Concurrent chemoenhancement with buslsulfoxamtne of intracarotid akylators and protection from chemotherapy-induced bone marrow toxicity with aortic thiol infusion in a rat model

Edward A. Neuwelt, Michael A. Pagel, Brant Hasler, Thomas G. Deloughery

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Abstract

Introduction: Modulation of glutathione (GSH) levels may alter the toxicity of chemotherapeutic agents. We investigated in vivo cytoenhancement with Buthionine Sulfoximine (BSO) which reduces cellular GSH levels, and chemoprotection with N-acetylcysteine (NAC) and sodium thiosulfate (STS), agents which can mimic GSH. Methods: NAC biodistribution was determined with radiolabelled tracer (n=12). Blood and tissue GSH levels were measured with a colorometric kit(n=19). For bone marrow toxicity studies, rats were treated with or without BSO (10 g/m2 i.p. b.i.d. × 3 days), followed by chemotherapy consisting of intra-carotid carboplatin (200 mg/m2), melphalan (10 mg/m2) and etoposide phosphate (100 mg/m2) (n=61). The dose of NAC was 1200 mg/m2 and STS was 8 gm/m2. White blood cell and platelet counts were obtained prior to, at 6 days and 9-10 days after chemotherapy. Results: BSO treatment for 3 days reduced blood and tissue GSH levels by 50-65% even in brain and intracerebral tumor in nude rats. BSO pretreatment enhanced the hone marrow toxicity of combination chemotherapy. Intraarterial administration of radiolabelled NAC in the right carotid artery resulted in high delivery to the right cerebral hemisphere. However, infusion of NAC via a new "aortic infusion" technique, retrograde in the left external carotid artery with the left internal carotid artery occluded to prevent infusion of the brain, reduced brain delivery to neglible levels while increasing systemic delivery. When NAC was administered via "aortic infusion" before intra-caroüd chemotherapy (no BSO), the magnitude of the bone marrow toxicity nadir at day 6 was reduced (no NAC: platlets 215 ±126, granulocytes 146 ± 160; with NAC: platlets 470 ± 234, granulocytes 785 ±494, which by non-parametic analysis gave a p value of < 0.02). Virtually no myelosuppression occurred if both NAC and STS were given via "aortic infusion" even in BSO-treated animals. Conclusions: Modulation of GSH levels with BSO treatment may enhance the chemotherapeutic cytotoxicity of intra-carotid carboplatin. and melphalan. Aortic infusion increases chemoprotectant delivery to systemic tissue with resultant bone marrow protection, but CNS delivery is neglible. Chemoprotection may be valuable in the clinical setting if chemotherapy (± chemoenhancers) and chemoprotectant can be physically and/or temporally separated by intra-carotid infusion of alkylators and "aortic infusion" of chemoprotectant.

Original languageEnglish (US)
Pages (from-to)183b
JournalBlood
Volume96
Issue number11 PART II
StatePublished - Dec 1 2000

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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