Chronic daily low dose of 4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz) in patients with previously resected colon polyps and first-degree female relatives of breast cancer patients

Al B Benson III, Olufunmilayo I. Olopade, Mark J. Ratain, Alfred W Rademaker, Sohrab Mobarhan, Lisa Stucky-Marshall, Suzanne French, M. Eileen Dolan

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The chemoprevention agent oltipraz, one of the most active chemopreventive compounds in preclinical studies, has been shown to induce glutathione-S-transferase (GST) activity in animals. Oltipraz was evaluated in a Phase I trial at daily oral doses of 20 mg (L1), 50 mg (L2), and 100 mg (L3) and twice weekly doses of 125 mg (L4) taken for 6 months with 6 patients entered at L1 and L2 and 7 patients entered at L3 and L4 (26 subjects: 19 females and 7 males). The subject population included patients with previously resected colon polyps and first-degree female relatives of breast cancer patients. Patients with resected colon polyps underwent rectal biopsy for GST and glutathione (GSH) analyses. Of the 26 subjects, the following completed 6 months of therapy: 4 of 6 patients (L1), 4 of 6 patients (L2), 5 of 7 patients (L3), and 4 of 7 patients (L4). Toxicities were mild to severe and included: gastrointestinal symptoms, photosensitivity/heat intolerance, and neurological symptoms. Monthly plasma samples were obtained 2-3 h after oltipraz ingestion with minimally detectable plasma concentrations at L1. There was a significant difference in mean oltipraz concentration across the four doses, with no significant differences in mean oltipraz concentration over time. Rectal tissue and lymphocyte GSH and GST were variable, with no significant difference in mean levels across doses. At the 100-mg/day dose (L3), I patient experienced significant increase in rectal tissue GSH and GST activity, whereas 3 additional patients (L1 and L4) had >50% increase in tissue GSH. Lymphocyte GSH level was significantly related to plasma oltipraz concentration. There were no significant correlations between plasma oltipraz concentration and lymphocyte GST level nor any significant correlation between plasma concentration and percentage of change in tissue GSH or GST. Further investigation of dose/schedule and biological end points is ongoing.

Original languageEnglish (US)
Pages (from-to)3870-3877
Number of pages8
JournalClinical Cancer Research
Volume6
Issue number10
StatePublished - Jan 1 2000

Fingerprint

Polyps
Colon
Breast Neoplasms
Glutathione Transferase
Lymphocytes
1,2-dithiol-3-thione
oltipraz
Chemoprevention
Glutathione
Appointments and Schedules
Eating
Hot Temperature
Biopsy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Benson III, Al B ; Olopade, Olufunmilayo I. ; Ratain, Mark J. ; Rademaker, Alfred W ; Mobarhan, Sohrab ; Stucky-Marshall, Lisa ; French, Suzanne ; Dolan, M. Eileen. / Chronic daily low dose of 4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz) in patients with previously resected colon polyps and first-degree female relatives of breast cancer patients. In: Clinical Cancer Research. 2000 ; Vol. 6, No. 10. pp. 3870-3877.
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abstract = "The chemoprevention agent oltipraz, one of the most active chemopreventive compounds in preclinical studies, has been shown to induce glutathione-S-transferase (GST) activity in animals. Oltipraz was evaluated in a Phase I trial at daily oral doses of 20 mg (L1), 50 mg (L2), and 100 mg (L3) and twice weekly doses of 125 mg (L4) taken for 6 months with 6 patients entered at L1 and L2 and 7 patients entered at L3 and L4 (26 subjects: 19 females and 7 males). The subject population included patients with previously resected colon polyps and first-degree female relatives of breast cancer patients. Patients with resected colon polyps underwent rectal biopsy for GST and glutathione (GSH) analyses. Of the 26 subjects, the following completed 6 months of therapy: 4 of 6 patients (L1), 4 of 6 patients (L2), 5 of 7 patients (L3), and 4 of 7 patients (L4). Toxicities were mild to severe and included: gastrointestinal symptoms, photosensitivity/heat intolerance, and neurological symptoms. Monthly plasma samples were obtained 2-3 h after oltipraz ingestion with minimally detectable plasma concentrations at L1. There was a significant difference in mean oltipraz concentration across the four doses, with no significant differences in mean oltipraz concentration over time. Rectal tissue and lymphocyte GSH and GST were variable, with no significant difference in mean levels across doses. At the 100-mg/day dose (L3), I patient experienced significant increase in rectal tissue GSH and GST activity, whereas 3 additional patients (L1 and L4) had >50{\%} increase in tissue GSH. Lymphocyte GSH level was significantly related to plasma oltipraz concentration. There were no significant correlations between plasma oltipraz concentration and lymphocyte GST level nor any significant correlation between plasma concentration and percentage of change in tissue GSH or GST. Further investigation of dose/schedule and biological end points is ongoing.",
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Chronic daily low dose of 4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz) in patients with previously resected colon polyps and first-degree female relatives of breast cancer patients. / Benson III, Al B; Olopade, Olufunmilayo I.; Ratain, Mark J.; Rademaker, Alfred W; Mobarhan, Sohrab; Stucky-Marshall, Lisa; French, Suzanne; Dolan, M. Eileen.

In: Clinical Cancer Research, Vol. 6, No. 10, 01.01.2000, p. 3870-3877.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Chronic daily low dose of 4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz) in patients with previously resected colon polyps and first-degree female relatives of breast cancer patients

AU - Benson III, Al B

AU - Olopade, Olufunmilayo I.

AU - Ratain, Mark J.

AU - Rademaker, Alfred W

AU - Mobarhan, Sohrab

AU - Stucky-Marshall, Lisa

AU - French, Suzanne

AU - Dolan, M. Eileen

PY - 2000/1/1

Y1 - 2000/1/1

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