High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer

Targeted plasma levels are achievable clinically

Primo N. Lara, David R. Gandara, Gregory T. Wurz, Derick Lau, Margaret Uhrich, Corinne Turrell, James Raschko, Martin J. Edelman, Timothy Synold, James Doroshow, Franco Muggia, Edith A. Perez, Mike DeGregorio

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Purpose: The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally ≤5 μM, at least tenfold higher than plasma levels observed in patients receiving these agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. Methods: Treatment consisted of toremifene, 600 mg orally on days 1-7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion. Results: In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (± 8.6) μM and 9.8 (± 4.4) μM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N- desmethyltoremifene were higher on day 11 relative to toremifene concentrations. Conclusions: We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.

Original languageEnglish (US)
Pages (from-to)504-508
Number of pages5
JournalCancer Chemotherapy and Pharmacology
Volume42
Issue number6
DOIs
StatePublished - 1998

Fingerprint

Toremifene
Non-Small Cell Lung Carcinoma
Modulators
Cisplatin
Cells
Plasmas
Tamoxifen
Metabolites
Protein Kinase C
Signal transduction
Body Surface Area
Proxy
Cytotoxicity
Assays
Signal Transduction
High Pressure Liquid Chromatography
Modulation

Keywords

  • Cisplatin
  • Lung cancer
  • Phase II trial
  • Protein kinase C
  • Toremifene

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer : Targeted plasma levels are achievable clinically. / Lara, Primo N.; Gandara, David R.; Wurz, Gregory T.; Lau, Derick; Uhrich, Margaret; Turrell, Corinne; Raschko, James; Edelman, Martin J.; Synold, Timothy; Doroshow, James; Muggia, Franco; Perez, Edith A.; DeGregorio, Mike.

In: Cancer Chemotherapy and Pharmacology, Vol. 42, No. 6, 1998, p. 504-508.

Research output: Contribution to journalArticle

Lara, PN, Gandara, DR, Wurz, GT, Lau, D, Uhrich, M, Turrell, C, Raschko, J, Edelman, MJ, Synold, T, Doroshow, J, Muggia, F, Perez, EA & DeGregorio, M 1998, 'High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer: Targeted plasma levels are achievable clinically', Cancer Chemotherapy and Pharmacology, vol. 42, no. 6, pp. 504-508. https://doi.org/10.1007/s002800050852
Lara, Primo N. ; Gandara, David R. ; Wurz, Gregory T. ; Lau, Derick ; Uhrich, Margaret ; Turrell, Corinne ; Raschko, James ; Edelman, Martin J. ; Synold, Timothy ; Doroshow, James ; Muggia, Franco ; Perez, Edith A. ; DeGregorio, Mike. / High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer : Targeted plasma levels are achievable clinically. In: Cancer Chemotherapy and Pharmacology. 1998 ; Vol. 42, No. 6. pp. 504-508.
@article{e71c5a1817a64d938154b5b28045a8e0,
title = "High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer: Targeted plasma levels are achievable clinically",
abstract = "Purpose: The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally ≤5 μM, at least tenfold higher than plasma levels observed in patients receiving these agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. Methods: Treatment consisted of toremifene, 600 mg orally on days 1-7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion. Results: In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (± 8.6) μM and 9.8 (± 4.4) μM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N- desmethyltoremifene were higher on day 11 relative to toremifene concentrations. Conclusions: We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.",
keywords = "Cisplatin, Lung cancer, Phase II trial, Protein kinase C, Toremifene",
author = "Lara, {Primo N.} and Gandara, {David R.} and Wurz, {Gregory T.} and Derick Lau and Margaret Uhrich and Corinne Turrell and James Raschko and Edelman, {Martin J.} and Timothy Synold and James Doroshow and Franco Muggia and Perez, {Edith A.} and Mike DeGregorio",
year = "1998",
doi = "10.1007/s002800050852",
language = "English (US)",
volume = "42",
pages = "504--508",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "6",

}

TY - JOUR

T1 - High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer

T2 - Targeted plasma levels are achievable clinically

AU - Lara, Primo N.

AU - Gandara, David R.

AU - Wurz, Gregory T.

AU - Lau, Derick

AU - Uhrich, Margaret

AU - Turrell, Corinne

AU - Raschko, James

AU - Edelman, Martin J.

AU - Synold, Timothy

AU - Doroshow, James

AU - Muggia, Franco

AU - Perez, Edith A.

AU - DeGregorio, Mike

PY - 1998

Y1 - 1998

N2 - Purpose: The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally ≤5 μM, at least tenfold higher than plasma levels observed in patients receiving these agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. Methods: Treatment consisted of toremifene, 600 mg orally on days 1-7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion. Results: In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (± 8.6) μM and 9.8 (± 4.4) μM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N- desmethyltoremifene were higher on day 11 relative to toremifene concentrations. Conclusions: We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.

AB - Purpose: The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally ≤5 μM, at least tenfold higher than plasma levels observed in patients receiving these agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. Methods: Treatment consisted of toremifene, 600 mg orally on days 1-7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion. Results: In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (± 8.6) μM and 9.8 (± 4.4) μM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N- desmethyltoremifene were higher on day 11 relative to toremifene concentrations. Conclusions: We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.

KW - Cisplatin

KW - Lung cancer

KW - Phase II trial

KW - Protein kinase C

KW - Toremifene

UR - http://www.scopus.com/inward/record.url?scp=15444344801&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=15444344801&partnerID=8YFLogxK

U2 - 10.1007/s002800050852

DO - 10.1007/s002800050852

M3 - Article

VL - 42

SP - 504

EP - 508

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 6

ER -