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.
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.
Ek
O
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Biotherapy Institute, University of Minnesota, Minneapolis, USA.
Reaman
G H
GH
Crankshaw
D L
DL
Chelstrom
L M
LM
Myers
D E
DE
Uckun
F M
FM
D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D001402:B-Lymphocytes / Q000473:pathology; D019070:Cell Lineage; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage*; D051379:Mice; D016513:Mice, SCID; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000008:administration & dosage*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D011799:Quinazolines / Q000008:administration & dosage*; D054789:Ribosome Inactivating Proteins, Type 1; D016019:Survival Analysis; D013876:Thiophenes / Q000008:administration & dosage*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
D018941:Antigens, CD19; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D000922:Immunotoxins; D010940:Plant Proteins; D011799:Quinazolines; D054789:Ribosome Inactivating Proteins, Type 1; D013876:Thiophenes; D013940:Thymidylate Synthase; D009699:N-Glycosyl Hydrolases; C024275:pokeweed antiviral protein; C068874:raltitrexed