Biomedical subjects

J Mendelsohn

Publications and source records attributed to J Mendelsohn.

At least 73 records · Page 4Linked to original sources

PubMed1996

Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer.

PURPOSE: Breast cancer frequently overexpresses the product of the HER2 proto-oncogene, a 185-kd growth factor receptor (p185HER2). The recombinant humanized monoclonal antibody (rhuMAb) HER2 has high affinity for p185HER2 and inhibits the growth of breast cancer cells that overexpress HER2. We evaluated the efficacy and toxicity of weekly intravenous administration of rhuMAb HER2 in patients with HER2-overexpressing metastatic breast cancer. PATIENTS AND METHODS: We treated 46 patients with metastatic breast carcinomas that overexpressed HER2. Patients received a loading dose of 250 mg of intravenous rhuMAb HER2, then 10 weekly doses of 100 mg each. Patients with no disease progression at the completion of this treatment period were offered a maintenance phase of 100 mg/wk. RESULTS: Study patients had extensive metastatic disease, and most had received extensive prior anticancer therapy. Adequate pharmacokinetic levels of rhuMAb HER2 were obtained in 90% of the patients. Toxicity was minimal and no antibodies against rhuMAb HER2 were detected in any patients. Objective responses were seen in five of 43 assessable patients, and included one complete remission and four partial remissions (overall response rate, 11.6%; 95% confidence interval, 4.36 to 25.9). Responses were observed in liver, mediastinum, lymph nodes, and chest wall lesions. Minor responses, seen in two patients, and stable disease, which occurred in 14 patients, lasted for a median of 5.1 months. CONCLUSION: rhuMAb HER2 is well tolerated and clinically active in patients with HER2-overexpressing metastatic breast cancers that had received extensive prior therapy. This is evidence that targeting growth factor receptors can cause regression of human cancer and justifies further evaluation of this agent.

Adult↗

PubMed1996

Formation of p27-CDK complexes during the human mitotic cell cycle.

In eukaryotic cells, the coordinated activation of different cyclin-dependent kinases regulates entry into S-phase. In vitro and in nonproliferating cells, p27 associates with and inhibits cyclin/cycin-dependent kinase (CDK) holoenzymes containing either CDK4, CDK6, or CDK2. Although many different types of proliferating cells contain p27 protein, neither the interactions of p27 with cyclin/CDK complexes nor the consequences of this interaction during the mitotic cycle have been fully explored. We report that, in MANCA cells, the amount of p27 is constant during the cell cycle. In addition, p27 associates with three different CDKs: CDK2, CDK4, and CDK6. Furthermore, the amount of p27 is significantly lower than the amount of cyclin D3 in these cells. The amount of CDK4 and CDK6 associated with p27 does not change in a cell cycle-dependent fashion; in contrast, the amount of CDK2 associated with p27 is lowest in early G1 cells and increases to a maximum in mid-G1 phase, reaching a steady-state level in late G1-phase cells. After mid-G1 phase, the amount of each p27/CDK complex remains constant through the remainder of the cell cycle. p27-immunoprecipitates contain an Rb-kinase activity. The substrate specificity, the expression pattern of this kinase, and the ability to deplete 50% of this kinase activity with a CDK6-specific antibody suggest that the CDK6 protein mediates, in part, the p27-associated Rb-kinase activity. In contrast, p27 complexes containing CDK2 are incapable of phosphorylating histone H1. These data are consistent with a model wherein cyclin D/CDK complexes sequester the CDK2-dependent kinase inhibitory activity of p27.

Animals↗

PubMed1996

Targeted therapy for prostate cancer: the Memorial Sloan-Kettering Cancer Center approach.

Carcinoma of the prostate represents a wide range of diseases with differing prognoses. A key to selecting treatment depends on the ability to predict the natural history of the disease for the individual. Thus far, non-hormonal approaches have not demonstrated a survival advantage in randomized comparisons and, clearly, innovative approaches are needed. The clinical trials program developed at Memorial Sloan-Kettering Cancer Center is based on specific manifestations and specific targets of the disease and the predicted prognosis, using prostate-specific antigen and acid phosphatase changes as biomarkers of progression and response. In patients with minimal disease who have received local treatments but progressed systemically, we are studying methods aimed at stimulating their immune systems either by nonspecific immunopotentiation or specific immunization to specific glycoprotein or carbohydrate targets on the cancer cells, or to anti-growth factor receptor antibody aimed at blocking the specific signalling pathways that contribute to hormonal failure. These and other approaches provide an opportunity to treat this disease while maintaining an acceptable quality of life for patients.

Animals↗

PubMed1996

Growth inhibition of human colon carcinoma cells by combinations of anti-epidermal growth factor-related growth factor antisense oligonucleotides.

GEO is a well-differentiated colon cancer cell line that coexpresses the epidermal growth factor-like growth factors CRIPTO (CR), amphiregulin (AR), and transforming growth factor alpha (TGF-alpha). Antisense 20-mer phosphorothioate oligodeoxynucleotides (AS S-oligos) directed against CR, AR, and TGF-alpha mRNAs were equipotent in their ability to inhibit both the anchorage-dependent growth and the anchorage-independent growth (AIG) of GEO cells, with a 50% inhibitory concentration of about 5 micrometer in the AIG assay. A supraadditive effect was observed when a combination of S-oligos was used. For example, a combination of two different AS S-oligos (either AR + CR, or TGF-alpha + CR, or TGF-alpha + AR) at a concentration of 1 micrometer each (total concentration, 2 micrometer) resulted in 50% inhibition of GEO cells AIG, whereas the use of each AS S-Oligo at a 1 or 2 micrometer concentration resulted respectively in about 10 and 20% growth inhibition. A combination of the three AS S-oligos was even more effective, resulting in about 60% inhibition of GEO cells AIG at a concentration of 1 micrometer each (3 micrometer total concentration). The AS S-oligos were also able to inhibit specifically the expression of either AR, CR, or TGF-alpha proteins in GEO cells, as assessed using immunocytochemistry or Western blot analysis. Finally, a supraadditive growth inhibitory effect of the AS S-oligos and an epidermal growth factor receptor-blocking antibody (monoclonal antibody 528) was observed. These data suggest that the use of a combination of AS S-oligos directed against different growth factors and antibodies directed against their receptors might result in an efficient inhibition of colon carcinoma cell growth.

Amphiregulin↗

PubMed1995

EGF receptor and p185erbB-2-specific single-chain antibody toxins differ in their cell-killing activity on tumor cells expressing both receptor proteins.

Many human tumors over-express erbB-2 and EGF receptors. The membrane localization of these receptor tyrosine kinases make them appropriate targets for directed tumor therapy. We have used recombinant DNA technology to produce single-chain antibody exotoxin A (scFv-ETA) fusion proteins which specifically bind the erbB-2 and EGF receptors. The scFv portion is composed of the heavy- and light-chain variable domains of monoclonal antibodies which recognize the extracellular portion of each receptor. We have previously described the anti-tumor activity of the bacterially produced scFv(FRP5)-ETA directed to the erbB-2 receptor. In this paper we describe the characteristics of scFv(225)-ETA, a protein which binds the EGF receptor. The bacterially produced recombinant protein binds to the receptor with high affinity and inhibits the in vitro growth of the EGF receptor over-expressing tumor cell lines A431 and MDA-MB468. Combination treatment with scFv-(FRP5)-ETA and scFv(225)-ETA led to an additive inhibitory effect on the in vitro growth of A431 cells. SKBR3 cells expressing low levels of EGF receptor but high levels of p185erbB-2 were not affected by scFv(225)-ETA treatment but were sensitive to scFv(FRP5)-ETA. Stimulation of SKBR3 cells and HCII RI#11 mouse mammary epithelial cells expressing the human erbB-2 with EGF led to an increase in scFv(FRP5)-ETA activity, showing that the EGF-induced activation of erbB-2 can potentiate the action of the erbB-2-directed toxin. Treatment of athymic nude mice with scFv(FRP5)-ETA and the combination of both scFv-ETA proteins led to the transient arrest of growth of established A431 tumors. scFv(225)-ETA treatment alone was the most effective, leading to tumor shrinkage during the course of treatment, whereas treatment with the parental monoclonal antibody 225 led to retarded tumor growth.

ADP Ribose Transferases↗

PubMed1995

Insulin-like growth factors modulate the growth inhibitory effects of retinoic acid on MCF-7 breast cancer cells.

Retinoids are currently being tested for the treatment and prevention of several human cancers, including breast cancer. However, the anti-cancer and growth inhibitory mechanisms of retinoids are not well understood. All-trans retinoic acid (RA) inhibits the growth of the estrogen receptor-positive (ER+) breast cancer cell line, MCF-7, in a reversible and dose-dependent manner. In contrast, insulin-like growth factors (IGF-I, IGF-II) and insulin are potent stimulators of the proliferation of MCF-7 and several other breast cancer cell lines. Pharmacologic doses of RA (> or = 10(-6) M) completely inhibit IGF-I-stimulated MCF-7 cell growth. Published data suggest that the growth inhibitory action of RA on IGF-stimulated cell growth is linear and dose-dependent, similar to RA inhibition of unstimulated or estradiol-stimulated MCF-7 cell growth. Surprisingly, we have found that IGF-I or insulin-stimulated cell growth is increased to a maximum of 132% and 127%, respectively, by cotreatment with 10(-7) M RA, and that 10(-9) - 10(-7) M RA increase cell proliferation compared to IGF-I or insulin alone. MCF-7 cells that stably overexpress IGF-II are also resistant to the growth inhibitory effects of 10(-9) - 10(-7) M RA. Treatment with the IGF-I receptor blocking antibody, alpha IR-3, restores RA-induced growth inhibition of IGF-I-treated or IGF-II-overexpressing MCF-7 cells, indicating that the IGF-I receptor is mediating these effects. IGFs cannot reverse all RA effects since the altered cell culture morphology of RA-treated cells is similar in growth-inhibited cultures and in IGF-II expressing clones that are resistant to RA-induced growth inhibition. These results indicate that RA action on MCF-7 cells is biphasic in the presence of IGF-I or insulin with 10(-9) - 10(-7) M RA enhancing cell proliferation and > or = 10(-6) M RA causing growth inhibition. As IGF-I and IGF-II ligands are frequently detectable in breast tumor tissues, their potential for modulation of RA effects should be considered when evaluating retinoids for use in in vivo experimental studies and for clinical purposes. Additionally, the therapeutic use of inhibitors of IGF action in combination with RA is suggested by these studies.

Breast Neoplasms↗

PubMed1995

Rheumatoid nodules of the larynx.

Two unique cases of rheumatoid nodules affecting the larynx are reported. These subcutaneous nodules represent localized laryngeal involvement from autoimmune disorders. The otolaryngologist should be aware of these possibilities as part of the differential diagnosis in the workup of dysphonia.

Adult↗

PubMed1995

Prolonged induction of p21Cip1/WAF1/CDK2/PCNA complex by epidermal growth factor receptor activation mediates ligand-induced A431 cell growth inhibition.

Proliferation of some cultured human tumor cell lines bearing high numbers of epidermal growth factor (EGF) receptors is paradoxically inhibited by EGF in nanomolar concentrations. In the present study, we have investigated the biochemical mechanism of growth inhibition in A431 human squamous carcinoma cells exposed to exogenous EGF. In parallel, we studied a selected subpopulation, A431-F, which is resistant to EGF-mediated growth inhibition. We observed a marked reduction in cyclin-dependent kinase-2 (CDK2) activity when A431 and A431-F cells were cultured with 20 nM EGF for 4 h. After further continuous exposure of A431 cells to EGF, the CDK2 activity remained at a low level and was accompanied by persistent G1 arrest. In contrast, the early reduced CDK2 activity and G1 accumulation in A431-F cells was only transient. We found that, at early time points (4-8 h), EGF induces p21Cip1/WAF1 mRNA and protein expression in both EGF-sensitive A431 cells and EGF-resistant A431-F cells. But only in A431 cells, was p21Cip1/WAF1 expression sustained at a significantly increased level for up to 5 d after addition of EGF. Induction of p21Cip1/WAF1 by EGF could be inhibited by a specific EGF receptor tyrosine kinase inhibitor, tyrphostin AG1478, suggesting that p21Cip1/WAF1 induction was a consequence of receptor tyrosine kinase activation by EGF. We also demonstrated that the increased p21Cip1/WAF1 was associated with both CDK2 and proliferating cell nuclear antigen (PCNA). Taken together, our results demonstrate that p21Cip1/WAF1 is an important mediator of EGF-induced G1 arrest and growth inhibition in A431 cells.

CDC2-CDC28 Kinases↗

PubMed1995

Inhibition of ligand-induced activation of epidermal growth factor receptor tyrosine phosphorylation by curcumin.

We explored the regulation of epidermal growth factor (EGF)-mediated activation of EGF receptor (EGF-R) phosphorylation by curcumin (diferuloyl-methane), a recently identified kinase inhibitor, in cultured NIH 3T3 cells expressing human EGF-R. Treatment of cells with a saturating concentration of EGF for 5-15 min induced increased EGF-R tyrosine phosphorylation by 4- to 11-fold and this was inhibited in a dose- and time-dependent manner by up to 90% by curcumin, which also inhibited the growth of EGF-stimulated cells. There was no effect of curcumin treatment on the amount of surface expression of labeled EGF-R and inhibition of EGF-mediated tyrosine phosphorylation of EGF-R by curcumin was mediated by a reversible mechanism. In addition, curcumin also inhibited EGF-induced, but not bradykinin-induced, calcium release. These findings demonstrate that curcumin is a potent inhibitor of a growth stimulatory pathway, the ligand-induced activation of EGF-R, and may potentially be useful in developing anti-proliferative strategies to control tumor cell growth.

3T3 Cells↗

PubMed1995

Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin.

Both EGF and insulin, or IGF, stimulate the growth of many cell types by activating receptors that contain tyrosine kinase activities. A monoclonal antibody (mAb 225) against the EGF receptor produced in this laboratory has been shown to competitively inhibit EGF binding and block activation of receptor tyrosine kinase. Here we report that a human colorectal carcinoma cell line, DiFi, which expresses high levels of EGF receptors on plasma membranes, can be induced to undergo G1 cell cycle arrest and programmed cell death (apoptosis) when cultured with mAb 225 at concentrations that saturate EGF receptors. Addition of IGF-1 or high concentrations of insulin can delay apoptosis induced by mAb 225, while the G1 arrest cannot be reversed by either IGF-1 or insulin. Insulin/IGF-1 cannot activate EGF receptor tyrosine kinase that has been inhibited by mAb 225. Moreover, an mAb against the IGF-1 receptor, which has little direct effect on DiFi cell growth, can block the capacity of insulin/IGF-1 to delay apoptosis induced by mAb 225, suggesting that the insulin/IGF-1-mediated delay of apoptosis is acting through the IGF-1 receptor. In contrast, insulin/IGF-1 cannot delay the apoptosis caused by the DNA damaging agent, cisplatin. The results indicate that EGF receptor activation is required both for cell cycle progression and for prevention of apoptosis in DiFi cells, and that a signal transduction pathway shared by receptors for insulin/IGF-1 and EGF may be involved in regulating apoptosis triggered by blockade of the EGF receptor.

Antibodies, Monoclonal↗

PubMed1995

Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model.

The epidermal growth factor receptor (EGFR) is a protein tyrosine kinase expressed on many types of tumor cells, including breast, ovarian, bladder, head and neck, and prostatic carcinoma. There seems to be an association between up-regulation of the EGFR and poor clinical prognosis for a number of human cancers. The 225 antibody is a highly specific murine monoclonal antibody that binds specifically to the human EGFR with an affinity equal to its ligand, competes with the ligand for binding, and blocks activation of the receptor tyrosine kinase. In addition, 225 has been shown to inhibit the growth of human tumor xenografts in athymic nude mice. The 225 antibody has recently been chimerized with human IgG1 in its constant region to increase its clinical utility by decreasing the potential for generation of human antimouse antibodies in recipients. This report compares the biological effects of 225 and its chimeric counterpart (designated C225) against established A431 tumor xenografts in nude mice. The results of these experiments indicated that C225 was more effective than 225 in inhibiting tumor growth in this model. In addition, many of the animals treated with C225 were tumor free at the end of each treatment protocol. It was determined that the dissociation constant of C225 was about 5-fold lower than 225. This suggested that the increased capacity of C225 to compete with ligand for binding to the EGFR was responsible for its enhanced in vivo antitumor effect.

Animals↗

PubMed1995

Cooperative antiproliferative effects of 8-chloro-cyclic AMP and 528 anti-epidermal growth factor receptor monoclonal antibody on human cancer cells.

8-Chloro-cyclic AMP (8-Cl-cAMP), a site-selective cAMP analogue, is a specific inhibitor of type I cAMP-dependent protein kinase (PKAI) and induces growth inhibition in several human and rodent tumor cell lines. The anti-epidermal growth factor receptor (EGFR) mAb 528 is a blocking antibody able to inhibit the in vitro and in vivo growth of several human cancer cell lines that express functional EGFRs. Since enhanced levels of PKAI are generally found in tumor cells and an increase in PKAI expression is induced by transformation through a transforming growth factor alpha/EGFR autocrine pathway, we have evaluated whether treatment with mAb 528 in combination with 8-Cl-cAMP may have an additive or synergistic growth inhibitory effect on human cancer cells. A dose-dependent inhibition of monolayer cell growth was observed in two human colon cancer cell lines (GEO and CBS) and in a human breast cancer cell line (MDA-468) by treatment with either mAb 528 or 8-Cl-cAMP with 50% inhibitory concentration of 2-10 microgram/ml or 20-25 micrometer, respectively. The combined treatment with low noninhibitory doses of mAb 528 (0.25 microgram/ml) and with 8-Cl-cAMP had a more than additive growth inhibitory effect with a 3- to 5-fold reduction in the 8-Cl-cAMP 50% inhibitory concentration in all cell lines tested. This combined treatment was similarly effective in inhibiting the soft agar cloning efficiency of GEO cells. 8-Cl-cAMP treatment of GEO cells induced a dose-dependent increase in cell membrane-associated EGFRs with a maximum 3- to 4-fold increase within 48-72 h of treatment. These results suggest that a double blockade of the PKAI serine-threonine kinase-dependent and of the EGFR tyrosine kinase-dependent pathways is potentially useful in cancer therapy.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1995

Changing pattern of expression of the epidermal growth factor receptor and transforming growth factor alpha in the progression of prostatic neoplasms.

The autocrine/paracrine interaction of the epidermal growth factor receptor (EGFr) and transforming growth factor alpha (TGF-alpha) has been implicated in prostate cancer cell growth and proliferation. To evaluate the role of EGFr and TGF-alpha in prostate cancer progression, we studied the immunohistochemical staining pattern of EGFr and TGF-alpha in malignant primary and hormone-independent metastatic prostate lesions. The specimens evaluated included 37 primary carcinomas (34 hormone-naive and 3 hormone-refractory tumors) and 22 metastases. For each specimen, the pattern of expression was evaluated and staining reactivities graded from 0-3, with 0 representing no staining and 3 representing homogeneous and intense staining. Primary malignant prostate epithelial cells in areas with discrete gland formation showed strong EGFr immunostaining, while stromal cells were generally nonreactive. In untreated primary tumors, TGF-alpha expression was primarily in the stroma, while epithelial cells were weakly positive in several cases. Malignant epithelial cells adjacent to neural elements that stained positive for TGF-alpha was frequently observed. A homogeneous staining pattern for EGFr was noted in 17 (89%) of 19 evaluable androgen-independent-refractory metastases, while TGF-alpha expression was found in 14 (78%) of 18 evaluable cases. Overall, 14 of 18 androgen-independent metastases coexpressed the receptor and the ligand. These results suggest that, unlike primary prostate tumors where a paracrine relationship between EGFr and TGF-alpha appears to predominate, the potential for autocrine stimulation may exist in the majority of metastatic androgen-independent tumors. Furthermore, the changing pattern of expression as the disease evolves from the localized hormone-naive to metastatic androgen-independent condition suggests that strategies aimed at blocking this growth factor pathway may be of therapeutic importance for androgen-independent disease.

Adrenal Gland Neoplasms↗

PubMed1995

Editorial

Explore the source record for details and available documents.

Journal Article↗

PubMed1995

Tumor receptor imaging: proceedings of the National Cancer Institute workshop, review of current work, and prospective for further investigations.

In February 1994, the National Cancer Institute held a workshop to evaluate the current and future role of emission tomographic imaging methods, positron emission tomography and single-photon emission computed tomography, in improving the accuracy of cancer diagnosis and the effectiveness of treatment and in elucidating basic aspects of human cancer biology. Reviews covered many of the receptor and transport systems for hormones and growth factors, as well as metabolic changes important in human cancer, and topical presentations reviewed the current status of receptor-based imaging in the most well-characterized systems: somatostatin receptor imaging of neuroendocrine tumors, estrogen receptor imaging of breast cancer, and epidermal growth factor receptor and tumor metabolic imaging. A critical analysis was made of the current research and of new directions for the future development and use of receptor-imaging methods in oncology. In each area, recommendations were made for further investigation, where emerging understanding of tumor cell biology and defined molecular targets might be combined with the methods of radiopharmaceutical design and evaluation, to develop new approaches to critical issues in the diagnosis, staging, and treatment of cancer through tumor receptor imaging.

Humans↗

PubMed1994

9-Cis retinoic acid inhibits growth of breast cancer cells and down-regulates estrogen receptor RNA and protein.

All-trans retinoic acid (tRA) inhibits growth of estrogen receptor-positive (ER+) breast cancer cells in vitro, and a variety of retinoids inhibit development of breast cancer in animal models. 9-cis retinoic acid (9-cis RA) is a naturally occurring high affinity ligand for the retinoid X receptors, as well as the retinoic acid receptors (RARs). Whether 9-cis RA has a different spectrum of biological activity from tRA, which only binds RARs with high affinity, is largely unknown. We studied the effects of 9-cis RA on growth and gene expression in ER+ and ER- human breast cancer cells. 9-cis RA inhibited the growth in monolayer culture of several ER+, but not ER-, cell lines in a dose-dependent manner. Growth inhibition and morphological changes by 9-cis RA were similar to those of tRA, suggesting that the ability to bind both RAR and retinoid X receptors did not significantly augment growth inhibition or confer sensitivity to tRA-resistant lines. MCF-7 cells exposed to 9-cis RA showed a dose-dependent accumulation in G1. Northern analyses showed that RAR-alpha and RAR-beta were not significantly regulated, while RAR-gamma was up-regulated and retinoid X receptor alpha was down-regulated by 9-cis RA. Since interactions between tRA and ER-dependent transcription have recently been reported, we investigated whether these retinoids regulate expression of ER itself or estrogen-responsive genes. Both 9-cis RA and tRA induce down-regulation of ER mRNA and protein in MCF-7 cells. 9-cis RA down-regulates expression of the estrogen-responsive genes PR and pS2 in MCF-7 cells as reported previously for tRA. In several ER-positive subclones, we found that the degree of ER expression and regulation, but not always estrogen-sensitivity, correlates with the growth-inhibitory effects of 9-cis RA. Further, in an ER-, retinoid-unresponsive breast cancer cell line, induced ER expression confers responsiveness to retinoid growth inhibition. These data, combined with reports of additive growth inhibition of tRA and tamoxifen in vitro, suggest that 9-cis RA might augment the ability of tamoxifen to inhibit growth of ER+ breast cancer cells in vivo.

Breast Neoplasms↗

PubMed1994

Antibody-induced epidermal growth factor receptor dimerization mediates inhibition of autocrine proliferation of A431 squamous carcinoma cells.

We previously reported that anti-epidermal growth factor (EGF) receptor monoclonal antibody (mAb) 225 can block receptor activation and inhibit proliferation of tumor cells bearing EGF receptors. To further explore the mechanism of mAb-mediated growth inhibition, we compared the capacities of bivalent 225 mAb and 225 F(ab')2, and monovalent 225 Fab' fragment to block ligand binding to EGF receptors, inhibit activation of receptor tyrosine kinase by exogenous and endogenous ligand, produce receptor dimerization, down-regulate receptors, and inhibit proliferation of cultured A431 squamous carcinoma cells. Unlike 225 mAb and 225 F(ab')2, 225 Fab' fragment was a poor inhibitor of A431 cell proliferation. The weak antiproliferative capacity of 225 Fab' was not due to depletion of active fragment from cultures. When cells were exposed to exogenous EGF, monovalent 225 Fab' remaining in conditioned culture medium could act as well as the bivalent forms of mAb to block binding and tyrosine kinase activation by exogenous EGF. However, unlike the bivalent forms, 225 Fab' fragment was unable to induce receptor dimerization and down-regulation, and it lacked the capacity to block autocrine activation of EGF receptors by endogenous ligand. These deficiencies were corrected by addition of rabbit anti-mouse IgG antibody, which also enabled 225 Fab' fragment to inhibit cell proliferation. We conclude that in A431 cells, inhibition of autocrine-stimulated proliferation by anti-EGF receptor mAbs requires antibody bivalency, which provides the capacity to produce EGF receptor dimerization accompanied by receptor down-regulation. These properties may explain the greater efficacy of bivalent mAb and F(ab')2, compared with monovalent Fab' fragment, in inhibiting proliferation of a variety of malignant and nonmalignant cultured cell lines.

Antibodies, Monoclonal↗

PubMed1994

The epidermal growth factor receptor as a target for therapy in breast carcinoma.

The epidermal growth factor (EGF) receptor and its ligands have an important regulatory role in breast carcinoma. We have produced a series of monoclonal antibodies (MAbs) directed against the external portion of the EGF receptor. These MAbs prevent the binding of the ligands to the receptor, block ligand-induced activation of the receptor, and can inhibit the growth of breast cancer cells both in tissue culture and in human tumor xenografts in nude mice. We have also shown that anti-EGF receptor antibodies greatly enhance the antitumor effects of chemotherapeutic agents active in breast cancer. Phase I clinical trials with single doses of MAb conducted in patients with tumors over-expressing EGF receptors demonstrated favorable pharmacokinetics, good tumor imaging, and a lack of toxicity. A human:murine chimeric antibody has been produced with comparable affinity and antitumor activity that will enable us to administer repeated doses of MAb either alone or in combination with chemotherapy. Our pre-clinical data support the concept that the EGF receptor may be an optimal target for treatment with receptor blocking antibodies, either alone or in combination with chemotherapy.

Adenocarcinoma↗