Enhanced cytotoxic interaction between 5-fluorouracil and 4-hydroperoxycyclophosphamide against L1210 murine leukemic cells: applicability to ex vivo purging.

Abstract

Eradication of contaminated tumor cells in bone marrow is a matter of utmost concern in the setting of autologous bone marrow transplantation. 4-Hydroperoxycyclophosphamide (4-HC) is often used for ex vivo chemical purging of contaminated tumor cells in bone marrow. The marrow from patients pretreated with 5-fluorouracil (5-FU) is enriched with multifactor-responsive high proliferative potential colony-forming cells. To develop an efficient ex vivo chemical purging system, we evaluated interaction between 4-HC and 5-FU. We investigated the antitumor effect of cyclophosphamide, a mother compound of 4-HC, and 5-FU against L1210 ascites tumor in B6D2F1 mice. The median lifespan of the mice treated with 4-HC or 5-FU alone was 8 and 12 days, respectively. The combination of both drugs significantly extended the median lifespan to 18.5 days. The median effect plot analysis indicated a synergistic cytotoxic interaction between 5-FU and 4-HC in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl terazolium bromide (MTT) assay. Clonogenic assay also showed that combination of 4-HC and 5-FU significantly reduced L1210 leukemic colonies to 20% of untreated control. Bone marrow cells from the mice treated with 5-FU at 150 mg/kg body weight was resistant to 4-HC at concentrations as high as 0.2 microgram/ml, which was more than 70% inhibitory concentration for colony formation in L1210 leukemic cells. Findings suggest that sequential treatment with in vivo 5-FU followed by ex vivo 4-HC could selectively enhance antitumor effects of 4-HC in tumor cells remaining in bone marrow.

• Authors: X Y Mao, M Higashigawa, T M'Soka, Y Shimono, T Nagata, H Inamochi, D C Cao, H Hori, H Kawasaki, M Sakurai
• Journal: Cancer investigation (Cancer Invest) Vol. 17 Issue 7 Pg. 486-93 ( 1999) ISSN: 0735-7907 [Print] England
• PMID: 10518193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-hydroxyperoxycyclophosphamide
• Antimetabolites, Antineoplastic
• Antineoplastic Agents
• Cyclophosphamide
• Fluorouracil

Topics

• Animals
• Antimetabolites, Antineoplastic (administration & dosage)
• Antineoplastic Agents (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Bone Marrow Purging
• Cell Division (drug effects)
• Cyclophosphamide (administration & dosage, analogs & derivatives)
• Drug Synergism
• Fluorouracil (administration & dosage)
• Hematopoietic Stem Cells (drug effects)
• Leukemia L1210 (drug therapy, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Neoplastic Stem Cells (drug effects)