Tiazofurin down-regulates expression of c-Ki-ras oncogene in a leukemic patient.
The increased activity in cancer cells of inosine 5'-monophosphate dehydrogenase (IMP DH, EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, was suggested as a sensitive target for chemotherapy. Tiazofurin (NSC 286193), through its conversion to the active metabolite, thiazole-4-carboxamide adenine dinucleotide (TAD), is a strong inhibitor of IMP DH. In our clinical trial, tiazofurin caused return to the chronic phase in patients with chronic granulocytic leukemia in blast crisis (Tricot, G.; Jayaram, H.N.; Weber, G.; Hoffman, R. Tiazofurin: Biological effects and clinical uses. Int. J. Cell Cloning 8:161-170; 1990). In K562 human leukemic cells, tiazofurin down-regulated the expression of c-Ki-ras and c-myc oncogenes, which was followed by induced differentiation. We now report down-regulation by tiazofurin of the c-Ki-ras oncogene in a patient with chronic granulocytic leukemia in blast crisis. A single tiazofurin infusion (2,200 mg/m2) on days one and two decreased IMP dehydrogenase activity (the apparent t1/2 was 30 min), GTP concentration (the apparent t1/2 was 6 hr), and expression of ras (the apparent t1/2 was 8 hr) and c-myc (the apparent t1/2 was 38.5 hr) oncogenes in the leukemic cells. No further tiazofurin was given, because on days three and four the chemotherapeutic impact became evident in a tumor-lysis syndrome and the blast cells were cleared from the periphery by day five. The decrease in IMP DH activity, GTP concentration, and expression of c-Ki-ras oncogene were early markers of the successful chemotherapeutic impact of tiazofurin in a patient with chronic granulocytic leukemia in blast crisis.
Weber
G
G
Laboratory for Experimental Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis 46202-5200.
Nagai
M
M
Natsumeda
Y
Y
Eble
J N
JN
Jayaram
H N
HN
Paulik
E
E
Zhen
W N
WN
Hoffman
R
R
Tricot
G
G
D000227:Adenine Nucleotides / Q000032:analysis; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001752:Blast Crisis / Q000188:drug therapy*; D015152:Blotting, Northern; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D011905:Genes, ras / Q000187:drug effects*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000097:blood; D007168:IMP Dehydrogenase / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D012313:RNA / Q000032:analysis; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014527:Uric Acid / Q000097:blood
D000227:Adenine Nucleotides; D000964:Antimetabolites, Antineoplastic; D007042:Hypoxanthines; D014527:Uric Acid; D019271:Hypoxanthine; D012254:Ribavirin; D012313:RNA; C038167:thiazole-4-carboxamide adenine dinucleotide; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; C033706:tiazofurin