancer. Inhibition of tumor growth by 454A12-RTA was related to the dose administered. The antitumor activity of the immunotoxin was blocked by coinjection of excess antibody with immunotoxin. An immunotoxin made using 454A12 and recombinant ricin A chain (rRTA) had an activity similar to that made with native RTA. The administration of 10 micrograms or greater of the immunotoxin 454A12-RTA/rRTA had significant antitumor activity. The injection of 30 micrograms of an irrelevant immunotoxin, MOPC21-RTA, or 30 to 500 micrograms of the 454A12 antibody had no antitumor activity.
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PMID:Antitumor activity of an immunotoxin in a nude mouse model of human ovarian cancer. 349 65

The ability of monoclonal antibodies (MAbs) against the murine transferrin receptor to inhibit the growth of transplanted syngeneic AKR/J SL-2 leukemic cells has been investigated. Two rat IgM antibodies, RI7 208 and REM 17.2, which both block transferrin receptor function, inhibited the growth of SL-2 leukemic cells in vitro at concentrations of 5-10 micrograms per ml. However, RI7 208 was more effective than REM 17.2 in prolonging survival of tumor-bearing mice. The antitumor effects of RI7 208 MAb were dependent on both the antibody dose and number of leukemic cells inoculated. The serum clearance of [75Se]methionine-labeled RI7 208 and REM 17.2 antibodies was similar and consisted of an initial rapid phase over the first 2 days followed by a slower phase. A single dose of 2 mg of antibody maintained a serum MAb concentration (greater than 10 micrograms/ml) sufficient to inhibit SL-2 leukemic cell growth in vitro for 2-3 days. The liver, kidney, and spleen were the major sites at which each of the antibodies accumulated regardless of whether trace or saturating amounts of antibody were administered. The specific activity of antibody found in s.c. SL-2 tumors was about 2-fold less than that of liver. It was shown that multiple doses of R17 208 MAb administered on a schedule aimed at maintaining a therapeutic serum level of MAb for 1-3 weeks were more effective than a single dose. Further, administration of RI7 208 MAb, in combination with the anti-Thy-1.1 MAb 19E12, was more effective than either antibody alone. SL-2 mutant cells were selected that were resistant to growth inhibitory effects of RI7 208 in vitro. The effects of RI7 208 MAb on the growth of these mutant cells in vivo suggests the major mechanism by which the MAb inhibits SL-2 tumor growth is by directly blocking receptor function. Acute toxicity associated with administration of the MAb was minimal. However, assays of myeloid and erythroid colony-forming units in bone marrow and spleen of mice given multiple doses of RI7 208 showed a depression of stem cell activity in bone marrow and elevated numbers of erythroid and cellular colony-forming units in the spleen.
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PMID:Effects of monoclonal antibodies that block transferrin receptor function on the in vivo growth of a syngeneic murine leukemia. 380 79


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