The α folate receptor is highly activated in malignant pleural mesothelioma

Bueno, Raphael; Appasani, Krishnarao; Mercer, Harriet; Lester, Susan C.; Sugarbaker, David J.

doi:10.1067/mtc.2001.111176

Cited by 142 publications

(79 citation statements)

References 11 publications

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“…A review on FRa (Kelemen, 2006) suggests that further research into the presence of FRa in tumours is necessary, as there is a lack of clinical studies using tumour samples, particularly in the context of pemetrexed trials. Until recently, there has been no antibody available to detect FRa by immunohistochemistry in paraffin-embedded tumour samples, although the antibodies Mov18 and Mov19 could be used on frozen sections (Bueno et al, 2001). Another study of FRa in samples of mesothelioma (Khokhar et al, 2002) showed no difference in FRa gene expression (by RT-RNA) in mesothelioma of differing histological type.…”

Section: Discussionmentioning

confidence: 99%

“…Chemotherapy for mesothelioma, using pemetrexed and platinum, is now the standard treatment of choice. In mesothelioma, FRa has been described as highly activated (Bueno et al, 2001), with 72% of 61 mesotheliomas showing a two-to four-fold higher mRNA expression compared with normal control tissues. Immunohistochemical studies using Mov 18 and Mov 19 antibodies on frozen sections confirmed the results by demonstrating FRa at the cellular membrane in 13 of 17 samples.…”

Section: Discussionmentioning

confidence: 99%

“…Expression is limited to specific tissues and is expressed in a characteristic distribution, for example, on syncytiotrophoblastic cells of the placenta and the proximal convoluted tubule of the kidney (Weitman et al, 1992;Mantovani et al, 1994). However, FRa has been reported to be highly expressed in some malignancies: in 90% of non-mucinous epithelial ovarian cancers (Toffoli et al, 1997) and in 72% of malignant mesotheliomas (Bueno et al, 2001). Folate receptor alpha has been believed to be important for the physiological transport of folic acid, but not generally for antifolates (Kamen and Smith, 2004).…”

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The role of folate receptor alpha (FRα) in the response of malignant pleural mesothelioma to pemetrexed-containing chemotherapy

et al. 2010

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BACKGROUND: The standard treatment of choice for malignant pleural mesothelioma is chemotherapy with pemetrexed and platinum, but the clinical outcome is poor. This study investigates the response to pemetrexed in a panel of eight mesothelioma cell lines and the clinical outcome for patients treated with pemetrexed in relation to folate receptor alpha (FRa). METHODS: Cell lines were treated with pemetrexed to determine the concentration that reduced growth to 50% (GI 50 ). FRa expression was determined by western blotting and that of FRa, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) by real-time quantitative RT -PCR. Immunohistochemistry for FRa was carried out on 62 paraffin-embedded samples of mesothelioma from patients who were subsequently treated with pemetrexed. RESULTS: A wide range of GI 50 values was obtained for the cell lines, H2452 cells being the most sensitive (GI 50 22 nM) and RS5 cells having a GI 50 value greater than 10 mM. No FRa protein was detected in any cell line, and there was no relationship between sensitivity and expression of folate transporters. FRa was detected in 39% of tumour samples, generally in a small percentage of cells. There was no correlation between the presence of FRa and the outcome of pemetrexed treatment, and no significant difference between histological subtypes. CONCLUSION: Response to treatment with pemetrexed does not depend on the presence of FRa.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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The role of folate receptor alpha (FRα) in the response of malignant pleural mesothelioma to pemetrexed-containing chemotherapy

et al. 2010

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“…Specifically, hFRα is consistently overexpressed in nonmucinous adenocarcinomas of the ovary, uterus, breast, cervix, kidney, and colon, as well as testicular choriocarcinoma, ependymal brain tumors, malignant pleural mesothelioma, and nonfunctioning pituitary adenocarcinoma (35,44). hFRβ expression is increased in certain leukemias, most consistently seen in chronic myelogenous leukemia and acute myelogenous leukemia (43,45).…”

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confidence: 99%

Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition

Wibowo

Singh

Reeder

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

176

190

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Antifolates, folate analogs that inhibit vitamin B 9 (folic acid)-using cellular enzymes, have been used over several decades for the treatment of cancer and inflammatory diseases. Cellular uptake of the antifolates in clinical use occurs primarily via widely expressed facilitative membrane transporters. More recently, human folate receptors (FRs), high affinity receptors that transport folate via endocytosis, have been proposed as targets for the specific delivery of new classes of antifolates or folate conjugates to tumors or sites of inflammation. The development of specific, FR-targeted antifolates would be accelerated if additional biophysical data, particularly structural models of the receptors, were available. Here we describe six distinct crystallographic models that provide insight into biological trafficking of FRs and distinct binding modes of folate and antifolates to these receptors. From comparison of the structures, we delineate discrete structural conformations representative of key stages in the endocytic trafficking of FRs and propose models for pH-dependent conformational changes. Additionally, we describe the molecular details of human FR in complex with three clinically prevalent antifolates, pemetrexed (also Alimta), aminopterin, and methotrexate. On the whole, our data form the basis for rapid design and implementation of unique, FR-targeted, folate-based drugs for the treatment of cancer and inflammatory diseases.isothermal titration calorimetry | targeted drug delivery

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“…1 Whereas normal cells rely almost exclusively on the reduced folate carrier (K M for folate 10 25 M) to supply their folate needs, solid tumors of epithelial origin [2][3][4] and hematopoietic cancers of the myeloid lineage 5 frequently overexpress FR (K D for folate 10 210 M) on their cell surfaces, perhaps to enhance their capacity to compete for the vitamin. This upregulation of the high-affinity FR on cancer cell surfaces has rendered the receptor an attractive target for cancer-specific interventions.…”

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confidence: 99%

Folate receptor-targeted immunotherapy: Induction of humoral and cellular immunity against hapten-decorated cancer cells

Sega

Low

2005

Int. J. Cancer

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We previously exploited the frequent overexpression of folate receptors on cancer cells to decorate malignant cell surfaces selectively with folate-hapten conjugates. In antihapten-immunized hosts, this targeted localization of foreign haptens to tumor cells led to rapid accumulation of autologous antihapten IgG, which in turn yielded potent antitumor activity upon stimulation with cytokines (IL-2, IFN-a). In an effort to understand the effector mechanisms responsible for tumor regression, we have now investigated the involvement of both humoral and cellular immune components in the tumor destruction process. We report that the dependence of therapeutic efficacy on folate-hapten concentration is bimodal, suggesting that the conjugate must bridge between a cell surface FR and an antihapten IgG in order to mediate killing. Studies with cancer cells in vitro further demonstrate that folatefluorescein-marked tumor cells are killed primarily by antibodydependent cellular cytotoxicity and phagocytosis, with no contribution from complement-dependent mechanisms. Investigations of specific immune cell involvement also reveal that asialo-GM1 1 -natural killer cells, macrophages, CD41 T cells and CD8 1 T cells contribute significantly to recognition/removal of the cancer mass, and that elimination of these cell types markedly compromises the therapy. Because the initial antibody-dependent stage of tumor cell killing is shown to lead to a long-term antibody-independent cellular immunity that involves both CD4 1 and CD8 1 T cells, we propose that F c receptor-expressing immune cells not only initiate destruction of the IgG-marked tumor cells, but also participate in presentation of endogenous tumor antigens in a manner that leads to long-term cellular immunity. ' 2005 Wiley-Liss, Inc.

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The α folate receptor is highly activated in malignant pleural mesothelioma

Cited by 142 publications

References 11 publications

The role of folate receptor alpha (FRα) in the response of malignant pleural mesothelioma to pemetrexed-containing chemotherapy

The role of folate receptor alpha (FRα) in the response of malignant pleural mesothelioma to pemetrexed-containing chemotherapy

Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition

Folate receptor-targeted immunotherapy: Induction of humoral and cellular immunity against hapten-decorated cancer cells

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