Molecular Mechanisms Underlying the Interaction Between ZD1839 ('Iressa') and Cisplatin/5-fluorouracil

Overview

Journal Br J Cancer

Specialty Oncology

Date 2003 Jul 31

PMID 12888834

Citations 13

Authors

N Magne

J-L Fischel

C Tiffon

P Formento

A Dubreuil

N Renee

J-L Formento

M Francoual

J Ciccolini

M-C Etienne

G Milano

Affiliations

Soon will be listed here.

Abstract

ZD1839 ('Iressa'), an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is currently being investigated in clinical trials as a treatment for cancer. 'Iressa' is a trademark of the AstraZeneca group of companies. We have previously demonstrated a synergistic interaction between ZD1839 and cisplatin/5-fluorouracil (5FU) in CAL33, a human head and neck cancer cell line that markedly expresses EGFR. This study examined the effects of this drug combination on the cell cycle, cell cycle regulators, apoptosis-related factors, EGFR-related signalling and DNA repair in CAL33 cells. The cells were incubated with ZD1839 alone for 48 h, then cisplatin and 5FU were added. Exposure to the drug combination continued for a further 48 h. ZD1839 alone induced accumulation of cells in the G0/G1 phase of the cell cycle at 24 h accompanied by a concomitant increase in p21, p27 and Bax, a significant decrease in Bcl2 and a decrease in Akt phosphorylation. A decrease in DNA-PK was observed at 48 h. ZD1839 alone had no effect on caspase-3 activity, but addition of ZD1839 to cisplatin-5FU led to a significant increase in caspase-3 activity at 96 h. Thus, ZD1839 affects key cellular pathways controlling cell proliferation, apoptosis and DNA repair. These data provide a rationale to support clinical trials combining ZD1839 and cisplatin-5FU and other protocols that combine EGFR-targeting agents with chemotherapy or radiotherapy.

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References

Huang S, Bock J, Harari P . Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res. 1999; 59(8):1935-40. View

Overholser J, Prewett M, Hooper A, Waksal H, Hicklin D . Epidermal growth factor receptor blockade by antibody IMC-C225 inhibits growth of a human pancreatic carcinoma xenograft in nude mice. Cancer. 2000; 89(1):74-82. View

Baselga J . The EGFR as a target for anticancer therapy--focus on cetuximab. Eur J Cancer. 2001; 37 Suppl 4:S16-22. DOI: 10.1016/s0959-8049(01)00233-7. View

Ciardiello F, Caputo R, Bianco R, Damiano V, Pomatico G, De Placido S . Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res. 2000; 6(5):2053-63. View

Baselga J, Norton L, Masui H, Pandiella A, Coplan K, Miller Jr W . Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J Natl Cancer Inst. 1993; 85(16):1327-33. DOI: 10.1093/jnci/85.16.1327. View

Chou T, Talalay P . Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984; 22:27-55. DOI: 10.1016/0065-2571(84)90007-4. View

Ciardiello F, Bianco R, Damiano V, De Lorenzo S, Pepe S, De Placido S . Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Clin Cancer Res. 1999; 5(4):909-16. View

Magne N, Fischel J, Dubreuil A, Formento P, Poupon M, Laurent-Puig P . Influence of epidermal growth factor receptor (EGFR), p53 and intrinsic MAP kinase pathway status of tumour cells on the antiproliferative effect of ZD1839 ("Iressa"). Br J Cancer. 2002; 86(9):1518-23. PMC: 2375374. DOI: 10.1038/sj.bjc.6600299. View

Sirotnak F, Zakowski M, Miller V, Scher H, Kris M . Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res. 2001; 6(12):4885-92. View

10.

Bancroft C, Chen Z, Yeh J, Sunwoo J, Yeh N, Jackson S . Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF-kappaB and AP-1 activation and IL-8 and VEGF expression in human head and neck squamous cell carcinoma lines. Int J Cancer. 2002; 99(4):538-48. DOI: 10.1002/ijc.10398. View

11.

Bianco C, Bianco R, Tortora G, Damiano V, GUERRIERI P, Montemaggi P . Antitumor activity of combined treatment of human cancer cells with ionizing radiation and anti-epidermal growth factor receptor monoclonal antibody C225 plus type I protein kinase A antisense oligonucleotide. Clin Cancer Res. 2000; 6(11):4343-50. View

12.

Johnstone R, Ruefli A, Lowe S . Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002; 108(2):153-64. DOI: 10.1016/s0092-8674(02)00625-6. View

13.

Bruns C, Harbison M, Davis D, Portera C, Tsan R, McConkey D . Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res. 2000; 6(5):1936-48. View

14.

Milas L, Mason K, Hunter N, Petersen S, Yamakawa M, Ang K . In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res. 2000; 6(2):701-8. View

15.

Perez R . Cellular and molecular determinants of cisplatin resistance. Eur J Cancer. 1999; 34(10):1535-42. DOI: 10.1016/s0959-8049(98)00227-5. View

16.

Kolfschoten G, Hulscher T, Schrier S, van Houten V, Pinedo H, Boven E . Time-dependent changes in factors involved in the apoptotic process in human ovarian cancer cells as a response to cisplatin. Gynecol Oncol. 2002; 84(3):404-12. DOI: 10.1006/gyno.2001.6537. View

17.

Ciardiello F, Caputo R, Borriello G, Del Bufalo D, Biroccio A, Zupi G . ZD1839 (IRESSA), an EGFR-selective tyrosine kinase inhibitor, enhances taxane activity in bcl-2 overexpressing, multidrug-resistant MCF-7 ADR human breast cancer cells. Int J Cancer. 2002; 98(3):463-9. DOI: 10.1002/ijc.10230. View

18.

Backus H, Dukers D, Van Groeningen C, Vos W, Bloemena E, Wouters D . 5-Fluorouracil induced Fas upregulation associated with apoptosis in liver metastases of colorectal cancer patients. Ann Oncol. 2001; 12(2):209-16. DOI: 10.1023/a:1008331525368. View

19.

Magne N, Fischel J, Dubreuil A, Formento P, Marcie S, Lagrange J . Sequence-dependent effects of ZD1839 ('Iressa') in combination with cytotoxic treatment in human head and neck cancer. Br J Cancer. 2002; 86(5):819-27. PMC: 2375300. DOI: 10.1038/sj.bjc.6600103. View

20.

Normanno N, Campiglio M, De L, Somenzi G, Maiello M, Ciardiello F . Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. Ann Oncol. 2002; 13(1):65-72. DOI: 10.1093/annonc/mdf020. View