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PubMed2003

Changes in apoptotic and mitotic index, bcl2, and p53 expression in rectum carcinomas after short-term cytostatic treatment.

Twenty patients with rectal adenocarcinoma were endoscopically biopsied and given short-term cytostatic therapy [5-fluorouracil (5-FU) (600 mg/m(2)) and Ca-folinate (60 mg/m(2)) for 2 days]. Seven days later, the tumor was resected or a second biopsy was performed. Apoptotic and mitotic indices as well as (mutant) p53 and bcl(2) expression were determined in the tumor tissue before and after the short-term chemotherapy. The patients were treated thereafter with long-term, intermittent 5-FU administration and followed up clinically for 7-26 months. Six patients showed progression of the disease and died, whereas 14 improved or showed no tumor progression. Significant increase of the apoptotic index and nonsignificant decrease of the mitotic index after the short-term cytostatic treatment were seen in the tumor tissue of responder cases. Nonresponders showed no change in both mitotic activity and apoptotic activity. Both survivors and deceased showed high mutant p53 expression, and the changes after short-term 5-FU treatment were not significant. Expression of bcl(2) was present in only 5 cases, with the postchemotherapy changes being not significant. These findings suggest that apoptotic response to short-term cytostatic therapy may be an additional predictive factor in rectal adenocarcinoma.

Aged↗
PubMed2003

Surface-enhanced Raman scattering for cancer diagnostics: detection of the BCL2 gene.

A method of detection for cancer genes, such as B-cell lymphoma 2 gene, has been developed using surface-enhanced Raman scattering-active substrates. This method uses Raman active dye-labeled DNA gene probes and metallic nanostructures as surface-enhanced Raman scattering-active platforms. A self-assembled monolayer system composed of mercapto hexane-labeled, single-strand DNA (SH-(CH2)6-ssDNA/ 6-mercapto-1-hexanol) is formed on a silver surface. The Raman-active dye-labeled gene is hybridized with its complementary probe, which is immobilized on the silver surface. The surface-enhanced Raman gene probes in this study can be used to detect DNA targets via hybridization to complementary DNA probes. The probes do not involve the use of radioactive labels and have great potential to provide both sensitivity and selectivity. The utility of this approach is investigated.

DNA Probes↗
PubMed1994

Interleukin-3 and bryostatin-1 mediate hyperphosphorylation of BCL2 alpha in association with suppression of apoptosis.

Using murine myeloid factor-dependent FDC-P1/ER cells, we demonstrate that the hematopoietic growth factors interleukin-3 and erythropoietin and bryostatin-1, a macrocyclic lactone natural product and potent activator of protein kinase C (PKC), suppress apoptosis and induce the rapid serine phosphorylation of Bc12 alpha. Expression of recombinant wild type Bc12 alpha in NFS/N1.H-7 cells confirms that murine Bc12 alpha is phosphorylated following PKC activation. The PKC inhibitors H-7 and staurosporine, but not the protein kinase A inhibitor HA1004, block not only interleukin-3- and bryostatin-1-induced hyperphosphorylation of Bc12 alpha but also their anti-apoptotic effect on growth factor-dependent cells, suggesting a role for activated PKC in both processes. A potential direct role for a classic isoform of PKC is indicated by the Ca(2+)-dependent nature of phosphorylation of Bc12 alpha mediated by purified PKC in vitro. Comparative phosphopeptide maps confirm that Bc12 alpha phosphorylation occurs on identical serine site(s) whether phosphorylation occurs in cells following agonist treatment or directly by PKC in vitro. These findings strongly support a role for activated PKC in growth factor-induced Bc12 alpha phosphorylation as well as suppression of apoptosis.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMedDate not supplied

Immunohistochemical detection of bcl2, p53, mdm2 and p21/waf1 proteins in small-cell lung carcinomas.

Thirty-one cases of small cell lung carcinomas (SCLC) were investigated by immunohistochemistry for the expression of bcl-2, p53 and the wild-type (wt) p53- induced proteins mdm2 and p21/waf1. Bcl-2 protein was detected in 24/31 cases of SCLC(77%) and p53 protein in 13/31 cases (42%). No correlation was found between histological subtype of SCLC and bcl-2 or p53 expression. Comparison between bcl-2 and p53 expression showed that 14/31 cases (45%) were only bcl-2 positive, 3/31 (11%) were only p53 positive, 10/31 (32%) were positive for both proteins and 4/31 (13%) were negative for both proteins. Mdm2 protein was detected in 2/32 SCLC which were also p53 positive. P21 protein was detected in 6/32 SCLC. Four of the p21 positive SCLC were negative for both p53 and mdm2, and two were positive for both p53 and mdm2 proteins. The significant expression of bcl-2 protein in SCLC suggests that bcl-2 may be involved in the pathogenesis of most SCLC by inhibiting apoptosis during neoplastic transformation. The expression of p53 protein in SCLC is likely to be related to underlying p53 gene mutations since these genetic alterations are very frequent in SCLC. This can be supported by our findings that 11/13 p53 positive SCLC were mdm2 and p21 negative. The two cases with p53+/mdm2+/p21+ phenotype may represent tumours with wt p53 gene and p53 protein immunoexpression due to binding to mdm2 protein. The four cases with p53-/mdm2-/p21+ phenotype may represent tumours with p53-independent p21 protein expression. Coexpression of p53 and bcl-2 proteins in a proportion of SCLC suggests that in these tumours p53 doses not maintain its suppressive effect on bcl-2 expression as it has been reported in vitro. Further studies at DNA and RNA level are required to clarify the involvement of bcl-2, p53, mdm2 and waf1 genes in SCLC pathogenesis.

Carcinoma, Small Cell↗
PubMedDate not supplied

Immunohistochemical detection of bcl2, p53, mdm2 and p21/waf1 proteins in small-cell lung carcinomas.

Thirty-one cases of small cell lung carcinomas (SCLC) were investigated by immunohistochemistry for the expression of bcl-2. P53 and the wild-type (wt) p53-induced proteins mdm2 and p21/waf1. Bcl-2 protein was detected in 24/31 cases of SCLC(77%) and p53 protein in 13/31 cases (42%). No correlation was found between histological subtype of SCLC and bcl-2 or p53 expression. Comparison between bcl-2 and p53 expression showed that 14/31 cases (45%) were only bcl-2 positive, 3/31 (11%) were only p53 positive, 10/31 (32%) were positive for both proteins and 4/31 (13%) were negative for both proteins. Mdm2 protein was detected in 2/32 SCLC which were also p53 positive. P21 protein was detected in 6/32 SCLC. Four of the p21 positive SCLC were negative for both p53 and mdm2, and two were positive for both p53 and mdm2 proteins. The significant expression of bcl-2 protein in SCLC suggests that bcl-2 may be involved in the pathogenesis of most SCLC by inhibiting apoptosis during neoplastic transformation. The expression of p53 protein in SCLC is likely to be related to underlying p53 gene mutations since these genetic alterations are very frequent in SCLC. This can be supported by our findings that 11/13 p53 positive SCLC were mdm2 and p21 negative. The two cases with p53+/mdm2+/p21+ phenotype may represent tumours with wt p53 gene and p53 protein immunoexpression due to binding to mdm2 protein. The four cases with p53-/mdm2-/p21+ phenotype may represent tumours with p53-independent p21 protein expression. Coexpression of p53 and bcl-2 proteins in a proportion of SCLC suggests that in these tumours p53 does not maintain its suppressive effect on bcl-2 expression as has been reported in vitro. Further studies at the DNA and RNA level are required to clarify the involvement of bcl-2, p53, mdm2 and wafl genes in SCLC pathogenesis.

Carcinoma, Small Cell↗
PubMed2006

Enhancing radiosensitivity of Hela cells by combining transfection of bcl-2 c-myc ASODNs.

Previous studies have detected bcl2 and c-myc upregulated in Hela cells. In this study, we investigated the effect on apoptosis of Hela cells by combining transfection of bcl2 and c-myc antisense oligonucleotides(ASODNs), and to explore the relationship between combining gene transfection and radiosensitivity of Hela cells, furthermore, to seek a new method to enhance the radiosensitivity of tumor cells. ASODNs of bcl2 and c-myc coated with cationic liposomes were designed and synthesized and transfected to Hela cells. The expressions of BCL2 and C-MYC were assessed by immunohistochemistry (IHC) staining and flow cytometry (FCM), and the induced-apoptosis phenomenon of Hela cells transfected with bcl2 ASODN or c-myc ASODN was observed by Giemsa Staining, DNA Ladder and FCM. Irradiation was performed on ASODNs transfected cells, then the radiosensitivity, biological reaction and cell proliferation of the transfected cells were investigated by cellular clone formation analysis, MTT assay and FCM. Both bcl2 and c-myc ASODNs could partially inhibit the growth of Hela cells by reducing the expression of bcl2 and c-myc (p < 0.05). The apoptosis rate of Hela cells treated with bcl2 ASODN was 6.60 +/- 0.70%, c-myc ASODN 10.29 +/- 0.66%, bcl2 + c-myc ASODNs 11.83 +/- 0.57 %, which were much higher than that of control 1.79 +/- 0.19%(p < 0.05). The sensitivity enhancement ratio(SER) of Hela cells transfected with bcl2 ASODN,c-myc ASODN and bcl2 + c-myc ASODNs was 1.20, 1.53 and 2.18 respectively. Combining transfection of bcl2 and c-myc ASODN could more effectively induce apoptosis of Hela cells, which subsequently enhanced radiosensitivity of Hela cells. Furthermore, combining transfection ASODNs of apoptosis-inhibiting genes or oncogenes followed radiotherapy to malignant tumor cells might be a new potential strategy.

Analysis of Variance↗
PubMed2006

Synthesis and reactivity of dichloroboryl complexes of platinum(II).

The reaction between [Pt(nbe)3] (nbe=norbornene), two equivalents of the phosphines PPh3, PMePh2 or PMe2Ph and 1 equivalent of BCl3 affords the platinum dichloroboryl species [PtCl(BCl2)(PPh3)2], [PtCl(BCl2)(PMePh2)2] and [PtCl(BCl2)(PMe2Ph)2]. All three complexes were characterised by X-ray crystallography and reveal that the boryl group lies trans to the chloride. With PMe3 as the phosphine, the complex [PtCl(BCl2)(PMe3)2] is isolated in high yield as a white crystalline powder although crystals suitable for X-ray crystallography were not obtained. Crystals were obtained of a product shown by X-ray crystallography to be the unusual dinuclear species [Pt2(BCl2)2(PMe3)4(micro-Cl)][BCl4] which reveals an arrangement in which two square planar platinum(II) centres are linked by a single bridging chloride which is trans to a BCl2 group on each platinum centre. The reaction of [PtCl(BCl2)(PMe3)2] with NEt3 or pyridine (py) affords the adducts [PtCl{BCl2(NEt3)}(PMe3)2] and [PtCl{BCl2(py)}(PMe3)2], respectively, both characterised spectroscopically. The reaction between [PtCl(BCl2)(PMe3)2] and either 4 equivalents of NHEt2 or piperidine (pipH) results in the mono-substituted boryl species [PtCl{BCl(NEt2)}(PMe3)2] and [PtCl{BCl(pip)}(PMe3)2], respectively, the former characterised by X-ray crystallography. Treatment of either [PtCl(BCl2)(PMe3)2] (in the presence of excess NEt3) or [PtCl{BCl(NEt2)}(PMe3)2] with catechol affords the B(cat) (cat=catecholate) derivative [PtCl{B(cat)}(PMe3)2] which is also formed in the reaction between [Pt(PMe3)4] and ClB(cat) and also from the slow decomposition of [Pt{B(cat)}2(PMe3)2] in dichloromethane over a period of months. The compound [Pt{B(cat)}2(PMe3)2] was prepared from the reaction between [Pt(PMe3)4] and B2(cat)2.

Boron Compounds↗
PubMed2004

Nuclear and environment morphometric profile in tumor size and nodal metastasis of resected typical pulmonary carcinoid.

As the biologic behavior in lung tumors with neuroendocrine differentiation is highly dependent on cell death (apoptosis) and extracellular matrix invasion, Bcl2 and extracellular matrix density have been targeted as potentially useful tumor markers. In this study, we sought to validate the importance of Bcl2 and ECM density and to study the relationships of Bcl2 and ECM density with clinical factors and other tumor or stromal markers. We examined Bcl2 and several other markers in tumor tissues from 55 patients with surgically excised pulmonary typical carcinoid. We used histochemistry, immunohistochemistry, and morphometry to evaluate the amount of tumor staining for Bcl2 and ECM; the surrogate markers for aggressive potential for our study were tumor size and lymph node metastasis determined at diagnosis. Multivariate logistic model analysis demonstrated that after surgical excision control, tumor size was significantly related to nodal metastasis (P = 0.01), but quantitative staining of the tumor for Bcl2 and ECM added prognostic information and was as strongly prognostic as tumor size (P<0.01). Cutpoints at the median staining of 3.1% and 9.8 microm2 for Bcl2 and ECM, respectively, divided patients into two groups with distinctive risk for nodal metastasis. Those with Bcl2 > 3.1% and ECM <9.8 microm2 had high risk for nodal metastasis. We concluded that tumor staining for Bcl2 and ECM in resected PTC is strongly related to tumor size and nodal metastasis. Patients with > 3.1% and <9.8 microm2 staining in their tumors comprise a subset with a high hazard for nodal metastasis and may be an appropriate target for prospective studies of adjuvant chemotherapy after surgical resection.

Adolescent↗
PubMed2025

Targeting anti-apoptosis as a therapeutic strategy in neuroendocrine neoplasms.

BCL-2 is an anti-apoptotic protein expressed by aggressive neuroendocrine neoplasms (NENs). We report a case of a patient with a pancreatic neuroendocrine tumor (pNET) who received venetoclax, a BCL-2-targeting drug for the treatment of chronic lymphocytic leukemia. We further characterized BCL2 expression in NENs from a large multi-institutional patient cohort. Clinical data were abstracted from the records of a patient with a pNET. Next-generation sequencing of DNA (592-gene panel or whole exome) and RNA (whole transcriptome) was performed on 636 NENs of pancreatic (P-NENs), small bowel (SB-NENs), colorectal (CR-NENs), and lung (L-NENs) origin by Caris Life Sciences. Comparisons were performed against site-matched non-NEN cancers. BCL2- or MKI67- high and low cohorts were defined based on the top and bottom quartiles of gene expression. The patient with a pNET who received venetoclax had a partial response in the primary tumor that lasted 30 months. CR-, L-, and P-NENs had significantly higher expression of BCL2 compared to non-NEN counterparts. BCL2 expression was significantly higher in MKI67-high tumors among all NEN subtypes. In P-NENs, there was a higher prevalence of RB1 mutations in BCL2-high vs BCL2-low (40 vs 4.9%, P < 0.005). Patients with BCL2-high P-NENs had significantly decreased overall survival (HR 1.94, 95% CI 1.0-3.76, P = 0.047). Immune checkpoint gene expression and T cells were enriched in BCL2-high tumors across all subtypes. In summary, we report the first known case of a pancreatic NET with response to venetoclax. BCL2 expression correlated with high MKI67 expression, worse survival, and a highly immune-enriched microenvironment.

Aged↗
PubMed2003

Follicular lymphoma lacking the t(14;18)(q32;q21): identification of two disease subtypes.

The clinical and pathological features, including karyotype data and BCL2 protein expression pattern, of follicular lymphoma without a t(14;18)(q32;q21) have not been well defined. We have identified and conducted a detailed analysis of 50 cases with follicular lymphoma who lack the t(14;18). Fluorescent in situ hybridization (FISH) analysis was used to exclude cases with a cryptic IGH/BCL2 rearrangement. BCL2 protein expression level was assessed by immunohistochemistry. The karyotypes were assessed for recurrent sites of structural rearrangement, duplications and deletions on a band-by-band basis, and compared with a large cohort of cases with t(14;18). A distinct pattern of chromosomal alterations was identified in the cases without t(14;18). BCL2 protein overexpression was detected in 33% of 49 tested cases. In this minority, the karyotypes frequently showed increased copies of chromosome 18. The majority of cases (67%) did not show BCL2 overexpression and were characterized prominently by the presence of t(3;14)(q27;q32), implying a role for BCL6. Follicular lymphomas that lack a t(14;18) were segregated into two subgroups with distinct cytogenetic, phenotypic and possibly clinical features: one with BCL2 protein overexpression not related to an IGH/BCL2 rearrangement and a second without BCL2 overexpression. Objective identification of BCL2 expression level as well as BCL2 and BCL6 status by cytogenetic or FISH analysis has potential clinical utility and may yield insights into alternative genetic mechanisms associated with B-cell lymphomas with a follicular growth pattern.

Adult↗
PubMed1992

Proto-oncogene analysis in multiple myeloma.

The genetic basis for the development of multiple myeloma (MM) remains poorly understood, in part because MM has thus far been relatively refractory to cytogenetic analysis. The few cases karyotyped have pointed to involvement of 11q13, site of the BCL1 proto-oncogene, or of 8q24, site of the MYC proto-oncogene. A recent molecular study detected rearrangements distal to the MYC gene in 16% of MM, using the MLVI-4 probe. The immunocytochemical demonstration of BCL2 protein overexpression in at least some cases of MM has suggested the possibility of translocation-mediated deregulation of the BCL2 proto-oncogene. The configuration of the BCL2 gene in MM, however, has not yet been defined using all available breakpoint probes. To address these issues, we studied 17 patients with plasma cell dyscrasias (16 MM, 1 plasmacytoma) by Southern blotting using the major breakpoint region (MBR), minor cluster region (MCR), and 5' cDNA (pB16) BCL2 breakpoint probes; with the BCL1 major translocation cluster (MTC) breakpoint probe; and with a probe to the MYC-associated MLVI-4 region (PA1.3SB). In all 17 cases, rearrangement of one or both alleles of the immunoglobulin heavy chain gene had been demonstrated, thereby confirming the presence of tumor DNA in the samples studied. None of the cases tested showed a rearrangement with the MBR BCL2 (0/16), MCR BCL2 (0/17), 5' cDNA BCL2 (0/16), BCL1 MTC (0/15), or MLVI-4 (0/15) probes. These results suggest that if BCL2 deregulation does indeed occur in MM, a mechanism other than translocation must be involved in most cases. Furthermore, rearrangements distal to the MYC gene, in the region of the MLVI-4 probe, may be less common than previously thought. Finally, a significant proportion of translocation breakpoints in band 11q13 may not be detected by the BCL1 MTC probe in MM, as is true in lymphomas.

Aged↗
PubMed2000

Bax protein expression in DCIS of the breast in relation to invasive ductal carcinoma and other molecular markers.

This study describes the incidence of Bax protein expression in a series of 106 cases of breast cancer including 56 cases of ductal carcinoma in situ (DCIS) and 50 cases of invasive ductal carcinoma (IDC). Relationships of Bax expression to the histological grades of DCIS & IDC, and to the expression of Ki67, ER, p53, cerbB2 & Bcl2 are described. The expression of Bax, Ki67, ER, p53, cerbB2 and Bcl2 proteins is determined immunohistochemically. Cases were regarded positive for Bax, Bcl2 and cerbB2 when they showed either moderate or strong staining for these markers. The nuclear stains (Ki67, ER, and p53) were quantified in terms of percentage positive cells and cases for ER and p53 were considered positive when more than 10% cells were labelled. DCIS were graded histologically as well (n=18), intermediately (n=18), and poorly differentiated (n=20) Invasive ductal carcinoma was graded as grade I (well-differentiated) n=7, grade II (intermediate) n=24 and grade III (poorly differentiated) n=19. 65/106 cases (61%) were Bax positive including 37/56 (66%) of DCIS and 28/50 (56%) of IDC. Bax expression did not correlate to increasing histological grades of either DCIS or IDC. It did not correlate to Ki67, ER, p53 or cerbB2 but positive correlation was seen with Bcl2 (p=0.003). Bcl2 immunostaining displayed a negative correlation with increasing histological grades both of DCIS and IDC (p=0.026), (p=0.041) respectively. There was a trend of negative correlation of Bcl2 with Ki67 (p=0.062). It correlated positively with Bax (p=0.003) and ER (p<0.0001). Results suggest that the regulation of apoptosis is important in ductal carcinoma in situ of the breast as well as invasive ductal carcinomas. Bcl2 is associated with good prognostic markers in both DCIS and IDC, whereas the regulation of Bax is complex and does not necessarily correlate with mutant p53.

Adult↗