The Role of α-Folate Receptor-Mediated Transport in the Antitumor Activity of Antifolate Drugs

Theti, Davinder S.; Jackman, Ann L.

doi:10.1158/1078-0432.ccr-03-0157

Cited by 65 publications

(63 citation statements)

References 40 publications

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“…Methotrexate primarily targets dihydrofolate reductase, raltitrexed targets thymidylate synthase and the more recently introduced pemetrexed has multiple targets in the folate pathway. The role of FRa in the uptake of both folates (essential for cellular purine and pyrimidine biosynthesis and eventually DNA synthesis) and antifolates has been the subject of numerous publications with contrasting results (Chattopadhyay et al, 2004;Theti and Jackman, 2004). Chemotherapy for mesothelioma, using pemetrexed and platinum, is now the standard treatment of choice.…”

Section: Discussionmentioning

confidence: 99%

“…Similar differences in pemetrexed sensitivity have also been reported (Chattopadhyay et al, 2006) between H28 andH2052 cells (GI 50 values 90 and40 nM, respectively). It has been reported that the effect of pemetrexed is enhanced in cell lines when there is a low or physiological concentration of folate in the medium (Theti and Jackman, 2004) and that higher extra-cellular folate levels correlate inversely with pemetrexed activity in vitro in mesothelioma and other solid tumour cell lines (Chattopadhyay et al, 2007). In our studies, it was found that when using normal or lowfolate medium (results using low-folate medium are not shown) and dialysed or normal serum, the main difference in the effect of pemetrexed was seen between the dialysed serum and normal serum as reported here; hence, low-folate medium was not routinely used.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is evidence to suggest that FRa may have an important role in folate and antifolate transport under certain circumstances. Studies performed on vulval epithelial cell lines A431 and A431-FBP, a highly expressing FRa transfectant, showed that A431-FBP was approximately three-fold more sensitive to pemetrexed than the isogenic non-FRa-expressing cell line when cells were maintained in a physiological level of folate (20 nM leucovorin) and was 14-fold more sensitive when maintained in sub-physiological levels (1 nM leucovorin) (Theti and Jackman, 2004). Membrane transport of folates has also been recently reported to occur through a ubiquitously expressed proton-coupled folate transporter (PCFT) (Wang et al, 2003;Zhao et al, 2008), a low-pH transporter with a high affinity for pemetrexed.…”

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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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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%

mentioning

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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“…These differential expressions offer the development of diagnostic agents and folate receptor-mediated tumor targeted therapy in the treatment of various cancers (Theti and Jackman, 2004). Disruption of folate metabolism has long been known to inhibit cell growth and has been established as a target in chemotherapy with the use of antifolates (Brzezinska et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Folic acid transport via high affinity carrier-mediated system in human retinoblastoma cells

Kansara¹,

Paturi²,

Luo³

et al. 2008

International Journal of Pharmaceutics

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The primary objective of this study was to investigate the expression of a specialized carriermediated system for folic acid and to delineate its uptake mechanism and intracellular trafficking in a human derived retinoblastoma cell line (Y-79). Uptake of [ 3 H]Folic acid was determined at various concentrations, pH, temperatures, in the absence of sodium and chloride ions and in the presence of structural analogs, methyltetrahydrofolate (MTF) and methotrexate (MTX), vitamins, membrane transport and metabolic inhibitors to delineate the mechanism of uptake. Kinetics of uptake was studied in the presence of various intracellular regulatory pathways; protein kinases A and C (PKA and PKC), protein tyrosine kinase (PTK) and calcium-calmodulin modulators. Reverse transcription polymerase chain reaction (RT-PCR) was performed to confirm the molecular identity of folate carrier systems. The uptake was found to be linear up to 30 min. The rate of uptake followed saturation kinetics with apparent K m of 8.29 ±0.74 nM, 17.03 ± 1.98 nM and 563.23 ±115.2 nM and V max of 393.47 ± 9.33, 757.58 ± 26.21 and 653.17 ± 31.7 fmol/(min mg) protein for folic acid, MTF and MTX, respectively. The process was chloride, temperature and energy dependent but sodium and pH independent; inhibited by the structural analogs MTF and MTX but not by structurally unrelated vitamins. Membrane transport inhibitors did not affect the uptake of [ 3 H]Folic acid, however endocytic inhibitor, colchicine, significantly inhibited the [ 3 H]Folic acid uptake indicating the involvement of receptor mediated endocytosis process. PKC, PTK and Ca 2+ /calmodulin pathways appeared to play important roles in the regulation of folic acid uptake. Molecular evidence of the presence of folate receptor (FR) precursor was identified by RT-PCR analysis. This research work demonstrated, for the first time, the functional and molecular existence of a specialized high affinity carrier-mediated system for folic acid uptake, in human retinoblastoma cells.

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“…This drug is a relatively poor substrate for FPGS compared to RTX . Fourthly, a-folate receptor (a-FR) mediated uptake may contribute to the activity of some antifolates, particularly BGC9331 (Theti and Jackman, 2004). The a-FR is overexpressed in up to 90% of epithelial ovarian cancers (Toffoli et al, 1997).…”

Section: Bgc9331 In Ovarian Cancermentioning

confidence: 99%

A phase I pharmacokinetic and pharmacodynamic study of BGC9331 and carboplatin in relapsed gynaecological malignancies

et al. 2005

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BGC9331 is a rationally designed, specific nonpolyglutamatable thymidylate synthase (TS) inhibitor that is active in gynaecological malignancies. In the light of the sensitivity of human ovarian tumour cell lines to BGC9331 and non-cross resistance to platinum drugs, we studied the combination BGC9331/carboplatin (BCA) in a phase I (PI) pharmacokinetic (PK) and pharmacodynamic (PD) study in platinum pretreated gynaecological malignancies. Patients were X18 years or over, with a histologically confirmed gynaecological malignancy, radiological evidence of relapse, and a platinum treatment free interval of at least 6 months. Up to three prior lines of chemotherapy were permitted. Carboplatin (AUC5) and BGC9331 were administered on day 1, and BGC9331 was also given on day 8 of a 21-day cycle. In total, 14 patients were enrolled, and treated with BGC9331 at four dose levels, 40, 65, 85 and 100 mg m À2 . The principal grade 3 and 4 haematological toxicity was neutropaenia. The principal nonhaematological toxicities were lethargy and nausea. Dose-limiting toxicities were seen in two patients at 100 mg m À2 BGC9331 (grade 4 neutropaenia 47 days, and grade 4 fatigue 47 days). Plasma BGC9331 was measured by an ELISA that was adapted for use in humans. Carboplatin was assayed by flameless atomic absorption spectrometry. There was no PK interaction between the two drugs. Plasma deoxyuridine was elevated indicating TS inhibition to at least day 12. Antitumour activity was observed in four out of 14 (28%) of patients. In conclusion, the combination of BGC9331 and carboplatin is well tolerated with no significant PK interaction between the two drugs. There is evidence of TS inhibition with the combination. We have demonstrated antitumour activity in platinum pretreated gynaecological malignancy. Further exploration of this combination in this disease is warranted.

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The Role of α-Folate Receptor-Mediated Transport in the Antitumor Activity of Antifolate Drugs

Abstract: Conclusions: Antifolate drugs, particularly ZD9331, have the potential for increased efficacy in tumors that highly overexpress the ␣-FR.

Cited by 65 publications

References 40 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

Folic acid transport via high affinity carrier-mediated system in human retinoblastoma cells

A phase I pharmacokinetic and pharmacodynamic study of BGC9331 and carboplatin in relapsed gynaecological malignancies

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