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T Metz

Publications and source records attributed to T Metz.

At least 19 recordsLinked to original sources
PubMed2001

c-erbB-2 expression in small-cell lung cancer is associated with poor prognosis.

Small-cell lung cancer (SCLC) carries a bad prognosis despite good initial response to chemotherapy. It is therefore important to identify molecular markers that influence survival as potential new therapeutic targets. In our study, expression of the tyrosine kinase c-erbB-2 (HER2/neu) receptor in tumor tissues of 107 consecutive newly diagnosed patients with primary SCLC was quantified using a monoclonal antibody directed against the c-terminal domain of c-erbB-2. A clear-cut positive expression of c-erbB-2 was observed in 13% of patients. Surprisingly, c-erbB-2 was an independent prognostic factor (RR = 2.16; p = 0.014) when a proportional-hazard model was adjusted to stage (limited vs. extensive disease) and performance status (WHO I-IV), the most relevant clinical parameters. Similarly, a significant association between c-erbB-2 and survival was obtained if a larger number of clinical parameters were included into the analysis, namely response to chemotherapy, TNM stage, lactate dehydrogenase (LDH), neuron-specific enolase (NSE), gender and age (p = 0.033). Interestingly, c-erbB-2 expression was more relevant for patients with advanced tumors. In the subgroup of patients with bad performance status (WHO II-IV), median survival of patients with undetectable c-erbB-2 expression was 274 days compared with only 23 days for patients with clear-cut positive c-erbB-2 immunohistochemistry (p = 0.0031; log-rank test). Similar results were obtained for patients with extensive disease (p = 0.028) and high TNM stages (T>2 or N>1 or M1; p < 0.068, all comparisons). In contrast, c-erbB-2 expression was not associated with survival in patients with limited disease (p = 0.97), low TNM stages (p > 0.56, all comparisons) and good performance status (p = 0.97). In conclusion, c-erbB-2 is expressed in more than 10% of SCLC. Expression of c-erbB-2 is an independent prognostic factor of survival. The effect of c-erbB-2 expression seems to become more important in advanced stages of the disease. Since c-erbB-2 is a therapeutical target in other types of cancer, further studies to identify the role of c-erbB-2 in SCLC are clearly warranted.

Age Factors↗
PubMed1999

A comparative cell-based high throughput screening strategy for the discovery of selective tyrosine kinase inhibitors with anticancer activity.

Growth factor receptor tyrosine kinases (RTK) have been implicated in tumor growth, metastasis and angiogenesis, and are thus considered promising targets for therapeutic intervention in malignant diseases. We present a novel drug discovery strategy to find inhibitors of RTKs based on comparative screening of compound libraries employing functional cellular assays. Cell lines stably expressing HER2 and the receptors for hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), insulin-like growth factor-I (IGF-I) and epidermal growth factor (EGF) have been established. All cell lines are based on FDC-P1, a murine myeloid progenitor cell line which allows a direct comparison of results obtained in primary screens. In addition, the same cell lines are suitable for compound optimization and for animal studies. Using this strategy we report the identification of promising lead candidates for further drug development which are highly selective, non-cytotoxic and cell permeable with potencies in the low micromolar range.

Animals↗
PubMed1995

Absence of p53 allows direct immortalization of hematopoietic cells by the myc and raf oncogenes.

The p53 tumor suppressor is implicated here as a crucial barrier to unlimited cell proliferation. Its role in transformation of hematopoietic cells was studied by infecting fetal liver cells from wild-type or p53-/- mice with oncogenic retroviruses. Transformed colonies arose with a raf and a myc-raf virus. Absence of p53 did not affect their frequency but proved critical for their continued propagation. Colonies of p53-/- cells bearing both myc and raf readily yielded continuous cell lines without apparent requirement for genetic alteration. The lines, mainly of erythroid or myelomonocytic origin, were diploid but highly tumorigenic from their inception. These findings imply that p53 loss contributes directly to immortalization and tumorigenesis, probably by abrogating an intrinsic senescence program.

Animals↗
PubMed1995

[Lymph node tuberculosis in HIV-1 seropositive patients in Central Africa. A characteristic histopathologic picture].

Sixty two patients fulfilling the definition established by the Centers for Disease Control in 1982 for persistent lymphadenopathy syndrome, thought to be related to the human immunodeficiency virus (HIV) infection, were selected at the Butare university hospital, in Rwanda, between 1987 and 1988. Forty-five (73%) of them were indeed seropositive. Fifteen patients of sixty two (24%) presented unexpectedly evidence of tuberculous adenitis on biopsy. Three of them, found HIV-1 seronegative, showed a classical follicular adenitis, whereas the twelve other seropositive patients presented unusual histologic features, consisting of more or less immature tuberculoid granulomas with an abundant caseating and often granular necrosis, containing acid fast bacilli. Numerous blood vessels and abundant plasmacytosis were found in non-necrotic areas. Semi-quantitative evaluation of the granulomatous reaction components provided a histological spectrum probably related to the degree of impairment of the cellular immune response, which could be of prognostic significance. In areas where populations are exposed to both HIV and M. tuberculosis, it appears that lymph node biopsy with mycobacterial culture should be recommended in order to detect occult tuberculosis among HIV-seropositive persons, allowing accurate medical care and adequate public health surveillance.

AIDS-Related Opportunistic Infections↗
PubMed1994

Oncogenes and erythroid differentiation.

Committed erythroid progenitors are the cellular targets of oncogene-carrying avian and murine retroviruses that induce acute erythroleukemia. Normally, these cells undergo a fixed program of 5-10 cell divisions while terminally differentiating into erythrocytes. The sustained self-renewal observed in the context of their retrovirus-mediated leukemic transformation has been viewed as an abnormal, oncogene-induced effect. Recently, however, it was found that certain combinations of growth/differentiation hormones (e.g. TGF-alpha and estradiol) can induce normal avian erythroid progenitors to undergo a similarly extensive self-renewal as caused by oncogenes. This leads to the hypothesis that leukemia-inducing oncogenes take advantage of the committed erythroid progenitors' capacity for self-renewal rather than reprogramming their targets to abnormal growth, as suspected previously. These findings and their implications will be discussed.

Animals↗
PubMed1992

The nuclear oncogenes v-erbA and v-ets cooperate in the induction of avian erythroleukemia.

The nuclear oncogenes v-erbA and v-ets are known to cooperate with other viral oncogenes in the induction of avian erythroleukemia. Thus, in the case of avian erythroblastosis virus (AEV), v-erbA enhances the effect of the tyrosine kinase-encoding v-erbB oncogene by blocking the terminal differentiation of erythroid cells. In the case of E26 virus a fusion of the product from v-ets to that of the nuclear oncogene v-myb is a prerequisite for leukemogenicity. Here we show that an artificial virus carrying both v-erbA and v-ets induces a rapid, acute erythroleukemia phenotypically similar to that induced by AEV. In contrast, virus constructs containing either v-erbA or v-ets alone are non-leukemogenic, although they are capable of transforming erythroid cells in vitro. Analysis of in vitro-transformed cells showed that v-erbA induces a block of differentiation without abrogating dependence on anemic serum, while v-ets predominantly causes anemic serum independence. As expected, cells transformed by both oncogenes exhibit an increased proliferative potential, are blocked in differentiation and are anemic serum independent. These data demonstrate that two separately expressed nuclear oncoproteins can complement each other in vitro and in vivo. They also show that the v-Ets protein on its own can contribute to leukemogenesis.

Animals↗
PubMed1991

Fusion of the nuclear oncoproteins v-Myb and v-Ets is required for the leukemogenicity of E26 virus.

The highly leukemogenic avian retrovirus E26 expresses the two transcriptional activator-type oncogenes v-myb and v-ets as a nuclear fusion protein. Previous studies have shown that both oncogenes cooperate in the transformation of erythroid cells in vitro and that the phenotypes of transformed cells differ, depending on whether the oncogenes are coexpressed as separate proteins or as a fusion protein. Here we show that virus constructs encoding either v-Myb or v-Ets as their only oncoprotein are nonleukemogenic and that constructs coexpressing nonfused v-Myb and v-Ets proteins appear to be weakly leukemogenic. Surprisingly, leukemic animals injected with the latter contain highly leukemogenic variant viruses that exhibit internal deletions in their genome, resulting in the synthesis of novel Myb-Ets fusion proteins. These results show that v-Myb and v-Ets must be fused to cause leukemia and establish a new mechanism of oncogene activation and cooperation.

Alpharetrovirus↗
PubMed1991

Activation of cMGF expression is a critical step in avian myeloid leukemogenesis.

A non-leukemogenic version of the v-myb oncogene causes in vitro transformation of avian myeloblasts, which are dependent on chicken myelomonocytic growth factor (cMGF). We have shown that this version of v-myb, when combined with the erythroleukemia-inducing v-erbB oncogene, is capable of causing a mixed myeloid and erythroid leukemia. Myeloid leukemic cells transformed by this construct produce cMGF. To test whether autocrine growth stimulation via cMGF is the essential contribution of the tyrosine kinase oncogene v-erbB in avian myeloid leukemogenesis we constructed another retrovirus containing both the non-leukemogenic v-myb and the cMGF cDNA. This virus induced myeloid leukemia at high efficiency. In a third construct we combined v-myb with the human EGF-receptor gene. Myeloid cells transformed by this construct could be stimulated to grow by the addition of cMGF or EGF. Growth stimulation with EGF was blocked by a cMGF antiserum indicating that activation of a normal tyrosine kinase-type receptor induces cMGF expression but does not bypass the cMGF requirement. We conclude that cMGF plays a key role in the growth regulation of normal and transformed avian myeloid cells.

Animals↗
PubMed1991

v-myb and v-ets transform chicken erythroid cells and cooperate both in trans and in cis to induce distinct differentiation phenotypes.

E26 is an acute avian leukemia virus that encodes the transcriptional activator oncogenes v-myb and v-ets in a single fusion protein. This virus is also unique in that it is able to transform hematopoietic cells of both the myeloid and the erythroid lineage. To determine the contributions of v-myb and v-ets to the transforming potential of the virus, derivatives expressing separate Myb and Ets proteins, either alone or in combination, were constructed. We found that in the myeloid lineage v-myb, but not v-ets, induces cell transformation. In the erythroid lineage both v-myb and v-ets weakly transform erythroblast-like cells. These cells exhibit a mature phenotype and a low self-renewal capacity. The transforming efficiency of the two oncogenes is enhanced if they are coexpressed as separate proteins or as a fusion protein, the transformed cells displaying an increased self-renewal capacity. Interestingly, however, cells transformed by the Myb-Ets fusion protein have a distinct phenotype in that they are very immature. These results demonstrate that v-myb and v-ets can cooperate in the transformation of erythroid cells both in trans and in cis and that the mode of cooperation is reflected by the differentiation phenotypes of the transformed cells.

Animals↗
PubMed1988

A point mutation in the DNA binding domain of the v-myb oncogene of E26 virus confers temperature sensitivity for transformation of myelomonocytic cells.

We have molecularly cloned a mutant of the v-myb, ets-containing E26 avian leukemia virus which is temperature sensitive for the transformation of myeloid cells. Cells infected with this mutant, ts21E26, are immature at 37 degrees C and can be induced to differentiate into resting, macrophage-like cells when shifted to 42 degrees C. The sequence of ts21E26 reveals a single relevant nucleotide alteration resulting in a threonine to arginine change in the highly conserved, putative DNA binding v-myb portion of the p135gag-myb-ets protein. Surprisingly, a ts21E26 viral construct in which the v-ets gene domain was deleted was only weakly temperature sensitive, although temperature sensitivity was largely restored in another v-ets deletion mutant whose 3' terminal sequences were replaced with those from the AMV v-myb gene. These results suggest that the temperature sensitive lesion in v-myb of ts21E26 alters the DNA binding capacity of p135 at 42 degrees C and that the primary structure of the C-terminus of this protein has an influence on the activity of sequences that are further upstream.

Animals↗