Alteration of EGF-receptor binding in human breast cancer cells by antineoplastic agents

Hanauske, Axel R.; Osborne, C. Kent; Chamness, Gary C.; Clark, Gary M.; Forseth, B; Buchok, Joy; Arteaga, Carlos L.; Hoff, Daniel D. Von

doi:10.1016/0277-5379(87)90318-x

Cited by 25 publications

(12 citation statements)

References 23 publications

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“…These data suggest that binding of rhuMAb HER2 to HER-2/ neu-overexpressing xenografts reduces serum rhuMAb HER2 concentrations HER-2/neu . An analogous mechanism has been postulated for the EGFR where low doses of DOX appear to increase receptor expression enhancing the antiproliferative activity of anti-EGFR antibody (Zuckier and Tritton, 1983;Hanauske et al, 1987;Baselga et al, 1992Baselga et al, , 1993. The current data demonstrate no change in p185 HER-2/neu expression levels or in HER-2/neu receptor tyrosine phosphorylation following exposure to cytotoxic drugs, suggesting that unlike the EGFR, this mechanism is not operative for the HER-2/neu receptor.…”

Section: Discussionsupporting

confidence: 78%

“…CI values for the combination of TSPA and rhuMAb HER2 were signi®cantly less than 1.0 across all combination doses tested (P=0.0008) indicating a synergistic interaction (Figure 1b). A summary of the data from the same analysis applied to each of the eight cytotoxic drug/rhuMAb HER2 combinations tested ( (Zuckier and Tritton, 1983;Hanauske et al, 1987;Baselga et al, 1992Baselga et al, , 1993. This phenomenon has been proposed to explain the synergistic cytotoxic eects of DOX used in combination with anti-EGFR monoclonal antibodies (Baselga et al, 1992).…”

Section: Resultsmentioning

confidence: 99%

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Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers

Pegram

Hsu

Lewis³

et al. 1999

Oncogene

612

282

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Previous studies have demonstrated a synergistic interaction between rhuMAb HER2 and the cytotoxic drug cisplatin in human breast and ovarian cancer cells. To de®ne the nature of the interaction between rhuMAb HER2 and other classes of cytotoxic drugs, we applied multiple drug eect/combination index (CI) isobologram analysis to a variety of chemotherapeutic drug/rhuMAb HER2 combinations in vitro. Synergistic interactions at clinically relevant drug concentrations were observed for rhuMAb HER2 in combination with cisplatin (CI=0.48, P=0.003), thiotepa (CI=0.67, P=0.0008), and etoposide (CI=0.54, P=0.0003). Additive cytotoxic eects were observed with rhuMAb HER2 plus doxorubicin (CI=1.16, P=0.13), paclitaxel (CI=0.91, P=0.21), methotrexate (CI=1.15, P=0.28), and vinblastine (CI=1.09, P=0.26). One drug, 5-¯uorouracil, was found to be antagonistic with rhuMAb HER2 in vitro (CI=2.87, P=0.0001). In vivo drug/rhuMAb HER2 studies were conducted with HER-2/neu-transfected, MCF7 human breast cancer xenografts in athymic mice. Combinations of rhuMAb HER2 plus cyclophosphamide, doxorubicin, paclitaxel, methotrexate, etoposide, and vinblastine in vivo resulted in a signi®cant reduction in xenograft volume compared to chemotherapy alone (P50.05). Xenografts treated with rhuMAb HER2 plus 5-¯uorouracil were not signi®cantly dierent from 5-uorouracil alone controls consistent with the subadditive eects observed with this combination in vitro. The synergistic interaction of rhuMAb HER2 with alkylating agents, platinum analogs and topoisomerase II inhibitors, as well as the additive interaction with taxanes, anthracyclines and some antimetabolites in HER-2/neuoverexpressing breast cancer cells demonstrates that these are rational combinations to test in human clinical trials.

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Section: Discussionsupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers

Pegram

Hsu

Lewis³

et al. 1999

Oncogene

612

282

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“…EGF-mediated stimulation may, therefore, be an interesting target for an ad ditional antineoplastic treatment approach [6]. Our results showed a decreased number of EGF receptors on tumor cells treated with a high dose of cisplatin.…”

Section: Discussionsupporting

confidence: 58%

Cisplatin Reduces Epidermal Growth Factor Receptors in Squamous-Cell Carcinoma in vitro

Bergler

Bier²

1990

ORL

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A radioreceptor assay was used to determine the number and affinity of epidermal growth factor (EGF) receptors in a human squamous carcinoma cell line of the larynx (HLac 79) after exposure to cisplatin (DDP). Cells exposed to high concentrations of cisplatin showed about 30 % fewer receptors compared to untreated and low-dose-treated cells. This reduction in the number of receptors might be responsible for the decreased growth when stimulated by EGF. Cisplatin appears to lower the concentration of EGF receptors on carcinoma cells, which might result in additional antiproliferative activity especially in carcinomas with high EGF receptor expression.

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“…We found previously that bombesin antagonists cause down-regulation of EGF receptors in breast cancers [25,40,41]. Even some cytotoxic compounds such as cisplatin and vinblastin can inhibit EGF binding, but others as 5-FU, cyclophosphamide, or doxorubicin do not have such an effect [42].…”

Section: Discussionmentioning

confidence: 97%

Effect of a cytotoxic analog of LH-RH (T-98) on the growth of estrogendependent MXT mouse mammary cancers: Correlations between growth characteristics and EGF receptor content of tumors

Szepesházi

Halmos

Szőke

et al. 1996

Breast Cancer Res Tr

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Female BDF mice bearing estrogen-dependent MXT mouse mammary cancers were treated for 4 weeks with a cytotoxic analog of luteinizing hormone-releasing hormone (LH-RH). T-98 (agonist [D-Lys6]LH-RH linked to glutaryl-2(hydroxymethyl)anthraquinone). The effects of T-98 were compared to those of equimolar amounts of the cytotoxic moiety 2-(hydroxymethyl)anthraquinone hemiglutarate (G-HMAQ) and carrier LH-RH agonist [D-Lys6]LH-RH. Both T-98 and [D-Lys6]LH-RH significantly inhibited the growth of MXT cancers, but G-HMAQ had only a minor non-significant effect. Cytotoxic analog T-98 and the carrier [D-Lys6]LH-RH had similar inhibitory hormonal activities on the pituitary-gonadal axis, but T-98 caused a larger reduction in tumor volume and decreased proliferation characteristics such as mitotic activity and AgNOR numbers in tumor cells to a greater extent than the carrier. Tumor inhibition by T-98, [D-Lys6]LH-RH, and ovariectomy was connected with a significant decrease in binding capacity of EGF receptors in tumor cell membranes. The concentration of EGF receptors remained high in tumors that continued to enlarge in spite of treatment and in all control untreated tumors, even those of small size. Thus, the changes in EGF receptors are likely to be the result of the therapy. Treatment with T-98 caused a greater reduction in the binding capacity of EGF receptors in tumors than [D-Lys6]LH-RH. This could explain the higher inhibitory effect of the cytotoxic analog on tumor growth. Since radiolabeled T-98 was shown to accumulate in MXT cancers 3 hours after a subcutaneous injection, this indicates that specific targeting might play a role in the antitumor effect exerted by this cytotoxic analog.

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Alteration of EGF-receptor binding in human breast cancer cells by antineoplastic agents

Cited by 25 publications

References 23 publications

Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers

Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers

Cisplatin Reduces Epidermal Growth Factor Receptors in Squamous-Cell Carcinoma in vitro

Effect of a cytotoxic analog of LH-RH (T-98) on the growth of estrogendependent MXT mouse mammary cancers: Correlations between growth characteristics and EGF receptor content of tumors

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