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Biomedical subjects

F J Hendler

Publications and source records attributed to F J Hendler.

At least 19 recordsLinked to original sources
PubMed1999

Decreased expression of CD80 is a marker for increased tumorigenicity in a new murine model of oral squamous-cell carcinoma.

We established a new syngeneic murine model of oral squamous-cell carcinoma (SCC) to analyze the potential role of immune recognition determinants in the early development of oral cancer. In this study, we examined whether SCC that undergo transformation and development in the absence of specific immunity exhibit differences in tumorigenicity that relate to differences in expression of CD80, CD86 or MHC class I. Mucosal keratinocytes from BALB/c mice were transformed in vitro with 4-nitroquinolone-1-oxide (4-NQO) and inoculated into SCID mice to obtain tumorigenic cell lines. Five SCC cell lines were re-isolated from tumors, and 4 retained cytokeratin and beta4-integrin markers of epithelial origin. Their growth was compared in BALB/c and in congenic SCID mice to establish whether the cell lines exhibit differences in immunogenicity. Three lines that showed slower growth or completely regressed when implanted in immune competent hosts retained or developed increased expression of CD80 during development in SCID mice. Conversely, 2 SCC lines that lost expression of CD80 after passage in vivo grew progressively in immune-competent hosts. MHC-class-I and CD86 expression did not correlate with tumorigenicity. These observations provide evidence that decreased expression of CD80 may serve as a marker for increased tumorigenicity during early development of oral SCC. The development of this new murine oral SCC model should prove useful in determining the potential effects of CD80 expression on the immune pathogenesis and therapy of SCC.

4-Nitroquinoline-1-oxide↗
PubMed1997

A region within murine chromosome 7F4, syntenic to the human 11q13 amplicon, is frequently amplified in 4NQO-induced oral cavity tumors.

Our previous reports have shown that two thirds of 4-nitroquinoline-1-oxide (4NQO)-induced murine oral squamous cell carcinomas (SCC) have Hras1 mutations. Loss of heterozygosity (LOH) involving the distal portion of chromosome (Chr) 7 occurred in half of the tumors with Hras1 mutations. Here, we demonstrate that five of six tumors with LOH have 4-8-fold amplification involving the distal portion of Chr 7 (7F4). Ccnd1. Fgf4 and Fgf3, within the most telomeric region of Chr 7 (70.5 cM), are co-amplified. The region is syntenic to a previously identified human amplicon at 11q13. Only one out of eight tumors without LOH at Chr 7 had twofold amplification; the other seven had no detectable amplification. Significant amplification is restricted to the chromosome with the Hras1 mutation. Gene amplification occurred without overexpression since only one of five tumors with amplification and one of six tumors without Ccnd1 amplification expressed increased protein. Although amplification of 11q13 occurs rather frequently in human tumors, 4NQO-induced oral cavity tumors in inbred mice are the first example of a murine tumor with consistent amplification. Our observations are strikingly similar to human head and neck SCC where overexpression of genes within the 11q13 amplicon is inconsistently detected. The amplification of genes localized to human 11q13 and the syntenic region on murine Chr 7 during tumorigenesis suggests that similar structural elements are present which predispose these regions to amplification during malignant transformation.

4-Nitroquinoline-1-oxide↗
PubMed1997

Consistent allelic loss on mouse chromosome 7 distal to tyrosinase in 4-nitroquinoline-1-oxide-induced oral cavity tumors with loss of heterozygosity at Ha-ras-1.

We have previously shown that all CBA/J mice exposed to 4-nitroquinoline-1-oxide (4NQO) eventually develop oral cavity squamous cell carcinomas, and two-thirds of these tumors have Ha-ras-1 (Hras1) point mutations at codon 12. Half of the tumors with Hras1 mutations have loss of heterozygosity (LOH) at Hras1. In the study reported here, seven tumors with LOH at Hras1, six heterozygous for Hras1, and six without Hras1 mutations were analyzed to define the extent of LOH on chromosome (Chr) 7. Microsatellite polymorphisms present in CBA/J mice were used as informative allelic markers. Tumors with LOH at Hras1 showed consistent allelic loss at the distal portion of Chr 7. The boundary of allelic loss lay between the tyrosinase and hemoglobin beta chain loci, which are 6 cM apart. None of the tumors that remained heterozygous for Hras1 or had no Hras1 mutations had evidence of chromosomal loss involving Chr 7. Because LOH was only detected in advanced lesions long after exposure to 4NQO had ceased, we presume that the chromosomal alterations by which LOH occurred were independent of the carcinogen exposure. The development of LOH in only half of the tumors with Hras1 point mutations suggests that LOH was not caused by the initial Hras1 point mutation but was a highly selected event during tumorigenesis.

4-Nitroquinoline-1-oxide↗
PubMed1996

Frequent DNA polymorphisms exist in inbred CBA/J and C3H/HeN mice.

Although occasional DNA polymorphisms have been observed in inbred mice, CBA/J and C3H/HeN mice have two microsatellite alleles at over 1/3 of microsatellite loci tested. Since DNA polymorphisms were not detected in DBA/2J, C57BL/6J, and BALB/cJ, the frequency of microsatellite polymorphisms appears to be strain specific. Thus, genetic studies in inbred mice require testing for preexisting polymorphisms. The polymorphisms detected in CBA/J mice appear to be stable and do not represent microsatellite instability or a mutator phenotype. Somatic mosaicism was not observed and no more than two alleles were detected per locus. CBA/J propagated only by brother-sister mating maintained seven of eight polymorphisms over 5 years. These data suggest that the polymorphisms are due to an inherited trait and that the pattern of inheritance is not due to Mendelian distribution. As breeding analysis was not performed, the pattern of allelic inheritance is unknown.

Animals↗
PubMed1994

Harvey ras (H-ras) point mutations are induced by 4-nitroquinoline-1-oxide in murine oral squamous epithelia, while squamous cell carcinomas and loss of heterozygosity occur without additional exposure.

Tumorigenesis is a multistep genetic process requiring several somatic mutations for neoplastic transformation. These mutations appear to be sequential, random, and independent events. However, we find linked, nonrandom ras mutations occurring during 4-nitroquinoline-1-oxide-induced tumorigenesis months after exposure to the carcinogen had ceased. The carcinogen had been topically applied to the oral cavity of CBA mice for 4 to 16 weeks. Dysplasia developed after 24 weeks, and carcinoma in situ and squamous cell carcinoma developed after 28 weeks. H-ras mutations were detected in 13 of 25 tissue specimens (10 of 14 invasive carcinomas and 2 of 4 carcinoma in situ, 1 of 5 dysplastic tissue, and 0 of 2 normal tissues). Approximately one-half of the tumors had G to A point mutations at codon 12 of the cellular H-ras proto-oncogene on mouse chromosome 7. None had codon 11, 13, or 61 mutations. Loss of heterozygosity occurred in 5 of 14 invasive cancers. Larger invasive squamous cell carcinomas consistently lost the wild-type allele, whereas preneoplastic lesions and small tumors were heterozygous for ras. This suggests a causal relationship between carcinogen treatment, H-ras activation, and initiation of tumorigenesis. The wild-type allele in mouse chromosome 7 is lost with the progression of tumorigenesis long after exposure to the carcinogen. Thus, loss of heterozygosity of the ras gene appears to occur without multiple carcinogen-induced mutations, i.e., as a result of a cascade of events induced by an earlier ras mutation.

4-Nitroquinoline-1-oxide↗
PubMed1994

Epidermal growth factor receptor expression by human squamous cell carcinomas of the head and neck, cell lines and xenografts.

Epidermal growth factor receptor (EGFR) overexpression has been associated frequently with squamous cell carcinomas (SCC) and SCC cell lines. In most cases the level of EGFR on the tumours from which the cell lines were derived has not been determined, nor have EGFR levels been determined for xenograft tumours from the cell lines. In this study we determined EGFR expression on a new series of head and neck SCC (SCCHN)-derived cell lines, which were obtained from tumours representing a spectrum of malignant progression, and two cell strains derived from erythroplakia premalignant lesions. The level of EGFR on cell lines was determined by [125I]EGF competitive binding assays. EGFR levels on some of the original tumours and xenografts of the cell lines were determined on cryosections by a competitive binding assay based on [125I]EGFR1, an EGFR-specific monoclonal antibody. EGFR expression on the tumour cryosections was compared with expression on cryosections of skin and buccal mucosa. Eight of the ten tumour cell lines had elevated EGFR. Two of the tumour-derived cell lines and the two erythroplakia-derived cell strains expressed EGFR at levels similar to that detected on normal keratinocytes in tissue culture. Only two of the tumours overexpressed EGFR when compared with normal tissue. The other tumours had levels similar to that detected on the basal layers of skin or buccal mucosa. The xenografts expressed EGFR, as did the original tumours, even though they were derived from cell lines that displayed significant overexpression of EGFR. This study suggests that most tumours have a latent potential to overexpress EGFR which is realised in tissue culture.

Animals↗
PubMed1994

Detection of epidermal growth factor receptor mRNA in tissue sections from biopsy specimens using in situ polymerase chain reaction.

Human epidermal growth factor (EGF) receptor mRNA was detected in cryopreserved tissue sections adherent to whole glass slides using in situ reverse transcriptase polymerase chain reaction. EGF receptor cDNA was synthesized in situ by reverse transcription using an EGF receptor-specific oligonucleotide primer. In situ polymerase chain reaction amplification in the presence of digoxigenin-11-dUTP and subsequent binding with an antidigoxigenin antibody conjugated to alkaline phosphatase allowed direct visualization. Because DNase, RNase, or proteinase K are not required, tissue integrity is maintained. EGF receptor mRNA is expressed in the basal layer of normal human skin epithelium and is significantly overexpressed in squamous cell tumor specimens, which is consistent with conventional analysis of EGF receptor expression. The assay is semiquantitative, quicker, more sensitive, and void of the nonspecific binding associated with in situ hybridization. In situ reverse transcriptase polymerase chain reaction using whole glass slides is ideally suited for detecting moderate to infrequently expressed transcripts in biopsy specimens.

Antisense Elements (Genetics)↗
PubMed1993

Variation in cellular EGF receptor mRNA expression demonstrated by in situ reverse transcriptase polymerase chain reaction.

Cell to cell variation of epidermal growth factor (EGF) receptor mRNA levels in heterogeneous tissues has been demonstrated with an in situ assay that couples reverse transcriptase with the polymerase chain reaction (in situ RT-PCR). EGF receptor mRNA is consistently more highly expressed in regions where cell division occurs; EGF receptor mRNA is markedly reduced if not absent in areas of squamous cell differentiation. Both human and mouse tumors overexpress EGF receptor mRNA when compared to normal tissue. In situ RT-PCR performed on thin sections obtained from cell pellets of cultured cells with known levels of EGF receptor mRNA expression demonstrated that the mRNA detected is consistent with that observed by Northern analysis and quantitative PCR on isolated RNA and by protein levels detected by antibody binding assays. In situ RT-PCR is significantly more sensitive than in situ hybridization (ISH). The method avoids background associated with hybridization reactions as in ISH or ISH following in situ PCR. In situ RT-PCR appears to be applicable to any gene as long as the oligonucleotide primers used have been proven to be specific and effective in a standard RT-PCR assay.

Animals↗
PubMed1992

Residual mediastinal mass after treatment of Hodgkin's disease: a decision analysis.

A residual mediastinal mass after completion of initial treatment for Hodgkin's disease is a frequent clinical problem. Investigators have suggested three possible approaches to this important problem: 1) observation, 2) additional diagnostic tests with subsequent action based upon test results, or 3) immediate treatment for high-risk patients. The method of decision analysis was applied to determine the optimal management for residual mediastinal abnormalities following treatment of Hodgkin's disease with combined modalities of MOPP chemotherapy and radiation therapy. The three parameters of the importance for making the best decision were: 1) the probability that the mass is truly active disease, 2) the salvage success rate using MOPP or ABVD treatment and 3) the specificity of the gallium scan. The analysis favored the gallium imaging strategy as an initial management choice when the probability was greater than 3% that the residual mass represented active disease and the specificity of gallium imaging was greater than 56%. This strategy proved to be the most cost effective, as well. Additional chemotherapy was favored only when there was a greater than 99% probability that the mass represented active disease. A nomogram has been constructed combining all three parameters of importance for graphically determining the best decision.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Breast diseases and the internist.

Benign breast disease affects almost all women, although only one out of 11 will eventually develop breast cancer. Fibrocystic disease or benign breast mastopathies have been associated with an increased propensity to progress to malignancy. However, the increased relative risk for women with benign breast disease developing breast cancer appears to be associated with proliferative benign disease in association with atypia. Their cumulative risk may be as high as 30%. These women represent 3-5% of women with benign disease. They clearly warrant more careful screening and follow-up. The etiology of benign breast mastopathies is unknown, but its incidence and relationship to hormonal events suggests that many of the histologic entities represent an endocrine response. Many hormonal manipulations have been shown to decrease mastodynia and reduce the incidence of breast aspirations and biopsies. However, these and other therapeutic interventions have not been shown to reduce the incidence of breast cancer in women who are at high risk.

Adult↗
PubMed1986

Estrogen regulation of H59 antigen in vivo and in vitro.

H59 antibody, a murine monoclonal antibody, recognizes a cell surface peptide of approximately 30,000 MW which is estrogen regulated. The data supporting this conclusion have been generated from in vitro systems and indirectly from human tissue specimens. The antigen is detected only in estrogen regulated breast cancer cells in culture and is not detected in two estrogen independent cell lines, R3 and R27, which were derived from estrogen sensitive MCF-7 that contain the antigen. The antigen is increased in estrogen stimulated cells and decreased in tamoxifen inhibited cells. H59 antigen appears estrogen regulated in human breast colostrum and milk and in endometrium. The antigen is found in 40% of breast cancer and most, if not all, normal breast tissue. In the more than 300 breast cancer specimens studied, H59 antigen was detected in predominately estrogen and/or progesterone receptor containing tumors. This antigen was found only in about 50% of ER positive tumors. When the presence of H59 was compared to other prognostic factors in breast cancer, it appeared to be an independent variable and correlated only with the presence of estrogen and progesterone receptor. The antigen can be detected in normal serum, and studies are underway to determine if it will serve as a circulating marker protein in hormone dependent breast cancer.

Animals↗
PubMed1985

Relationship of monoclonal antibody binding to estrogen and progesterone receptor content in breast cancer.

Three monoclonal antibodies--H59, H71, and H72--which react with human breast cancers have been developed using the estrogen-dependent human breast cancer cell line, ZR-75-1, as the immunogen. H59 bound only to estrogen receptor-positive, estrogen-regulated breast cancer cells in culture, whereas H71 and H72 bound breast cancer cells irrespective of the estrogen receptor content. All three antibodies have minimal cross-reactivity with non-breast tissue culture cell lines. The three antigens appear to be glycoproteins located on the cell surface. H59 and H72 antigens bound preferentially to the apical surface of duct cells and may be secreted; H71 antigen demonstrated no evidence of an apical orientation or secretion. The binding of the antibodies to fixed cryosections from 152 breast cancer and 111 benign breast disease specimens has been evaluated using a radioimmunoassay. Eighty-five % of breast cancer and almost 100% of benign disease specimens were bound by at least one antibody. H59 bound 39%, H71 bound 51%, and H72 bound 65% of cancer specimens. Estrogen receptor and progesterone receptor analyses were obtained on 141 specimens. H59 bound almost exclusively to tumor specimens which contained estrogen and/or progesterone receptor, but not to all receptor-positive tumors. Therefore, the H59 antigen appeared to be present on a subset of estrogen receptor-positive tumors. Considering that it bound only to estrogen-regulated cells in culture, the antigen may be estrogen regulated, and its presence may predict a response to hormone therapy. H71 and H72 recognized cell surface differentiation antigens but bound tumor specimens regardless of the receptor content. These antibodies may be useful as independent variables for predicting response to therapy and prognosis of patients with breast cancer.

Adenofibroma↗
PubMed1985

Presence of breast cancer antigens in uninvolved axillary lymph nodes.

Monoclonal antibodies which bind to breast cancer have been used to evaluate the detection of metastatic disease in axillary lymph nodes. Three monoclonal antibodies (H59, H71, and H72) were reacted with tissue sections of primary tumors and axillary nodes from 24 mastectomy specimens and four specimens from glandular mastectomies for benign disease. All three antibodies had been shown to react with subsets of normal and malignant breast tissue; did not bind erythroid, myeloid, or lymphoid tissue; and recognized antigens in paraffin-embedded tissue. The antibodies recognized cell surface antigens, and H59 and H72 bound to glycoproteins which are either sloughed or secreted. Primary tumors and tumors in lymph nodes from the same specimen were always bound by the same antibodies. Antibodies detected unrecognized microscopic tumor in nodes from one previously node-negative specimen and two specimens with positive nodes. This suggests that monoclonal antibodies may be useful for detecting metastatic breast cancer in nodes which by light microscopy are negative. Moderate binding of H59 and H72 antibodies to sinus histiocytes and perivascular cells was observed in all uninvolved nodes with sinus hyperplasia obtained from benign and malignant specimens. Thus, breast antigens can be identified in hyperplastic nodes in patients with no evidence of breast cancer. The antigens are detected predominately in the lymphoid sinuses and are bound to nonneoplastic cells. Therefore, breast antigens are regularly being processed and presented by normal lymphoid cells within the sinus. The binding of these monoclonal antibodies to axillary lymph nodes does not necessarily indicate the presence of metastatic disease. Dense binding to paracortical single cells was observed in tumor-containing lymph nodes and in uninvolved nodes obtained from mastectomy specimens with breast cancer. These cells are infrequent, and their number in an uninvolved node correlates with the pathological stage. They represent either binding to isolated lymphoid cells or metastatic tumor. Studies are under way to determine the origin of these cells.

Adult↗
PubMed1984

Human squamous cell lung cancers express increased epidermal growth factor receptors.

Epidermal growth factor (EGF) promotes the growth of cultured benign and malignant cells. Recent studies have demonstrated that the amount of EGF receptor is elevated in squamous cell carcinoma cells in tissue culture when compared with normal epidermal cells. This study demonstrates that elevated levels of EGF receptor are detected in biopsy specimens of human squamous cell carcinomas of the lung with a murine monoclonal antibody, EGF-R1, which binds specifically to the receptor. The increased receptor ranged from 2.5- to 5-fold that of normal skin. These findings have been observed in 11 of 11 squamous carcinomas and two of two epidermoid head and neck cancers. Seven of eight adenocarcinomas, two of two small cell, and four of eight undifferentiated lung cancers had negligible amounts of EGF receptor. The EGF receptor antibody did not bind significantly to normal lung tissues and 35 nonepidermoid tumors. Therefore, EGF receptor may be an excellent marker for epidermoid malignancies.

Adenocarcinoma↗
PubMed1982

Characterization of a monoclonal antibody reactive with a subset of human breast tumors.

Fusion of spleen cells, from mice immunized against the human hormone-dependent breast cancer cell line ZR-75-1, with murine myeloma cells resulted in the establishment of a hybridoma cell line, HY59-H10 (H59). The purified monoclonal IgM produced by the hybridoma reacts with the most differentiated human breast tumor cell lines but not with cells derived from normal breast secretions or with numerous other malignant cell lines. Of 106 biopsy specimens examined, H59 bound to 54% of malignant breast specimens, to 83% of fibroadenomas, and to 82% of specimens containing fibrocystic disease.

Adenofibroma↗