Modulation of plasma thiols and mixed disulfides by BNP7787 in patients receiving paclitaxel/cisplatin therapy

Lakshmi Pendyala, Gary Schwartz, Patrick Smith, Joseph Zdanowicz, Michael Murphy, Frederick Hausheer

Research output: Contribution to journalArticlepeer-review

Abstract

Background: BNP7787 (disodium 2,2′-dithio-bis-ethane sulfonate) was evaluated in a phase I clinical trial with paclitaxel and cisplatin to assess the safety and potential efficacy for preventing or reducing cisplatinand paclitaxel-induced toxicities. During this trial the effects of BNP7787 administration on the total concentrations (oxidized plus free) of cysteine, homocysteine and GSH in plasma, free and total GSH in WBC and rate of urinary excretion of cysteine were studied. The pharmacokinetics of ultrafilterable (free, non-protein bound) platinum were also determined after cisplatin (75 mg/m2) treatment which followed paclitaxel (175 mg/m2) and BNP7787 (8.2 to 27.6 g/m2). Method: Plasma thiols were measured by HPLC with fluorescence detection and platinum was measured by atomic absorption spectrophotometry. Results: BNP7787 administration produced a significant depletion of all plasma thiols in all the patients studied. Differences were noted in the kinetics of BNP7787-induced depletion of cysteine and other thiols. A significant depletion of cysteine occurred with a time lag of about 2 h after the end of BNP7787 infusion, while a reversible depletion of GSH and homocysteine occurred immediately following the start of BNP7787 infusion, with the plasma thiol/disulfide nadir corresponding to the end of infusion. The mean half-life of cysteine depletion following BNP7787 administration was 2.2 h, significantly longer than for homocysteine (0.23 h), or GSH (0.18 h; P

Original languageEnglish (US)
Pages (from-to)376-384
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume51
Issue number5
StatePublished - May 1 2003
Externally publishedYes

Keywords

  • BNP7787
  • Cysteine Homocysteine
  • Disulfides
  • Glutathione
  • Thiols

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

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