Targeting Folate Receptors to Treat Invasive Urinary Bladder Cancer

Dhawan, Deepika; Ramos‐Vara, José A.; Naughton, James F.; Liu, Cheng; Low, Philip S.; Rothenbuhler, Ryan; Leamon, Christopher P.; Parker, Nikki; Klein, Patrick; Vlahov, Iontcho R.; Reddy, Joseph A.; Koch, Michaël; Murphy, Linda; Fourez, Lindsey M.; Stewart, Janet; Knapp, Deborah W.

doi:10.1158/0008-5472.can-12-2101

Cited by 54 publications

(63 citation statements)

References 30 publications

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“…Epofolate (BMS-753493), a folic acidepothilone conjugate, completed Phase I and Phase II assessments for the treatment of advanced solid tumours but, owing to lack of efficacy, has been withdrawn from further clinical investigation 168,169 . A considerably more potent folate-tubulysin conjugate, EC1456, entered clinical trials this year (NCT01999738), and EC0905, a folate-vinblastine conjugate, has shown considerable promise in preclinical studies for treating spontaneous bladder cancers in dogs 170 .…”

Section: Mip-1072mentioning

confidence: 99%

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Srinivasarao

Galliford

Low

2015

Nat Rev Drug Discov

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564

502

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Most cancer drugs are designed to interfere with one or more events in cell proliferation or survival. As healthy cells may also need to proliferate and avoid apoptosis, anticancer agents can be toxic to such cells. To minimize these toxicities, strategies have been developed wherein the therapeutic agent is targeted to tumour cells through conjugation to a tumour-cell-specific small-molecule ligand, thereby reducing delivery to normal cells and the associated collateral toxicity. This Review describes the major principles in the design of ligand-targeted drugs and provides an overview of ligand-drug conjugates and ligand-imaging-agent conjugates that are currently in development.

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Section: Mip-1072mentioning

confidence: 99%

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Srinivasarao

Galliford

Low

2015

Nat Rev Drug Discov

Self Cite

564

502

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“…As such, it has been considered as target in several therapeutic strategies. [26][27][28][29][30][31][32][33] The bidirectional RFC, which is ubiquitously expressed in mammalian cells and reported to be overexpressed in cancer, is also an important uptake mechanism of folate and antifolates. [34][35][36][37][38][39][40][41] An impairment of RFC synthesis or mutations in the RFC protein can lead to cellular dysfunctions and therefore to resistances against chemotherapeutic drugs like MTX.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous response of different tumor cell lines to methotrexate-coupled nanoparticles in presence of hyperthermia

Stapf¹,

Pömpner²,

Teichgräber³

et al. 2016

IJN

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Today, the therapeutic efficacy of cancer is restricted by the heterogeneity of the response of tumor cells to chemotherapeutic drugs. Since those therapies are also associated with severe side effects in nontarget organs, the application of drugs in combination with nanocarriers for targeted therapy has been suggested. Here, we sought to assess whether the coupling of methotrexate (MTX) to magnetic nanoparticles (MNP) could serve as a valuable tool to circumvent the heterogeneity of tumor cell response to MTX by the combined treatment with hyperthermia. To this end, we investigated five breast cancer cell lines of different origin and with different mutational statuses, as well as a bladder cancer cell line in terms of their response to exposure to MTX as a free drug or after its coupling to MNP as well as in presence/absence of hyperthermia. We also assessed whether the effects could be connected to the cell line-specific expression of proteins related to the uptake and efflux of MTX and MNP. Our results revealed a very heterogeneous and cell line-dependent response to an exposure with MTX-coupled MNP (MTX–MNP), which was almost comparable to the efficacy of free MTX in the same cell line. Moreover, a cell line-specific and preferential uptake of MTX–MNP compared with MNP alone was found (probably by receptor-mediated endocytosis), agreeing with the observed cytotoxic effects. Opposed to this, the expression pattern of several cell membrane transport proteins noted for MTX uptake and efflux was only by tendency in agreement with the cellular toxicity of MTX–MNP in different cell lines. Higher cytotoxic effects were achieved by exposing cells to a combination of MTX–MNP and hyperthermal treatment, compared with MTX or thermo-therapy alone. However, the heterogeneity in the response of the tumor cell lines to MTX could not be completely abolished – even after its combination with MNP and/or hyperthermia – and the application of higher thermal dosages might be necessary.

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“…Approximately 80% of bladder cancer cases are superficial in the early stage, and 70% of such patients suffer relapse following surgery, with 30% of relapses developed towards the later stages of the disease (1). In addition, 15-30% of cases are invasive at the early stage, even if therapy is received for early metastasis (22). The prognosis of patients with urothelial bladder carcinoma is determined by the depth of invasion, metastasis and recurrence.…”

Section: Discussionmentioning

confidence: 99%

Expression of cyclin D1 and cyclin E in urothelial bladder carcinoma detected in tissue chips using a quantum dot immunofluorescence technique

Shan

Tang

2015

Oncology Letters

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Abstract. The present study aimed to investigate the expression of cyclin D1 and cyclin E in tissue chips of bladder cancer using quantum dots (QDs), as well as examine its clinicopathological significance. The QD-based immunofluorescence tissue chemical technique was adopted to detect cyclin D1 and cyclin E expression in 75 tissue chips of human urothelial bladder carcinoma (including 70 cases of urothelial bladder carcinoma and 5 cases of cystitis), and its correlation with clinicopathological features was analyzed. The positive rates of cyclin D1 and cyclin E expression in urothelial bladder carcinoma were 68.6% (48/70) and 70.0% (49/70), respectively; however, no expression was observed in cystitis. Based on the results of statistical analysis, the difference in the positive rates of cyclin D1 and cyclin E expression between urothelial bladder carcinoma and cystitis was significant (P<0.05). QD staining and statistical analysis revealed that the expression of cyclin D1 and cyclin E in urothelial bladder carcinoma was significantly higher compared with that in cystitis (P<0.05). However, no statistically significant difference (P>0.05) in cyclin D1 expression was observed in relation to pathological stage, clinical stage or invasion of urothelial bladder carcinoma; however, there was a significant difference (P<0.05) in cyclin E expression with respect to these factors. These results demonstrated that overexpression of cyclin D1 may be an early event in the occurrence of urothelial bladder carcinoma. Cyclin D1 may play a role in the initial stage where cell proliferation is a necessary step, without invasion or metastasis. In addition, overexpression of cyclin E was correlated with the stage and depth of invasion of urothelial bladder carcinoma. In conclusion, the abnormal expression of cyclin D1 and cyclin E may be involved in the occurrence and development of urothelial bladder carcinoma.

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Targeting Folate Receptors to Treat Invasive Urinary Bladder Cancer

Cited by 54 publications

References 30 publications

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Heterogeneous response of different tumor cell lines to methotrexate-coupled nanoparticles in presence of hyperthermia

Expression of cyclin D1 and cyclin E in urothelial bladder carcinoma detected in tissue chips using a quantum dot immunofluorescence technique

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