A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies Journal Article
| Authors: | Perrine, S. P.; Hermine, O.; Small, T.; Suarez, F.; O'reilly, R.; Boulad, F.; Fingeroth, J.; Askin, M.; Levy, A.; Mentzer, S. J.; Di Nicola, M.; Gianni, A. M.; Klein, C.; Horwitz, S.; Faller, D. V. |
| Article Title: | A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies |
| Abstract: | Malignancies associated with latent Epstein-Barr virus (EBV) are resistant to nucleoside-type antiviral agents because the viral enzymetarget of these antiviral drugs, thymidine kinase (TK), is not expressed. Short-chain fatty acids, such as butyrate, induce EBV-TK expression in latently infected B cells. As butyrate has been shown to sensitize EBV+ lymphoma cells in vitro to apoptosis induced by ganciclovir, arginine butyrate in combination with ganciclovir was administered in 15 patients with refractory EBV+ lymphoid malignancies to evaluate the drug combination for toxicity, pharmacokinetics, and clinical responses. Ganciclovir was administered twice daily at standard doses, and arginine butyrate was administered by continuous infusion in an intrapatient dose escalation, from 500 mg/(kg/day) escalating to 2000 mg/(kg/day), as tolerated, for a 21-day cycle. The MTD for arginine butyrate in combination with ganciclovir was established as 1000 mg/(kg/day). Ten of 15 patients showed significant antitumor responses, with 4 CRs and 6 PRs within one treatment cycle. Complications from rapid tumor lysis occurred in 3 patients. Reversible somnolence or stupor occurred in 3 patients at arginine butyrate doses of greater than 1000 mg/(kg/day). The combination of arginine butyrate and ganciclovir was reasonably well-tolerated and appears to have significant biologic activity in vivo in EBV+ lymphoid malignancies which are refractory to other regimens. © 2007 by The American Society of Hematology. |
| Keywords: | adolescent; adult; child; clinical article; controlled study; protein expression; treatment response; aged; child, preschool; middle aged; unclassified drug; clinical trial; constipation; drug tolerability; fatigue; hepatitis; diarrhea; drug dose reduction; drug safety; drug withdrawal; side effect; unspecified side effect; antineoplastic agents; cancer patient; drug megadose; anorexia; disease association; apoptosis; controlled clinical trial; multiple cycle treatment; phase 2 clinical trial; anemia; mucosa inflammation; thrombocytopenia; deep vein thrombosis; urea nitrogen blood level; in vivo study; antineoplastic activity; continuous infusion; in vitro study; b lymphocyte; backache; drug dose escalation; fever; pneumonia; rash; confusion; drug fatality; hypokalemia; insomnia; drug therapy, combination; hepatomegaly; lymphoma cell; pancreatitis; lymphoma; nausea and vomiting; sepsis; vision; thymidine kinase; antiemetic agent; virus infection; headache; intestine perforation; drug blood level; maximum tolerated dose; phase 1 clinical trial; somnolence; staphylococcus infection; standing; lethargy; hallucination; ganciclovir; mycosis; epstein barr virus; arginine; hypesthesia; adult respiratory distress syndrome; epstein-barr virus infections; lung hemorrhage; disorientation; pharyngitis; gastrointestinal infection; restlessness; arginine butyrate; arginine derivative; butyric acid derivative; auditory hallucination; latent virus infection; lung graft rejection; sinus pain; stupor; butyrates |
| Journal Title: | Blood |
| Volume: | 109 |
| Issue: | 6 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2007-03-15 |
| Start Page: | 2571 |
| End Page: | 2578 |
| Language: | English |
| DOI: | 10.1182/blood-2006-01-024703 |
| PUBMED: | 17119113 |
| PROVIDER: | scopus |
| PMCID: | PMC1852196 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 59" - "Export Date: 17 November 2011" - "CODEN: BLOOA" - "Source: Scopus" |
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