Combined therapeutic efficacy of the thymidylate synthase inhibitor ZD1694 (Tomudex) and the immunotoxin B43(anti-CD19)-PAP in a SCID mouse model of human B-lineage acute lymphoblastic leukemia.

Abstract

The quinazoline antifolate N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N- methylamino]-2-thenoyl)-L-glutamic acid (ZD1694; Tomudex) is a potent inhibitor of thymidylate synthase and causes cell death through disruption of DNA synthesis and repair by blocking the obligatory thymidine nucleotide synthesis. B43(anti-CD19)-PAP immunotoxin is a potent inhibitor of protein synthesis in CD19+ B-lineage acute lymphoblastic leukemia (ALL) cells and causes apoptosis. In this model, 100% of SCID mice challenged with 1 x 10(6) human NALM-6 B-lineage ALL cells develop overt and invariably fatal leukemia. All of the 22 control SCID mice treated with phosphate-buffered saline died of disseminated human leukemia between 31 and 61 days with a median survival of 41.2 days. Treatment with ZD 1694 resulted in improved leukemia-free survival with a median survival of 69.2 days (P < 0.001, log-rank test). B43-PAP treatment was more effective than ZD1694 (P=0.026) and resulted in 51.0% long-term leukemia-free survival with a median survival of 187.5 days (P < 0.0001. log-rank test). The combination of ZD1694 and B43-PAP was more effective than either agent alone and resulted in 100% long-term leukemia-free survival. To our knowledge, this preclinical study is the first to demonstrate the feasibility and therapeutic advantage of combining an anti-leukemia immunotoxin with a thymidylate synthase inhibitor.

• Authors: O Ek, G H Reaman, D L Crankshaw, L M Chelstrom, D E Myers, F M Uckun
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 28 Issue 5-6 Pg. 509-14 (Feb 1998) ISSN: 1042-8194 [Print] United States
• PMID: 9613980 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, CD19
• Antimetabolites, Antineoplastic
• Antineoplastic Agents, Phytogenic
• Enzyme Inhibitors
• Immunotoxins
• Plant Proteins
• Quinazolines
• Ribosome Inactivating Proteins, Type 1
• Thiophenes
• Thymidylate Synthase
• N-Glycosyl Hydrolases
• pokeweed antiviral protein
• raltitrexed

Topics

• Animals
• Antigens, CD19 (immunology)
• Antimetabolites, Antineoplastic (administration & dosage)
• Antineoplastic Agents, Phytogenic (administration & dosage)
• B-Lymphocytes (pathology)
• Cell Lineage
• Combined Modality Therapy
• Disease Models, Animal
• Enzyme Inhibitors (administration & dosage)
• Humans
• Immunotoxins (administration & dosage)
• Mice
• Mice, SCID
• N-Glycosyl Hydrolases
• Plant Proteins (administration & dosage)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (immunology, pathology, physiopathology, therapy)
• Quinazolines (administration & dosage)
• Ribosome Inactivating Proteins, Type 1
• Survival Analysis
• Thiophenes (administration & dosage)
• Thymidylate Synthase (antagonists & inhibitors)