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Biomedical subjects

A Berchuck

Publications and source records attributed to A Berchuck.

At least 109 records · Page 6Linked to original sources
PubMed1994

Transforming growth factor beta 1 can induce CIP1/WAF1 expression independent of the p53 pathway in ovarian cancer cells.

Transforming growth factor beta (TGF beta) is an important regulator of cellular proliferation. In normal ovarian epithelial cells, TGF beta acts to inhibit growth. However, in ovarian cancer cell lines, this effect is usually lost. Although the regulatory pathway of TGF beta remains unclear, TGF beta-treated cells arrest late in G1. This inhibition appears to involve blocking of the cyclin-dependent kinase phosphorylation of the retinoblastoma protein. Recently, a general inhibitor of cyclin-dependent kinases, CIP1/WAF1/p21, was identified. Expression of CIP1 is positively regulated by binding of wild-type p53 to a consensus response element upstream of the CIP1 gene. Overexpression of the CIP1 protein causes growth suppression, analogous to TGF beta and wild-type p53. We have examined the induction of CIP1 by TGF beta 1 in ovarian cancer cell lines that have been previously characterized for their proliferative response to TGF beta 1. OVCA420, a cell line that is dramatically growth inhibited by TGF beta 1, significantly induced CIP1 expression in response to TGF beta 1. CIP1 induction was accompanied by a decrease in cdk2 kinase activity and cdk2 protein levels. In three other cell lines that respond weakly to TGF beta 1, CIP1 expression was not induced. To determine if TGF beta 1 induction occurs via p53, regulation of p53 RNA and protein was examined. No differences in p53 transcription, steady-state protein level, de novo synthesis, phosphorylation, or subcellular accumulation were noted. Furthermore, TGF beta 1 could not induce transcription from a consensus p53 DNA binding site in the TGF beta 1-response cell line.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1994

Serum progesterone for the exclusion of early pregnancy in women at risk for recurrent gestational trophoblastic neoplasia.

OBJECTIVE: To evaluate the utility of the serum progesterone level for discriminating pregnancy from gestational trophoblastic neoplasia. METHODS: Serum progesterone levels were measured in 61 women with histories of trophoblastic disease who developed a re-elevation in hCG during surveillance and underwent a work-up to differentiate pregnancy from gestational trophoblastic neoplasia. Progesterone levels were analyzed in the context of diagnostic outcome (pregnancy versus gestational trophoblastic neoplasia) to identify optimal threshold levels of progesterone to be used for classifying outcome. RESULTS: Of the 61 women, 37 proved to be pregnant and 24 had gestational trophoblastic neoplasia. Progesterone less than 2.5 ng/mL was predictive of trophoblastic malignancy, with a sensitivity of 83% (20 of 24 subjects were classified correctly as having gestational trophoblastic neoplasia) and a specificity of 95% (35 of 37 patients with progesterone levels at or above 2.5 ng/mL were correctly classified as pregnant). Progesterone of at least 10 ng/mL was associated with viable pregnancy in 97% of the cases. Furthermore, the progesterone level predicted outcome regardless of the serum hCG value. CONCLUSION: The serum progesterone level is useful for discriminating early pregnancy from gestational trophoblastic neoplasia.

Adolescent↗
PubMed1994

Evaluation of prognostic factors and staging in gestational trophoblastic tumor.

OBJECTIVE: To evaluate factors influencing survival and compare current classification systems in women treated for malignant gestational trophoblastic tumor. METHODS: A consecutive series of 454 women treated between 1968-1992 was reviewed retrospectively to identify potential clinical prognostic factors using univariate analysis of life tables. All patients were evaluated using clinical classification, World Health Organization, and recently modified International Federation of Gynecology and Obstetrics (FIGO) staging systems, applied retrospectively. Multivariate Cox regression analysis was used to model potential independent prognostic factors within subsets of the patient population. RESULTS: Factors identified by univariate analysis as potential prognostic influences included age, duration of disease, type of antecedent pregnancy, clinicopathologic diagnosis, site of metastases, number of metastatic sites and foci, tumor size, and prior therapy. The pre-therapy hCG level was not significantly associated with survival (P < .04). Multivariate Cox modeling consistently identified prior therapy, type of antecedent pregnancy, number of metastatic sites, and duration of disease as independent prognostic factors. Clinicopathologic diagnosis and hCG level were of borderline significance only in some models of the total patient population. All classification systems were able to identify low- and high-risk subsets of patients with approximately equal efficiency. The addition of FIGO substages enhanced discrimination between prognostic groups in patients with stage III disease. CONCLUSIONS: Existing systems for the classification of malignant gestational trophoblastic tumor are based in part on factors that are not independently prognostic, such as hCG level or tumor size. These systems discriminate between low- and high-risk patients with approximately equal efficiency. The clinical classification system is currently preferred for determining initial therapy in women with malignant gestational trophoblastic tumors.

Chorionic Gonadotropin↗
PubMed1994

Preoperative coagulation testing on a gynecologic oncology service.

OBJECTIVE: To determine the prevalence and clinical significance of abnormalities of preoperative coagulation tests in gynecologic oncology patients. METHODS: Three hundred fifty-one patients presenting for inpatient surgical procedures on the gynecologic oncology service at Duke University Medical Center from January 1, 1990 to December 31, 1990, underwent preoperative coagulation testing. Twenty-nine patients had only prothrombin time (PT) and partial thromboplastin time (PTT) measured; the remaining 322 had preoperative measurement of PT, PTT, fibrinogen, and fragment D-dimer. Outcomes assessed were perioperative hemorrhage resulting in death or reoperation, postoperative hematomas, and need for intraoperative and postoperative transfusion. RESULTS: Twelve of 351 patients (3.4%) had abnormally elevated PT or PTT; six of these were attributable to risk factors unrelated to malignancy. One hundred fifty-six of 322 subjects (48.4%) had abnormal levels of fibrinogen, mostly elevations above 360 mg/dL, and 88 of 322 subjects (27.3%) had positive tests for D-dimer. Fifty-seven (17.7%) had both elevated fibrinogen and positive D-dimer. One hundred eighty-eight of 322 subjects had at least one abnormal test result. There were no perioperative deaths or reexplorations because of hemorrhage. There was one postoperative hematoma. The combination of an elevated fibrinogen and a positive D-dimer test was a significant predictor of perioperative transfusion in a logistic regression model incorporating stage, preoperative hematocrit, and age (odds ratio 1.96, 95% confidence interval 1.03-3.76). However, the attributable risk associated with this abnormality was only 7.7% in patients at highest risk of transfusion. CONCLUSION: Although abnormalities in coagulation are common in patients undergoing surgery for gynecologic malignancy, preoperative testing for occult coagulopathy provides little clinically useful information.

Adult↗
PubMed1994

The negative prognostic implications of thrombocytosis in women with stage IB cervical cancer.

OBJECTIVE: To determine the association between pretreatment platelet count and survival in women with stage IB cervical cancer. METHODS: Clinical records were reviewed for 219 women with stage IB cervical cancer treated by radical hysterectomy from 1971-1984. Univariate and multivariate analyses were performed to identify clinicopathologic variables associated with poor survival. Survival as a function of the preoperative platelet count was analyzed further and corrected for known prognostic factors. RESULTS: The cumulative 5-year survival of women with a preoperative platelet count greater than 300,000/microL (n = 85) was 65%, as compared to 84% for a count equal to or less than 300,000/microL (n = 134) (P = .004). Univariate Cox regression analysis revealed non-white race, large lesion size (greater than 4 cm), platelet count greater than 300,000/microL, and the presence of nodal metastases to be factors related to poor prognosis. A comparison of patients with platelet counts of 300,000/microL or less and patients with platelet counts greater than 300,000/microL revealed no difference with regard to race, nodal metastases, and median age. However, a larger percentage of women with a platelet count greater than 300,000/microL had large lesion size (29 of 60, versus 32 of 114 with a count of 300,000/microL or less). In a multivariate analysis, after adjusting for age, race, the presence of nodal metastases, and lesion size, high platelet count was still associated with poor prognosis (P = .04). CONCLUSION: An elevated platelet count is an independent prognostic factor for poor survival in patients with early-stage cervical cancer.

Adult↗
PubMed1994

Alternating weekly chemotherapy with etoposide-methotrexate-dactinomycin/cyclophosphamide-vincristine for high-risk gestational trophoblastic disease.

OBJECTIVE: To evaluate the response rate and toxicity of alternating weekly therapy with etoposide-methotrexate-dactinomycin/cyclophosphamide-vincristine for women with high-risk gestational trophoblastic disease. METHODS: Twenty-two women with gestational trophoblastic disease received 126 cycles of the study regimen. Response was evaluated by serial hCG monitoring. Toxicity was assessed using standard criteria. RESULTS: Six women (27%) were treated for primary therapy and 16 (73%) for secondary therapy. The median prognostic index score was 11 (range 7-19). Only 23% of the patients and 11% of the 126 treatment cycles had grade 4 neutropenia, despite the heavily pretreated patient population. Only 2% of the cycles were associated with neutropenic sepsis or required platelet transfusions. Nonhematologic toxicity was modest. Among 16 women who received chemotherapy alone, there were 11 (69%) complete and three (19%) partial responses. When adjuvant therapies are included, the overall complete and partial response rates were 77 and 14%, respectively. Six (35%) of 17 complete responders developed recurrences. Five patients with partial response or relapse were salvaged with additional therapy. Fifteen of the 22 patients (68%) have sustained remissions. CONCLUSION: The regimen of alternating weekly etoposide-methotrexate-dactinomycin/cyclophosphamide-vincristine is effective and well-tolerated chemotherapy for patients with high-risk gestational trophoblastic disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Mutation and overexpression of the p53 tumor suppressor gene frequently occurs in uterine and ovarian sarcomas.

OBJECTIVE: To determine the frequency of mutation and overexpression of the p53 tumor suppressor gene in female genital tract sarcomas. METHODS: Immunostaining for p53 was performed in frozen sections of 46 ovarian and uterine sarcomas. Single-stranded conformation polymorphism analysis of exons 4-9 of the p53 gene was performed in 33 sarcomas. We performed DNA sequencing of the p53 gene in 22 cases in which we found p53 protein overexpression and/or shifted bands on single-stranded conformation polymorphism analysis. RESULTS: Overexpression of p53 was seen in 27 of 46 sarcomas (59%), including 26 of 41 (63%) mixed mesodermal tumors, one of four (25%) leiomyosarcomas, and zero of one endometrial stromal sarcoma. Among the 33 sarcomas subjected to molecular analysis, 21 demonstrated mutations in the p53 gene (64%). Eighteen cancers had a single mutation, whereas three cases showed two mutations in the p53 gene. There was one mutation in exon 4, seven mutations in exon 5, three mutations in exon 6, six mutations in exon 7, six mutations in exon 8, and one mutation in exon 9. With the exception of one microdeletion, which predicted a truncated protein product, all of the mutations were missense point mutations. All but one of the point mutations resulted in changes in the predicted amino acid sequence. There were 18 transition mutations (75%), five transversions (21%), and one deletion (4%). CONCLUSIONS: Mutation of the p53 tumor suppressor gene, with resultant overexpression of p53 protein, frequently occurs in ovarian and uterine sarcomas. Because most of the mutations are transitions, p53 mutations in these cancers likely arise from spontaneous errors in DNA synthesis and repair rather than from exposure to carcinogens.

Adult↗
PubMed1993

Intraperitoneal cisplatin and regional hyperthermia for ovarian carcinoma.

PURPOSE: To review the theoretical basis and results of a Phase I study of concurrent intraperitoneal cisplatin and hyperthermia in the treatment of ovarian carcinoma. METHODS AND MATERIALS: Previously treated patients with epithelial ovarian carcinoma received intraperitoneal instillation of cisplatin and 60 minutes of regional hyperthermia, with a goal temperature of 41.5 degrees C. Cisplatin dose started at 20 mg/m2 with escalation to the maximally tolerated dose. Six such cycles given every 3 weeks were planned. Pharmacokinetic studies with and without hyperthermia were performed. RESULTS: Fifteen patients receiving 17 courses of treatment were evaluable. The maximally tolerated dose of cisplatin was between 80 and 120 mg/m2. The dose limiting toxicity was nephrotoxicity in all but one course. The median intraperitoneal temperature was 40.7 degrees C; the majority of treatments in which the goal temperature was not reached had power limited by patient discomfort. No major toxicities attributable to hyperthermia were noted. Pharmacokinetic studies noted no significant differences between treatments with vs. without hyperthermia, with intraperitoneal to plasma area under the curve ratios being 30-35. Ten patients had a decline in their CA-125 count during treatment, although in only two patients did this response persist beyond their course of treatment. CONCLUSION: Intraperitoneal cisplatin and regional hyperthermia can be performed with reasonable toxicity. The maximally tolerated dose of 80-120 mg/m2 in pretreated patients (which is similar to those reported with cisplatin alone) and median intraperitoneal temperatures of 40.7 degrees C, however, are felt to be too low to be efficacious in a significant percentage of women with bulky recurrent disease. Further study using intravenous thiosulfate and controlled analgesia is being performed.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1993

Elevation of multiple serum markers in patients with stage I ovarian cancer.

BACKGROUND: The high overall mortality from ovarian cancer (> 60%) relates, in part, to delays in diagnosis. When ovarian cancer is detected in stage I (International Federation of Gynecology and Obstetrics staging), up to 90% of patients can be cured. Transvaginal sonography can detect early-stage disease with great sensitivity, but it is expensive and lacks specificity. Although serum marker assays could provide a less expensive and more convenient initial screening test, the sensitivity of assays varies. Measurement of serum CA 125 in conjunction with ultrasound screening as a second-line test confers high specificity but detects only about one half of early stage ovarian carcinomas. PURPOSE: The purpose of this retrospective study was to determine whether assays of multiple serum markers would improve sensitivity by detecting a higher percentage of stage I ovarian cancers than the CA 125 assay alone. METHODS: Using immunoradiometric assays, we measured preoperative serum levels of CA 125 tumor-associated antigen, macrophage colony-stimulating factor (M-CSF), and OVX1 in 46 patients with stage I ovarian cancer of different histologies and 237 patients with benign pelvic masses. We also assayed sera from 204 apparently healthy women who had participated in a screening trial and remained free from cancer at 1 year of followup. All specimens were obtained from cryopreserved aliquots. Marker levels were considered to be elevated when levels of CA 125 were greater than 30 U/mL, M-CSF levels were greater than 3.1 ng/mL, or OVX1 levels were greater than 12.1 U/mL. RESULTS: At least one of the serum markers was elevated in 98% of patients with stage I ovarian cancer; CA 125 levels were elevated in 67%. By the same criteria, 11% of healthy individuals and 51% of patients with benign pelvic masses had at least one elevated marker value. Thus, the sensitivity of the combination of assays for the three serum markers was significantly greater than the sensitivity of the CA 125 assay (P < .0005) and specificity was moderate. CONCLUSION: A panel of these three tumor markers can identify early-stage ovarian cancer with extremely high sensitivity and moderate specificity. IMPLICATIONS: Elevation of one or more serum markers should be evaluated further as an indication for transvaginal sonography in apparently healthy women. Such a strategy might substantially reduce the expense and improve the specificity of screening compared to the use of ultrasound alone. Prospective studies with a large cohort of patients at high risk for ovarian cancer will be required to confirm these findings.

Antigens, Neoplasm↗
PubMed1993

Genetic instability of microsatellites in endometrial carcinoma.

Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by a familial predisposition to colorectal carcinoma and extracolonic cancers of the gastrointestinal, urological, and female reproductive tracts, notably the endometrium. A genetic locus for HPNCC was recently determined by linkage analysis to exist on chromosome 2p; both sporadic and HNPCC-associated colorectal carcinomas exhibit a "replication error" phenotype, characterized by instability of dinucleotide repeat sequences throughout the genome. Here, we address the hypothesis that the replication error phenotype would be evident in some fraction of sporadic endometrial carcinomas or in those associated with HNPCC. Microsatellite instability was observed in 17% of sporadic endometrial carcinomas and in 75% of those tumors associated with HNPCC. These data indicate that the HNPCC gene is also involved in heritable and somatic forms of endometrial carcinoma.

Adult↗
PubMed1993

Spectrum of mutation and frequency of allelic deletion of the p53 gene in ovarian cancer.

BACKGROUND: The p53 gene encodes a nuclear phosphoprotein present in low levels in normal human cells. The wild-type form of this protein functions to restrain inappropriate cellular proliferation. Approximately one half of human epithelial ovarian cancers have mutations in the p53 gene and overexpress the mutant protein product. Deletion of one allele of the p53 gene also frequently occurs in these cancers. PURPOSE: We sought to define the spectrum of mutations in the p53 gene in epithelial ovarian cancer with respect to both the specific codons involved and the type of mutations observed. We also examined the frequency of allelic deletion of the p53 gene in cancers containing p53 gene mutations. METHODS: Tissue samples from the epithelial ovarian cancers of 62 patients were obtained during initial laparotomy. Histologic examination was done to ensure that the experimental samples used in this study contained more than 75% cancer cells. Total RNA was extracted from these samples and separately from matched control noncancerous regions of the surgical specimen or white blood cells. The purified RNAs were reverse transcribed to generate cDNA copies of exons 4-10 of the p53 gene. Two rounds of polymerase chain reaction (PCR) were conducted to produce enough template for DNA sequence analysis of the regions of interest within the p53 gene. Dideoxy sequencing of at least two independent productions of each amplified DNA template was done to confirm the validity of the mutations found. Allelic deletions were identified by PCR and gel electrophoretic techniques to examine three polymorphisms within the p53 gene in cancer-normal DNA pairs. RESULTS: We identified 45 mutations in exons 5-8 of the p53 gene, where mutations frequently have been found in other cancer types. An additional mutation was identified in exon 4. Overall, 72% of the mutations were transitions, 24% transversions, and 4% microdeletions. Allelic deletion of the other p53 allele was seen in 67% of ovarian cancers in which a p53 mutation was present. Germ-line p53 mutations were not found in any patients whose cancers had p53 mutations. CONCLUSIONS AND IMPLICATIONS: Like p53 mutations in other types of human cancers, those in epithelial ovarian cancers are diverse and occur frequently in exons 5-8. The predominance of transition mutations suggests that p53 mutations in ovarian cancer arise because of spontaneous errors in DNA synthesis and repair rather than the direct interaction of carcinogens with DNA. These molecular data are consistent with data from epidemiologic studies that have failed to demonstrate a convincing relationship between exposure to environmental carcinogens and the development of ovarian cancer.

Alleles↗
PubMed1993

Serum levels of HER-2 neu (C-erbB-2) correlate with overexpression of p185neu in human ovarian cancer.

BACKGROUND: The HER-2 neu (c-erbB-2) oncogene product p185neu is expressed by most ovarian cancers and overexpressed in approximately 30%. METHODS: Sera from patients with ovarian cancer were evaluated for neu antigen using an enzyme-linked immunoassay and for CA 125 antigen by radioimmunoassay. Tissue levels of neu from the same patients were determined by immunohistochemical staining with anti-neu monoclonal antibody. RESULTS: Elevated levels (> 2050 human neu unit [HNU]/ml) of circulating neu determinants have been detected in sera from 15% of 48 patients. Of 45 patients for whom tumor tissue had been cryopreserved, overexpression of neu was found in 17 by immunohistochemical analysis; of these 17, serum neu levels were elevated in 5 (29%). Among the 28 patients with normal to moderate tissue expression of neu, only 2 (7%) had elevated serum neu levels. Thus, elevated serum neu levels predicted tissue overexpression with a specificity of 93%. Serum neu levels were not related to serum levels of CA 125. CONCLUSION: Serum and tissue levels of neu correlate in patients with epithelial ovarian cancer.

Adult↗
PubMed1993

Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer: monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression.

Ovarian tumor cells produce macrophage colony stimulating factor, a potent chemoattractant for monocytes. Monocytes and macrophages produce tumor necrosis factor alpha (TNF-alpha) and interleukin 1 alpha or interleukin 1 beta (IL-1 beta) that can stimulate ovarian tumor cell growth. The present study has explored whether paracrine stimulation by monocyte derived cytokines might induce autocrine growth stimulation of normal and malignant ovarian epithelial cells. Endogenous expression of TNF-alpha mRNA was detected in ascites ovarian cancer cells isolated directly from patients, but not in established cultures of normal or malignant ovarian epithelial cells. When ascites tumor cells were cultured for 7 days, TNF-alpha expression ceased but could be reinduced by treatment with TNF-alpha or IL-1 beta. Ascites fluid contained concentrations of the cytokines that could mediate these effects. Similarly, treatment of normal or malignant ovarian epithelial cells with purified recombinant IL-1 beta or TNF-alpha induced transcription of TNF-alpha mRNA within 1 h. TNF-alpha protein could be detected by enzyme-linked immunosorbent assay in conditioned medium from IL-1 beta treated ovarian cancer cells. [3H]thymidine incorporation by normal or malignant ovarian epithelial cells was stimulated by a 24-h incubation with IL-1 beta or TNF-alpha. Stimulation of proliferation by IL-1 beta could be partially blocked by an antibody against TNF-alpha or by soluble TNF-alpha-receptor. Thus, TNF-alpha may function as both an autocrine and a paracrine growth factor in ovarian cancer.

Animals↗
PubMed1993

Mutation of the Ki-ras protooncogene in human endometrial hyperplasia and carcinoma.

Previous studies have demonstrated that some human endometrial carcinomas contain an activating point mutation in codon 12 of the Ki-ras protooncogene. To examine the hypothesis that this mutation may occur at an earlier stage of neoplastic progression in the endometrium, we analyzed 89 samples of premalignant endometrial hyperplasia and an additional 84 samples of endometrial carcinoma for point mutations of Ki-ras codon 12. Mutations were found in all three types of endometrial hyperplasia, simple, complex, and atypical, with no clear evidence of a differential distribution in any particular type. Furthermore, the overall incidence of Ki-ras mutations in the hyperplasia specimens (16%) was similar to the incidence detected in carcinomas (18%), indicating that ras mutation may represent an early event in a subset of endometrial carcinomas. When the tissue samples were segregated as to country of origin, the frequency of this mutation was approximately 2-fold higher in hyperplasia and carcinoma samples from Japan than from the United States, where the incidence, clinicopathological characteristics, and risk factors for endometrial carcinoma differ dramatically. There was no apparent correlation, however, between ras mutation and any pathological, histological, or clinical parameter examined, except survival. The presence of a ras mutation was inversely associated with death from disease, suggesting that this molecular feature may characterize a subset of endometrial carcinomas with a good prognosis.

Adult↗
PubMed1993

A deletion unit on chromosome 17q in epithelial ovarian tumors distal to the familial breast/ovarian cancer locus.

Linkage analysis in familial breast and ovarian cancer and studies of allelic deletion in sporadic ovarian tumors have suggested that chromosome 17q may be the location of a gene of importance in ovarian carcinogenesis. We have examined tumor and normal DNA samples from 120 patients with ovarian tumors for allelic deletion at 12 loci on chromosome 17q. Allelic deletion was observed in 64 cases (53%) of which 56 showed loss of heterozygosity at all loci analyzed on 17q. The pattern of allele loss at metastatic sites was consistent with loss of heterozygosity having occurred prior to metastasis. A common region of deletion, defined by 6 cases of invasive epithelial ovarian cancer and a benign serous cystadenoma, spanned 16 cM and was delimited by nm23 and GH. This region is distal to the region on chromosome 17q to which the familial breast/ovarian cancer susceptibility gene has been mapped. The results suggest that a tumor suppressor gene involved in sporadic ovarian carcinogenesis is located on the distal portion of chromosome 17q and is distinct from the gene linked to familial cases.

Alleles↗
PubMed1993

Cell growth regulation in epithelial ovarian cancer.

BACKGROUND: As in the case of other epithelial neoplasms, most ovarian cancers arise from single clones of cells that have undergone multiple genetic alterations. A comparison of normal and malignant ovarian epithelium has identified several differences in growth regulation by peptide growth factors, protooncogenes, and tumor suppressor genes. METHODS: Recent articles and abstracts have been reviewed. RESULTS: The malignant ovarian epithelial phenotype has been associated with (1) autocrine growth stimulation by transforming growth factor-alpha, (2) loss of autocrine growth inhibition by transforming growth factor-beta, (3) mutation or amplification of ras in 2-12% of cases, (4) amplification of myc in 23% of specimens, (5) expression of fms in 56% of cases with potential autocrine stimulation by macrophage colony stimulating factor, (6) paracrine stimulation by macrophage products including interleukin-1, interleukin-6 and tumor necrosis factor, (7) overexpression of c-erbB-2 (HER-2/neu) in 30% of cases, and (8) mutation with consequent overexpression of p53 in 50% of advanced ovarian cancers. A poor clinical prognosis is associated with expression or overexpression of the epidermal growth factor receptor, fms, and HER-2/neu. Antibodies against the extracellular domain of the HER-2/neu gene product p185 inhibit the growth of tumor cells that overexpress HER-2/neu and are associated with marked decreases in diacylglycerol levels. The intracellular kinase domain is required for growth inhibition. Antibodies that inhibit growth stimulate phosphorylation of intracellular substrates. Ricin A chain monoclonal antibody conjugates that react with p185 also inhibit the growth of tumor cells that overexpress p185. The intracellular kinase region is not required for immunotoxin-mediated killing. Coexpression of HER-2/neu and the epidermal growth factor receptor has been observed in 65% of epithelial ovarian cancers and in a limited number of normal tissue from a fraction of donors. CONCLUSIONS: Multiple alterations in growth factors, protooncogenes and growth factors have been detected in different epithelial ovarian cancers. Inappropriate signalling from receptor tyrosine kinases may be particularly important for ovarian oncogenesis. Drugs that affect tyrosine kinase and phosphatase activity deserve attention as potential therapeutic agents for ovarian cancer. The extracellular domains of the HER-2/neu gene product p185 and the epidermal growth factor receptor may provide useful targets for serotherapy.

Carcinoma↗
PubMed1993

Antibody-induced growth inhibition is mediated through immunochemically and functionally distinct epitopes on the extracellular domain of the c-erbB-2 (HER-2/neu) gene product p185.

Over-expression of the c-erbB-2 (HER-2/neu) gene product p185 occurs in 30% of breast and ovarian cancers. The p185 protein might serve as a target for serotherapy in that antibodies against different epitopes on the extracellular domain of p185 can inhibit growth of tumor cells in the absence of cellular or humoral effector mechanisms. To define epitopes of functional relevance, 11 monoclonal antibodies (MAbs) were evaluated for their ability to bind to the extracellular domain of p185. Results of competition studies with 125I-labeled and non-labeled antibodies indicated that 10 of 11 epitopes were grouped in a linear array. Antibodies against 7 epitopes inhibited anchorage-independent growth and antibodies against 2 of these epitopes also inhibited anchorage-dependent growth of SKBr3 breast-cancer cells that over-expressed p185. Treatment with antibodies exerted cytotoxic rather than cytostatic effects. When antibodies were used in combination, additive or supra-additive inhibition of anchorage-independent and anchorage-dependent growth was observed between pairs of antibodies. Growth inhibition did not relate to the affinity of the antibody or its isotype. Two antibodies that inhibited both anchorage-dependent and anchorage-independent growth also blocked binding of the HER-2/neu ligand, whereas 5 antibodies that inhibited only anchorage-independent growth had no effect on ligand binding. Inhibition of cell growth did not correlate with internalization of p185 or down-regulation of p185 on the cell surface. Fab fragments of active antibodies could also inhibit anchorage-independent growth of SKBr3. Thus, murine MAbs and their fragments recognized both immunochemically distinct and functionally distinct epitopes on the p185 molecule. Whereas inhibition of anchorage-dependent growth correlated with the ability of antibodies to block ligand binding, inhibition of anchorage-independent growth did not correlate with effects on ligand binding, internalization, cell-surface expression or cross-linking of p185.

Antibodies, Monoclonal↗