Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Investigational New Drugs
Published in: Investigational New Drugs 5/2007

01-10-2007 | PRECLINICAL STUDIES

In vitro chemosensitivity of freshly explanted tumor cells to pemetrexed is correlated with target gene expression

Authors: Axel-Rainer Hanauske, Ulrike Eismann, Olaf Oberschmidt, Heike Pospisil, Steve Hoffmann, Hartmut Hanauske-Abel, Doreen Ma, Victor Chen, Paolo Paoletti, Clet Niyikiza

Published in: Investigational New Drugs | Issue 5/2007

Login to get access

Summary

Aim of the study

mRNA expression of genes involved in the mechanism of action of pemetrexed was correlated with in vitro chemosensitivity of freshly explanted human tumor specimens.

Experimental design

Chemosensitivity to pemetrexed was studied in soft-agar. Multiplex rtPCR experiments for reduced folate carrier (RFC), folate receptor-α (FR-α), folylpolyglutamate synthetase (FPGS), thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyl transferase (GARFT), mrp4, and mrp5 were performed in parallel. Correlations, threshold optimization, sensitivity, specificity, and efficiency were analyzed using the appropriate statistical methodologies.

Results

In 61 samples, low levels of TS, GARFT, DHFR, and mrp4 gene expression significantly correlated with chemosensitivity to pemetrexed. Optimization analyses demonstrated threshold values of 144 copies for TS and six copies for mrp4 relative to 104 copies of β-actin.

Conclusions

These results form a rational basis for the design of clinical trials to evaluate the expression of these enzymes as predictors for treatment outcome.
Literature
1.
Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636–2644PubMedCrossRef
2.
Hanna N, Shepherd FA, Fossella FV, et al. (2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589–1597PubMedCrossRef
3.
Shih C, Habeck LL, Mendelsohn LG, et al. (1998) Multiple folate enzyme inhibition: mechanism of a novel pyrrolopyrimidin-based antifolate LY231514 (MTA). Adv Enzyme Regul 38:135–52PubMedCrossRef
4.
Westerhof GR, Schornagel JH, Kathmann I, Jackman AL, Rosowsky A, Forsch RA, Hynes JB, Boyle FT, Peters GJ, Pinedo HM, et al. (1995) Carrier- and receptor-mediated transport of folate antagonists targeting folate-dependent enzymes: correlates of molecular-structure and biological activity. Mol Pharmacol 48(3):459–471PubMed
5.
Habeck LL, Mendelsohn LG, Shih C, Taylor EC, Colman PD, Gossett LS, Leitner TA, Schultz RM, Andis SL, Moran RG (1995) Substrate specificity of mammalian folylpolyglutamate synthetase for 5,10-dideazatetrahydrofolate analogs. Mol Pharmacol 48(2):326–333PubMed
6.
Hanauske AR (2004) The role of Alimta in the treatment of malignant pleural mesothelioma: an overview of preclinical and clinical trials. Lung Cancer 45(Suppl 1):121–124CrossRef
7.
Hanauske AR, Dittrich C, Otero J. Overview of phase I/II pemetrexed studies. Oncology 2004 (Williston Park);18:18–25PubMed
8.
Niyikiza C, Hanauske AR, Rusthoven JJ, et al. (2002) Pemetrexed safety and dosing strategy. Semin Oncol 29:24–29PubMed
9.
Schultz RM, Chen VJ, Bewley JR, et al. (1999) Biological activity of the multitargeted antifolate, MTA (LY231514), in human cell lines with different resistance mechanisms to antifolate drugs. Semin Oncol 26(Suppl 6):68–73PubMed
10.
Wang Y, Zhao R, Goldman ID (2003) Decreased expression of the reduced folate carrier and folylpolyglutamate synthetase is the basis for acquired resistance to the pemetrexed antifolate (LY231514) in an L1210 murine leukaemia cell line. Biochem Pharmacol 65(7):1163–1170PubMedCrossRef
11.
Sigmond J, Backus HH, Wouters D, Temmink OH, Jansen G, Peters GJ (2003) Induction of resistance to the multitargeted antifolate pemetrexed (Alimta) in WiDr human colon cancer cells is associated with thymidylate synthase overexpression. Biochem Pharmacol 66(3):431–438PubMedCrossRef
12.
Giovannetti E, Mey V, Nannizzi S, et al. (2005) Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells. Mol Pharmacol 68:110–118PubMed
13.
Kim JH, Lee KW, Jung Y, et al. (2005) Cytotoxic effects of pemetrexed in gastric cancer cells. Cancer Sci 96:365–371PubMedCrossRef
14.
Vogel M, Hilsenbeck SG, Depenbrock H, et al. (1993) Preclinical activity of taxotere (RP56976, NSC628503) against freshly explanted clonogenic human tumor cells: comparison with taxol and conventional antineoplastic agents. Eur J Cancer 29A(14):2009–2014PubMedCrossRef
15.
Hanauske AR, Hilsenbeck SG, von Hoff DD (2004) Human tumor screening. In: Teicher BA, Andrews PA (eds) Cancer drug discovery and development: Anticancer drug development guide: Preclinical screenings, clinical trials, and approval. 2nd edition. Humana, Totowa, NJ, USA pp 63–76
16.
R Development Core Team (2003) R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing
17.
18.
Gomez H, Santillana S, Vallejos C, et al. (2006) A phase II trial of pemetrexed in locally advanced breast cancer: clinical response and association with molecular target expression. Clin Cancer Res 12(3):832–838PubMedCrossRef
19.
Ardalan B, Dang Z (1996) Thymidylate synthase gene expression in normal and malignant colorectal tissues: relation to in vivo response and survival. Proc Am Assoc Cancer Res 37:201
20.
Bathe O, Francesci D, Livingstone A, Moffatt FL, Tian E, Ardalan B (1999) Increased thymidylate synthase gene expression in liver metastases from colorectal carcinoma: implications for chemotherapeutic options and survival. Cancer J Sci Am 5:34–40PubMed
21.
Cascinu S, Achsele C, Barni S, et al. (1999) Thymidylate synthase protein expression in advanced colon cancer: correlation with site of metastasis and the clinical response to leucovorin-modulated bolus 5-fluorouracil. Clin Cancer Res 5:1996–1999PubMed
22.
Johnston PG, Lenz HJ, Leichman CG, et al. (1995) Thymidylate synthase gene and protein expression correlate and are associated with response to 5-FU in human colorectal and gastric tumors. Cancer Res 55:1407–1412PubMed
23.
Lenz HJ, Leichman CG, Danenberg KD, et al. (1996) Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. J Clin Oncol 14:176–182PubMed
24.
Paradiso A, Simone G, Petroni S, et al. (2000) Thymidylate synthase and p53 primary tumour expression as predictive factors for advanced colorectal cancer patients. Br J Cancer 82:560–567PubMedCrossRef
25.
Salonga D, Danenberg KD, Johnson M, et al. (2000) Colorectal tumors responding to 5-Fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 6:1322–1327PubMed
26.
Sympath J, Adachi M, Hatse S, Naesens L, Balzari J, Flatley RM, Metherly LH, Schuetz JD (2002) Role of MRP4 and MRP5 in biology and chemotherapy. AAPS PharmSci 4:E14CrossRef
27.
Reid G, Wielinga P, Zelcer N, De Haas M, Van Deemter L, Wijnholds J, Balarini J, Borst P (2003) Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol Pharmacol 63:1094–1103PubMedCrossRef
28.
Pratt S, Shepard RL, Kandasamy RA, Johnston PA, Perry W III, Dantzig AH (2005) The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Mol Cancer Ther 4:855–863PubMedCrossRef
29.
Pratt s, Chen V, Perry WI 3rd, Starling JJ, Dantzig AH (2006) Kinetic validation of the use of carboxydichlorofluoresceine as a drug surrogate for MRP5-mediated transport. Eur J Pharm Sci 27:524–532PubMedCrossRef
Metadata
Title
In vitro chemosensitivity of freshly explanted tumor cells to pemetrexed is correlated with target gene expression
Authors
Axel-Rainer Hanauske
Ulrike Eismann
Olaf Oberschmidt
Heike Pospisil
Steve Hoffmann
Hartmut Hanauske-Abel
Doreen Ma
Victor Chen
Paolo Paoletti
Clet Niyikiza
Publication date
01-10-2007
Publisher
Springer US
Published in
Investigational New Drugs / Issue 5/2007
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-007-9060-9

Other articles of this Issue 5/2007

Investigational New Drugs 5/2007 Go to the issue

PRECLINICAL STUDIES

Modulation of tumor radiation response with G3139, a bcl-2 antisense oligonucleotide

PHASE II STUDIES

Docetaxel–ifosfamide combination in patients with HER2-non-overexpressing advanced breast cancer failing prior anthracyclines

PHASE II STUDIES

The efficacy of hybrid chemotherapy with intravenous oxaliplatin and folinic acid and intra-hepatic infusion of 5-fluorouracil in patients with colorectal liver metastases: a phase II study

PHASE II STUDIES

Phase II study of Triapine® in patients with metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC IND.161)

PRECLINICAL STUDIES

Silencing of endo-exonuclease expression sensitizes mouse B16F10 melanoma cells to DNA damaging agents

PHASE I STUDIES

Phase I dose escalation and pharmacokinetic study of AZD2171, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinase, in patients with hormone refractory prostate cancer (HRPC)
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits