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)

Adriamycin (ADM) was chemically coupled to two monoclonal antibodies (MAb) expressed on human B-cell lymphomas. Immunoconjugates were prepared by linking to the MAb an ADM derivative, Adriamycin 13-[3-(2-pyridyldithio)propionyl]hydrazone (ADM-HZN), which releases ADM under mild acidic conditions (see preceding article). The (ADM-HZN) conjugates were tested for antitumor activity on two human B-lymphoma xenografts, Daudi and Ramos, which were growing as solid tumors in athymic mice. The conjugates, injected i.p., significantly inhibited tumor growth when antibody protein doses were greater than or equal to 500 mg/kg (approximately 10 mg/mouse). At these input antibody doses, (ADM-HZN) conjugates were more potent and had greater antitumor activity than free ADM given at an optimized dose and schedule. MAb-conjugated ADM was also tolerated to much higher levels than unconjugated drug. Antitumor activity was not obtained using mixtures of MAb plus free drug or with MAb-drug conjugates that did not bind to the tumor target cell. Thus, the antitumor activity of the immunoconjugate was directed by binding of the MAb portion of the conjugate to target tumor cells.
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PMID:Antitumor activity of adriamycin (hydrazone-linked) immunoconjugates compared with free adriamycin and specificity of tumor cell killing. 220 23

SJL/J B-cell lymphomas induce proliferation of syngeneic CD4 cells, on which the tumors are dependent for growth. We sought to determine whether cyclophosphamide (CY) treatment of tumor-bearing mice would be successful through effects on tumor cells, CD4 cells, or both. The markedly increased survival of treated mice derived predominantly from reduced proliferation of CD4 cells in response to tumor. Reduced proliferation of CD4 cells created a microenvironment that was not conducive to tumor growth, as evidenced by the failure of a subsequent tumor cell challenge to treated mice to significantly increase the rate of the mice. We concluded that CY affected the tumor-stimulated environment of SJL/J mice by killing CD4 cells that had been activated by a pre-existing tumor stimulus and by promoting the appearance of a population of CD8 cells that suppressed the ability of residual or recovering CD4 cells to proliferate in response to tumor. The CD8 population from treated mice was specific, based on the ability to suppress a tumor-stimulated mixed lymphocyte response (MLR) and the related autologous MLR and an inability to suppress an allogeneic- or Con A-induced response. Since CD8 cells from CY treated mice had no demonstrable antitumor activity, the most likely suppressor targets were responder CD4 cells in the tumor-stimulated MLR. The results emphasize that the design of a treatment protocol can take advantage of the immunodependency of a tumor.
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PMID:The CD4 cell dependency of SJL/J B-cell lymphomas as a target for cyclophosphamide therapy. 251 99

Two Epstein-Barr virus (EBV)-negative lymphoma B-cell lines, HBL-1 and HBL-2, were established from a pleural effusion and a lymph node biopsy of two patients with diffuse large cell lymphoma. HBL-1 and HBL-2 showed the characteristics of activated B-cells in B-cell lineage, as did original lymphoma cells. Chromosome analyses revealed that HBL-1 exhibiting 14q+ marker-positive lymphoid cancer showed a new subclass of 14q32 translocation resulting from a translocation between chromosomes 14 and 16, which had been masked in a complex translocation involving five chromosomes, and that HBL-2 had a 14q+ marker chromosome, the result of an 11;14 translocation [t(11;14)(q13;32)]. Successful heterotransplantation into athymic nude mice demonstrated tumorigenicity of HBL-1 and HBL-2. The transplantability and tumor growth rate of HBL-2 were higher and more rapid than those of HBL-1. HBL-1 and HBL-2 appear useful for facilitating therapeutic investigations as well as immunologic and oncogenic studies in B-cell lymphomas.
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PMID:Characterization and comparison of two newly established Epstein-Barr virus-negative lymphoma B-cell lines. Surface markers, growth characteristics, cytogenetics, and transplantability. 333 18

Epstein-Barr Virus (EBV) is implicated in the pathogenesis of endemic Burkitt's lymphoma (BL), B-cell lymphomas occurring under immunosuppression, nasopharyngeal carcinoma and Hodgkin's disease. Two distinct patterns of latent EBV gene expression occur in EBV-associated lymphomas. BLs typically display expression of the nuclear antigen EBNAI only, whereas EBV-associated, non-Burkitt B-cell lymphomas express at least 9 latent viral genes (6 EBNAs and 3 latent membrane proteins), reminiscent of in vitro EBV-immortalized lymphoblastoid cell lines (LCL). BLs are characterized by local, extra-nodal growth, whereas EBV-associated B-cell lymphomas often disseminate to peripheral lymphoid tissue. We show here that BL cells forming local tumors after xenotransplantation into SCID mice disseminate to lymphoid tissue following introduction of the latent membrane protein I (LMP 1) gene. Introduction of LMP 1 into BL cells induced expression of CD44 on the cell surface, a molecule implicated in enhanced lymphoid tumor growth and dissemination. Introduction of CD44 into LMP 1-/CD44-BL cells was observed to confer the disseminated tumor growth pattern associated with LMP 1 expression. Taken together our results show that expression of LMP 1 may regulate expression of CD44 and play an important role in the behavior of EBV-based lymphomas.
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PMID:Induction of CD44 expression by the Epstein-Barr virus latent membrane protein LMP1 is associated with lymphoma dissemination. 753 55

In malignant non-Hodgkin lymphomas (NHL), cytogenetic analysis may provide prognostic information including prediction of histologic evolution and responsiveness to therapy. In this study, we correlate clinical data and chromosomal aberrations in 70 adult patients with newly diagnosed NHL followed for a median of 20 months. Clonal aberrations were detected in 68/70 patients (97%). Besides t(2;5)(p23;q35), observed exclusively in three patients with anaplastic large cell lymphoma, Ki-1 positive, none of the characteristic aberrations observed was specific for a given histological subtype. Aberrations of chromosome 7 (n = 21) occurred in all histological subtypes together with aberrations of chromosome 3 and of the short arm of chromosome 17. They were clinically associated with a high serum lactate dehydrogenase level (LDH) and a trend to short survival. Anomalies of the long arm of chromosome 13 (n = 10) were found in patients with high grade B-cell lymphomas and bulky disease. In t(14;18)(q32;q21) bearing lymphomas (n = 27), distinct patterns of additional aberrations were observed in low grade and high grade lymphomas: trisomy 3 and trisomy 18 occurred concomitantly in high grade lymphomas (n = 6, p < 0.001) as well as aberrations of 1q, 5q, 6q and +der (18)(q21). In conclusion, cytogenetic analysis provides information about the complexity of genetic changes in NHL. These changes act not only as indicators of disease activity, but influence clinical outcome as demonstrated by their stringent correlation to the International Index and might reveal more general rules of tumor growth and spreading.
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PMID:Karyotype and prognosis in non-Hodgkin lymphoma. 796 39

Lymphomas (formerly reticulum cell sarcomas (RCS)) which develop spontaneously in SJL mice are a murine counterpart of human low grade B-cell non-Hodgkin's lymphoma. Tumor cells stimulate proliferation of syngeneic CD4+ T-lymphocytes which secrete cytokines required for tumor growth. Cyclophosphamide treatment of tumor-bearing mice (RCS/Cy) decreases in vitro tumor-stimulated CD4+ T-cell proliferation and, in turn, tumor growth, in part, through the suppressive action of CD8+ T-lymphocytes. In RCS/Cy compared to untreated tumor-bearing (RCS5) mice we report marked in vivo decreases in: (1) the activation (CD44HI/CD45RBLO phenotype) and proliferation (S + G2M phases of the cell cycle) of CD4+ T-lymphocytes; (2) the ratio of activated and/or proliferating CD4+ to CD8+ T-lymphocytes, and; (3) the proliferation of tumor cells. Also, depletion of CD8+ T-lymphocytes from RCS/Cy mice abrogated much of the efficacy of the RCS/Cy treatment and led to changes in lymphoid populations more reminiscent of those in RCS5 than RCS/Cy mice. The data support our hypothesis that the RCS/Cy treatment achieves its efficacy by preventing the predominance of CD4+ over CD8+ T-lymphocytes which is essential to maximum tumor growth in RCS5 mice. The results imply that analogous B-cell lymphomas in humans also may be treatable by shifting the T-cell balance toward inhibitory CD8+ rather than the tumor-stimulatory CD4+ T-lymphocytes.
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PMID:Cyclophosphamide treatment of an SJL murine B-cell lymphoma increases the proportion of suppressive CD8+ over tumor-stimulatory CD4+ T-lymphocytes. 823 Dec 37

B-cell lymphomas of mucosa-associated lymphoid tissue invariably contain large numbers of reactive tumor-infiltrating T cells. In the stomach, these lymphomas develop secondary to Helicobacter pylori infection, and clinical and in vitro studies have shown that their growth depends on help provided by H. pylori-specific T cells. In this study we characterized tumor-infiltrating T cells in low- and high-grade B-cell lymphomas of mucosa-associated lymphoid tissue using immunohistochemistry. In most cases, CD4+ T cells dominated and almost all T cells were CD45RO+ memory cells. In 11 of 13 cases studied, the proliferating T cells were CD4+ and no proliferation was observed in the CD8+ subset. In low-grade lymphomas, between 7 and 24% of T cells expressed CD40L whereas no CD40L expression was observed in the majority of high-grade tumors. Examination of homing receptor profile showed that both alpha 4 beta 7 integrin+ and L-selectin+ T cells were present. Examination of T cell diversity by a panel of antibodies against different T-cell receptor V beta regions and by analysis of T-cell receptor genes using polymerase chain reaction suggested that the T cells in these tumors were polyclonal. These results show that low-grade B-cell lymphomas of mucosa-associated lymphoid tissue contain a significant population of activated helper T cells that may be important in supporting tumor growth.
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PMID:Characterization of tumor-infiltrating T lymphocytes in B-cell lymphomas of mucosa-associated lymphoid tissue. 935 61

Epstein-Barr virus (EBV) has been detected in the large majority of HIV-related primary central nervous system lymphomas (PCNSL) suggesting a pathogenetic role of the virus. Unlike HIV-related PCNSL, conflicting data exist with regard to the presence of EBV in non immunodeficiency-related (sporadic) PCNSL. For this reason, a population based material of 41 sporadic PCNSL was analysed for the presence of EBV genome (EBER, BHLF) using RNA in situ hybridisation (RISH). Furthermore, the expression of the gene products of the bcl-2 oncogene and the p53 tumor suppressor gene and the tumor growth fraction reactive with the monoclonal antibody Ki-67 have been evaluated. All cases but two were EBV genome negative. In the two positive cases less than 5% of tumor cells showed EBER positivity. In contrast, more than 75% of cells morphologically belonging to the tumor-cell population stained positively for EBER in two cases of HIV related PCNSL. Immunostaining for the bcl-2 oncoprotein was positive in 28 (72%) of 39 cases examined. In most cases more than 75% of tumor cells showed cytoplasmic expression. Of 37 cases investigated for p53 expression, 21 (57%) stained positively. However, in the large majority of positive cases less than 10% of the neoplastic cells stained. The percentage of Ki-67 positive cells ranged between 10% and 80% with a mean of 50%. The expression of the p53 and bcl-2 oncoproteins and the growth fraction did not have any prognostic impact. We conclude that the EBV genome is rarely detected in sporadic PCNSL, indicating that a pathogenetic role of EBV is unlikely. Like extracerebral B-cell lymphomas a large fraction of PCNSL expresses the p53 and bcl-2 oncoproteins, a feature, however, which does not seem to have prognostic implications.
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PMID:Primary central nervous system lymphomas in immunocompetent individuals: histology, Epstein-Barr virus genome, Ki-67 proliferation index, p53 and bcl-2 gene expression. 966 83

The role of angiogenesis in neoplastic disorders is supported by the evidence that tumor growth beyond a certain size requires induction of new blood vessels. The extent of tumor-associated angiogenesis, measured as microvessel density (MVD), has shown to correlate with aggressiveness and the prognostic outcome in several malignant neoplasms. Few data have been reported on the angiogenic response in lymphoproliferative diseases. In this study, the MVD has been assessed in benign and malignant primary cutaneous B-cell lymphoproliferative disorders. MVD was determined in formaldehyde-fixed, paraffin-embedded specimens of primary cutaneous B-cell lymphomas (CBCL; n = 18) and cutaneous B-cell pseudolymphomas (B-PSL; n = 22) according to previously described protocols but was performed using computer-aided microscopic morphometry. The endothelial cells of microvessels were identified by immunohistochemical staining for factor VIII-related antigen and CD31. The MVD was 99 dots/mm2 for CBCL and 68 dots/mm2 for PSL, and a MVD of 115 dots/mm2 for CBCL and 73 dots/mm2 for PSL by using an antibody against factor VIII-related antigen and CD31 antigen, respectively. Univariate analysis revealed statistically highly significant differences in MVD between CBCL and B-PSL (P = 0.0036 with staining for factor VIII-related antigen and P = 0.0002 with staining for CD31 antigen). This study analyzes for the first time the angiogenic response in CBCL compared with that of B-PSL and demonstrates that MVD discriminates between CBCL and B-PSL. However, because of an overlap in the ranges of MVD in CBCL and PSL, the MVD is not useful as a diagnostic tool in individual cases.
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PMID:Angiogenesis in cutaneous lymphoproliferative disorders: microvessel density discriminates between cutaneous B-cell lymphomas and B-cell pseudolymphomas. 1077 Apr 34

The expression of the cyclin-dependent kinase inhibitor (CDKI) p27 protein was investigated in relation to (1) the expression of the cell cycle regulators p53, Rb and p16 and (2) the proliferation profile as determined by the expression of Ki67, cyclin A, and cyclin B1 in 80 cases of de novo diffuse large B-cell lymphomas (DLBCL). P27 expression was low/null in large tumor cells in 58/80 cases and intermediate/high in 22/80 cases. Increased expression of p53 protein was observed in 39/80 cases. Decreased expression of Rb and p16 proteins was mutually exclusive and was observed in 5/80 and 14/80 cases, respectively. The analysis of the p27 expression status (low/null versus intermediate/high) with respect to the p53 and/or Rb/p16 expression status showed that low/null p27 expression was significantly correlated with increased p53 expression (P =.018) and showed a strong trend for correlation with concurrent increased p53 expression and decreased Rb or p16 expression (P =.050). These findings suggest a tendency for concurrent alterations of the cell cycle regulators p27, p53, and Rb or p16 in DLBCL, which might result in impaired tumor growth control. Indeed, the analysis of the combined p27/p53/Rb/p16 expression status with respect to the proliferation profile showed that (1) three alterations in the combined p27/p53/Rb/p16 status (i.e., low/null P27 expression, increased expression of p53, and decreased expression of Rb or p16) were significantly correlated with increased expression of cyclin B1 (P =.005) and (2) two or three alterations were significantly correlated with increased expression of cyclin A (P =.014). These findings suggest combined impairment of a complex cell-cycle control network involving the CDK inhibitor p27, the P53 pathway, and the Rb1 pathway, which exerts a cooperative effect resulting in enhanced tumor cell proliferation.
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PMID:Low expression of p27 protein combined with altered p53 and Rb/p16 expression status is associated with increased expression of cyclin A and cyclin B1 in diffuse large B-cell lymphomas. 1170 71


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