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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HER2 is a ligand-less member of the human epidermal growth factor receptor or ErbB family of tyrosine kinases. In normal biological systems, HER2 functions as a co-receptor for a multitude of epidermal growth factor-like ligands that bind and activate other HER family members. HER2 overexpression is observed in a number of human adenocarcinomas and results in constitutive HER2 activation. Specific targeting of these tumors can be accomplished with antibodies directed against the extracellular domain of the HER2 protein. One of these antibodies, 4D5, has been fully humanized and is termed trastuzumab (Herceptin; Genentech, San Francisco, CA). Treatment of HER2-overexpressing breast cancer cell lines with trastuzumab results in induction of p27KIP1 and the Rb-related protein, p130, which in turn significantly reduces the number of cells undergoing S-phase. A number of other phenotypic changes are observed in vitro as a consequence of trastuzumab binding to HER2-overexpressing cells. These phenotypic changes include downmodulation of the HER2 receptor, inhibition of tumor cell growth, reversed cytokine resistance, restored E-cadherin expression levels, and reduced vascular endothelial growth factor production. Interaction of trastuzumab with the human immune system via its human immunoglobulin G1 Fc domain may potentiate its antitumor activities. In vitro studies demonstrate that trastuzumab is very effective in mediating antibody-dependent cell-mediated cytotoxicity against HER2-overexpressing tumor targets. Trastuzumab treatment of mouse xenograft models results in marked suppression of tumor growth. When given in combination with standard cytotoxic chemotherapeutic agents, trastuzumab treatment generally results in statistically superior antitumor efficacy compared with either agent given alone. Taken together, these studies suggest that the mechanism of action of trastuzumab includes antagonizing the constitutive growth-signaling properties of the HER2 system, enlisting immune cells to attack and kill the tumor target, and augmenting chemotherapy-induced cytotoxicity.
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PMID:Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). 1048 95

Antibody to the Her-2/neu gene product has been shown to inhibit the growth of breast cancer cells overexpressing Her-2/neu and to have clinical utility in treating breast cancer. We studied a recombinant, humanized anti-Her-2/neu antibody (Herceptin) in preclinical models of human prostate cancer. The androgen-dependent CWR22 and LNCaP human prostate cancer xenograft models and androgen-independent sublines of CWR22 were used. Her-2/neu staining of the parental, androgen-dependent, and androgen-independent CWR22 tumors and LNCaP tumors demonstrated variable Her-2/neu expression. Herceptin was administered i.p. at a dose of 20 mg/kg twice weekly after the xenograft had been established. No effect of Herceptin on tumor growth was observed in any of the androgen-independent tumors; however, significant growth inhibition was observed in both of the androgen-dependent xenograft models, CWR22 (68% growth inhibition at the completion of the experiment; P = 0.03 for trajectories of the average tumor volume of the groups) and LNCaP (89% growth inhibition; P = 0.002). There was a significant increase in prostate-specific antigen (PSA) index (ng PSA/ml serum/mm3 tumor) in Herceptin-treated androgen-dependent groups compared with control (CWR22, 18-fold relative to pretreatment value versus 1.0-fold, P = 0.0001; LNCaP, 2.35-fold relative to pretreatment value versus 0.6-fold, P = 0.001). When paclitaxel (6.25 mg/kg s.c., five times/week) was given to animals with androgen-dependent and -independent tumors, there was growth inhibition in each group. Paclitaxel and Herceptin cotreatment led to greater growth inhibition than was seen for the agents individually. Thus, in these prostate cancer model systems, Herceptin alone has clinical activity only in the androgen-dependent tumor and has at least an additive effect on growth, in combination with paclitaxel, in both androgen-dependent and androgen-independent tumors. Response to Herceptin did not correlate with the PSA levels, because the PSA index markedly increased in the Herceptin-treated group, whereas it remained constant in the control group. These results suggest the utility of Herceptin in the treatment of human prostate cancer.
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PMID:Response of prostate cancer to anti-Her-2/neu antibody in androgen-dependent and -independent human xenograft models. 1051 79

Inhibitory receptors have been proposed to modulate the in vivo cytotoxic response against tumor targets for both spontaneous and antibody-dependent pathways. Using a variety of syngenic and xenograft models, we demonstrate here that the inhibitory FcgammaRIIB molecule is a potent regulator of antibody-dependent cell-mediated cytotoxicity in vivo, modulating the activity of FcgammaRIII on effector cells. Although many mechanisms have been proposed to account for the anti-tumor activities of therapeutic antibodies, including extended half-life, blockade of signaling pathways, activation of apoptosis and effector-cell-mediated cytotoxicity, we show here that engagement of Fcgamma receptors on effector cells is a dominant component of the in vivo activity of antibodies against tumors. Mouse monoclonal antibodies, as well as the humanized, clinically effective therapeutic agents trastuzumab (Herceptin(R)) and rituximab (Rituxan(R)), engaged both activation (FcgammaRIII) and inhibitory (FcgammaRIIB) antibody receptors on myeloid cells, thus modulating their cytotoxic potential. Mice deficient in FcgammaRIIB showed much more antibody-dependent cell-mediated cytotoxicity; in contrast, mice deficient in activating Fc receptors as well as antibodies engineered to disrupt Fc binding to those receptors were unable to arrest tumor growth in vivo. These results demonstrate that Fc-receptor-dependent mechanisms contribute substantially to the action of cytotoxic antibodies against tumors and indicate that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner FcgammaRIIB.
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PMID:Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. 1074 35

Overexpression of epidermal growth factor receptor (EGFr) has been demonstrated on many human tumors, and the increase in receptor expression levels has been linked with a poor clinical prognosis. Blocking the interaction of EGFr and the growth factors could lead to the arrest of tumor growth and possibly result in tumor cell death. To this end, using XenoMouse technology, ABX-EGF, a human IgG2 monoclonal antibody (mAb) specific to human EGFr, has been generated. ABX-EGF binds EGFr with high affinity (5x10(-11) M), blocks the binding of both EGF and transforming growth factor-alpha (TGF-alpha) to various EGFr-expressing human carcinoma cell lines, and inhibits EGF-dependent tumor cell activation, including EGFr tyrosine phosphorylation, increased extracellular acidification rate, and cell proliferation. In vivo ABX-EGF prevents completely the formation of human epidermoid carcinoma A431 xenografts in athymic mice. More importantly, administration of ABX-EGF without concomitant chemotherapy results in complete eradication of established tumors. No tumor recurrence was observed for more than 8 months following the last antibody injection, further indicating complete tumor cell elimination by the antibody. Inhibition of human pancreatic, renal, breast and prostate tumor xenografts which express different levels of EGFr by ABX-EGF was also achieved. Tumor expressing more than 17000 EGFr molecules per cell showed significant growth inhibition when treated with ABX-EGF. ABX-EGF had no effect on EGFr-negative tumors. The potency of ABX-EGF in eradicating well-established tumors without concomitant chemotherapy indicates its potential as a monotherapeutic agent for treatment of multiple EGFr-expressing human solid tumors, including those where no effective chemotherapy is available. Utilization of mAbs directed to growth factor receptors as cancer therapeutics has been validated recently by the tumor responses obtained from clinical trials with Herceptin, the humanized anti-HER2 antibody, in patients with HER2 overexpressing metastatic breast cancer. Being a fully human antibody, ABX-EGF is anticipated to exhibit a long serum half-life and minimal immunogenicity with repeated administration, even in immunocompetent patients. These results demonstrate the potent anti-tumor activity of ABX-EGF and its therapeutic potential for the treatment of multiple human solid tumors that overexpress EGFr.
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PMID:Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. 1125 78

The HER2/neu oncogene is overexpressed in human pancreatic cancer, but the clinical significance of that overexpression is uncertain. In the present study we investigated the antitumor efficacy of Herceptin, a new recombinant humanized anti-HER2/neu antibody, which exhibits cytostatic activity on breast and prostate cancer cells that overexpress the HER2 oncogene. That antibody may retard tumor growth in certain patients with those diseases. We quantified HER2 expression in various human pancreatic cancer cell lines and studied the bioactivity of this antibody both in vitro and in vivo. Growth inhibition by Herceptin was observed in vitro in cell lines with high levels of HER2/neu expression. Cell lines with low levels of this protein did not respond significantly to the antibody. In vivo we studied two different pancreatic cancer cell lines in an orthotopic mouse model of the disease. Herceptin treatment suppressed tumor growth in the MIA PaCa-2 tumor cell line, which expressed high levels of HER2/neu. These data suggest that Herceptin treatment of patients with pancreatic cancer who express high levels of the HER2/neu oncogene may be reasonable.
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PMID:Therapy for pancreatic cancer with a recombinant humanized anti-HER2 antibody (herceptin). 1133 75

Despite progressive developments in therapeutic interventions, including surgery, radiotherapy and chemotherapy, there has been no major improvement in the survival of women with metastatic breast cancer (MBC). Based on knowledge of tumor growth patterns, approaches addressing this issue have included increasing chemotherapy dose or dose density and extending the duration of therapy. However, only the latter approach has resulted in improved clinical benefit, although not survival; and its use is restricted by the cumulative toxicity of chemotherapeutic agents. Therefore, the best hope for improved survival lies with new classes of anticancer drug and particularly biological agents. This review focuses on the first oncogene-targeted therapy for human epidermal growth factor receptor-2 (HER2)+ MBC patients. The humanized anti-HER2 monoclonal antibody Herceptin has proven clinical benefits in HER2+ MBC patients, most importantly improved survival, and is rapidly becoming a standard of care for these patients. In contrast to the fixed number of cycles used for chemotherapeutic agents, Herceptin is administered until disease progression, with some data suggesting that continuation beyond disease progression should be investigated. The preclinical and clinical findings on which the current recommended duration of Herceptin therapy are based are reviewed and alternative strategies are discussed.
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PMID:Duration of therapy in metastatic breast cancer: management using Herceptin. 1148 11

Trastuzumab is a humanized monoclonal antibody that binds to human epidermal growth factor-2 (HER2) and is approved by the US Food and Drug Administration for the treatment of advanced breast cancer that overexpresses HER2/neu protein. Preclinical data suggests a role for trastuzumab in the treatment of non-small cell lung cancer (NSCLC). HER2 protein is overexpressed in 20% to 66% of resected NSCLC tumors, and has been shown to predict poor patient outcome in multiple series. Experiments with NSCLC cell lines show that HER2 overexpression increases chemoresistance, invasiveness, and metastatic potential of the cells. In mouse xenograft experiments, trastuzumab halts tumor growth and is synergistic with cytotoxic chemotherapy. Ongoing phase II trials are showing that trastuzumab can be added to standard chemotherapy in the treatment of patients with advanced NSCLC without additional toxicity, and with promising efficacy. Whether trastuzumab will show a clear benefit for patients with NSCLC, either alone or in combination with established chemotherapy, remains to be proven in phase III testing.
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PMID:Trastuzumab in the treatment of non-small cell lung cancer. 1189 15

The anti-HER-2 antibody, trastuzumab (Herceptin), and the oral fluoropyrimidine, capecitabine (Xeloda), are both effective in breast cancer with different modes of action and toxicity profiles. Therefore, the efficacy in combination therapy of these agents for the treatment of HER-2-overexpressing breast cancer was of interest. An antagonistic interaction in vitro between trastuzumab and 5-fluorouracil (5-FUra) in combination has previously been reported. In the same study, the in vivo antitumor activity of this combination was investigated. However, the results were inconclusive since 5-FUra at the dose used had sufficient antitumor efficacy as a single agent and therefore it was not possible to clarify the potential difference between 5-FUra alone and the combination. In the present study, we investigated the efficacy of trastuzumab in combination with capecitabine or its intermediate metabolite 5'-dFUrd in HER-2-overexpressing human breast cancer cell lines and xenograft models. In vivo antitumor activity of the combination was at least additive, in terms of tumor growth inhibition and tumor growth delay, in human breast cancer models KPL-4 and BT-474. The combination treatment in vivo was superior to the treatment with either single agent alone, even though in vitro treatment with trastuzumab and 5'-dFUrd/5-FUra showed antagonistic antiproliferative activity in these cell lines. The reason for the discrepancy between the in vivo and in vitro results was not clarified. However, observed additive in vivo antitumor activity clearly indicates that the clinical efficacy of the combination of trastuzumab and capecitabine/5'-dFUrd against HER-2-overexpressing breast cancer is worth investigating.
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PMID:Antitumor activity of combinations of anti-HER-2 antibody trastuzumab and oral fluoropyrimidines capecitabine/5'-dFUrd in human breast cancer models. 1193 13

The ability of Herceptin to prolong survival in women with HER2-overexpressing breast tumors has proven the concept of using humanized or chimeric monoclonal antibodies (MAbs) for cancer therapy. MAbs have been developed that are specific for many tumorigenic molecules and receptors. They can potentially be used to treat a range of solid tumors. Among the most promising targets for therapy are members of the human epidermal growth factor receptor (HER/ErbB) family, particularly HER1 and HER2. Several MAbs have been produced that are directed against HER1. One of these agents, cetuximab (Erbitux), is now advanced in clinical development. HER2 is also a key target and methods are being investigated to maximize the effect of using MAbs to inhibit this receptor. One approach aims to augment the efficacy of trastuzumab (Herceptin) by coupling it to a chemotherapeutic agent, thus enabling the delivery of cytotoxic therapy at a cellular level. Another opportunity is based on research that shows that HER2 acts as a dimerization partner for other HER receptors and consequently is important in HER-ligand-dependent tumor growth. Therefore, anti-HER2 MAbs that inhibit the association of HER2 with other HER family members have the potential to be highly effective. This article reviews some of these alternative approaches to MAb-based anti-HER therapy that will hopefully improve treatment outcome for patients with a range of solid tumors.
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PMID:Perspectives on anti-HER monoclonal antibodies. 1242 51

Cyclin-dependent kinase (CDK) inhibitor p27Kip1 binds to the cyclin E.CDK2 complex and plays a major role in controlling cell cycle and cell growth. Our group and others have reported that anti-HER2 monoclonal antibodies exert inhibitory effects on HER2-overexpressing breast cancers through G1 cell cycle arrest associated with induction of p27Kip1 and reduction of CDK2. The role of p27Kip1 in anti-HER2 antibody-induced cell cycle arrest and growth inhibition is, however, still uncertain. Here we have provided several lines of evidence supporting a critical role for p27Kip1 in the anti-HER2 antibody-induced G1 cell cycle arrest and tumor growth inhibition. Induction of p27Kip1 and G1 growth arrest by anti-HER2 antibody, murine 4D5, or humanized trastuzumab (Herceptin) are concentration-dependent, time-dependent, irreversible, and long-lasting. The magnitude of G1 cell cycle arrest induced by trastuzumab or 4D5 is well correlated with the level of p27Kip1 protein induced. Up-regulation of p27Kip1 and G1 growth arrest could no longer be removed with as little as 14 h of treatment with trastuzumab. Anti-HER2 antibody-induced p27Kip1 protein, G1 arrest, and growth inhibition persist at least 5 days after a single treatment. The magnitude of growth inhibition of breast cancer cells induced by anti-HER2 antibody closely parallels the level of p27Kip1 induced. Induced expression of exogenous p27Kip1 results in a p27Kip1 level-dependent G1 cell cycle arrest and growth inhibition similar to that obtained with anti-HER2 antibodies. Reducing p27Kip1 expression using p27Kip1 small interfering RNA blocks anti-HER2 antibody-induced p27Kip1 up-regulation and G1 arrest. Treatment with anti-HER2 antibody significantly increases the half-life of p27Kip1 protein. Inhibition of ubiquitin-proteasome pathway, but not inhibition of calpain and caspase activities, up-regulates p27Kip1 protein to a degree comparable with that obtained with anti-HER2 antibodies. We have further demonstrated that anti-HER2 antibody significantly decreases threonine phosphorylation of p27Kip1 protein at position 187 (Thr-187) and increases serine phosphorylation of p27Kip1 protein at position 10 (Ser-10). Expression of S10A and T187A mutant p27Kip1 protein increases the fraction of cells in G1 and reduces a further antibody-induced G1 arrest. Consequently, p27Kip1 plays an important role in the anti-HER2 antibody-induced G1 cell cycle arrest and tumor growth inhibition through post-translational regulation. Regulation of the phosphorylation of p27Kip1 protein is one of the post-translational mechanisms by which anti-HER2 antibody upregulates the protein.
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PMID:The role of cyclin-dependent kinase inhibitor p27Kip1 in anti-HER2 antibody-induced G1 cell cycle arrest and tumor growth inhibition. 1270 Feb 33


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