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.
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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.)
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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
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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)
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