Role of cyclin D1 in tumor radioresponse

Milas, Luka; Akimoto, Taishi; Hunter, Nancy; Mason, Kathy; Buchmiller, Lara; Yamakawa, Michitaka; Muramatsu, Hirohito; Ang, Khong Wei

doi:10.1016/s0360-3016(00)80115-7

Cited by 9 publications

(10 citation statements)

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“…As with chemotherapy, preclinical studies have also shown that anti-EGFr mAbs enhance the antitumor e ect of radiation therapy (Huang et al, 1999;Milas et al, 2000). In A431 human tumor xenografts, response to radiation was enhanced by a factor of 3.6 with concomitant use of IMC-C225.…”

Section: Anti-egfr Monoclonal Antibodies That Block Receptor Kinasementioning

confidence: 99%

The EGF receptor family as targets for cancer therapy

2000

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Human carcinomas frequently express high levels of receptors in the EGF receptor family, and overexpression of at least two of these receptors, the EGF receptor (EGFr) and closely related ErbB2, has been associated with a more aggressive clinical behavior. Further, transfection or activation of high levels of these two receptors in nonmalignant cell lines can lead to a transformed phenotype. For these reasons therapies directed at preventing the function of these receptors have the potential to be useful anti-cancer treatments. In the last two decades monoclonal antibodies (MAbs) which block activation of the EGFr and ErbB2 have been developed. These MAbs have shown promising preclinical activity and`chimeric' and`humanized' MAbs have been produced in order to obviate the problem of host immune reactions. Clinical activity with these antibodies has been documented: trastuzumab, a humanized anti-ErbB2 MAb, is active and was recently approved in combination with paclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer; IMC-C225, a chimeric anti-EGFr MAb, has shown impressive activity when combined with radiation therapy and reverses resistance to chemotherapy. In addition to antibodies, compounds that directly inhibit receptor tyrosine kinases have shown preclinical activity and early clinical activity has been reported. A series of phase III studies with these antibodies and direct tyrosine kinase inhibitors are ongoing or planned, and will further address the role of these active anti-receptor agents in the treatment of patients with cancer. Oncogene (2000) 19, 6550 ± 6565.

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Section: Anti-egfr Monoclonal Antibodies That Block Receptor Kinasementioning

confidence: 99%

The EGF receptor family as targets for cancer therapy

2000

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“…With regard to the antiangiogenesis activity, we and others have shown that treatment of human cancer cell lines in vitro (in normoxic culture) and in vivo with cetuximab or gefitinib reduces the production of vascular endothelial growth factor (VEGF), a key factor promoting tumor angiogenesis (Petit et al, 1997;Perrotte et al, 1999;Ciardiello et al, 2000;Milas et al, 2000;Shaheen et al, 2001a;Huang et al, 2002a, b;Karashima et al, 2002). Together with the demonstrated antiproliferative and proapoptotic effects, this antiangiogenic activity of cetuximab and gefitinib is believed to contribute to their overall antitumor activity in vivo (Mendelsohn and Baselga, 2000).…”

Section: Introductionmentioning

confidence: 99%

The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression

et al. 2005

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We have previously shown that the antiepidermal growth factor receptor monoclonal antibody cetuximab (C225; Erbitux), which was recently approved for the treatment of metastatic colorectal cancer, has antiangiogenic properties, inhibiting vascular endothelial growth factor (VEGF) secretion in culture and in animal models. Here, we have furthered the study by demonstrating that cetuximab reduces cellular levels of hypoxia-inducible factor-1 alpha (HIF-1a), a transcriptional regulator of VEGF expression, in A431 epidermoid carcinoma cells under both normoxic and hypoxic culture conditions. Expression of a constitutively active Ras in A431 cells rendered cellular resistance to the cetuximab-mediated reduction of the HIF-1a level. Cell lines with naturally occurring phosphatase and tensin homologue deleted on chromosome 10 mutations or deletions were also resistant to cetuximab-mediated reduction of the HIF-1a level. Pharmacologic inhibition of phosphatidylinositol 3-kinase with LY294002 reduced the HIF-1a level in both normoxic and hypoxic A431 cells, whereas inhibition of the mitogen-activated protein kinase kinase by PD98059 reduced the level of HIF-1a only in normoxic A431 cells. In addition, cetuximab reduced the cellular level of HIF1a in the presence of a proteasome inhibitor, lactacystin, indicating that cetuximab acts mainly at the level of protein synthesis. The reduction of HIF-1a in response to cetuximab treatment was accompanied by transcriptional inhibition of VEGF expression, measured by a luciferase assay in A431 cells transfected with a vector containing the VEGF hypoxia response element. Taken together, our results indicate that the previously demonstrated inhibition of VEGF by cetuximab occurs at the level of transcription in response to a reduced level of HIF-1a and justify further testing of therapeutic strategies that combine cetuximab with approaches inhibiting the function of VEGF or the VEGF receptor.

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“…A number of studies have shown a positive relation between EGFR expression and tumor resistance to radiation (Sheridan et al, 1997). Experimentally, Milas et al (2000) demonstrated in mice with H&N carcinoma xenografts enhanced tumor radiosensitivity after combined treatment with C225 (monoclonal anti-EGFR antibody) and radiation. Bonner et al (2000) have shown that combining C225 and radiation results in greater cell killing of squamous cell carcinoma lines than with either treatment alone.…”

Section: Introductionmentioning

confidence: 99%

The RAS signal transduction pathway and its role in radiation sensitivity

et al. 2003

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RAS has been shown to increase radiation resistance. Upstream and downstream pathways from RAS could thus be targets for manipulation of radiosensitivity. EGFR expression and AKT phosphorylation are also associated with the response to radiation. A retrospective study evaluating EGFR and AKT in patients treated with multimodality therapy found a significant association between P-AKT and treatment failure. Moreover, these data are strengthened by in vitro studies showing that inhibition of EGFR, RAS, PI3K, and AKT radiosensitized cancer cell lines. We have previously shown that PI3K is a mediator of RAS-induced radiation resistance. We now suggest that EGFR, which is upstream of PI3K, may also mediate resistance through a common pathway. In addition to EGFR and RAS, PTEN can also regulate the PI3K pathway. Identifying a common signal for EGFR, RAS, or PTEN that results in radiation resistance may uncover targets for developing molecular-based radiosensitization protocols for tumors resistant to radiation and thus improve local control.

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Role of cyclin D1 in tumor radioresponse

Cited by 9 publications

References 0 publications

The EGF receptor family as targets for cancer therapy

The EGF receptor family as targets for cancer therapy

The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression

The RAS signal transduction pathway and its role in radiation sensitivity

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