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Titolo:
Toxicology and pharmacokinetics of DTGM, a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human granulocyte-macrophage colony-stimulating factor, in cynomolgus monkeys
Autore:
Hotchkiss, CE; Hall, PD; Cline, JM; Willingham, MC; Kreitman, RJ; Gardin, J; Latimer, A; Ramage, J; Feely, T; DeLatte, S; Tagge, EP; Frankel, AE;
Indirizzi:
Wake Forest Univ, Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA Wake Forest Univ Winston Salem NC USA 27157 , Winston Salem, NC 27157 USA Wake Forest Univ, Sch Med, Dept Pathol, Winston Salem, NC 27157 USA Wake Forest Univ Winston Salem NC USA 27157 , Winston Salem, NC 27157 USA Med Univ S Carolina, Coll Pharm, Charleston, SC 29425 USA Med Univ S Carolina Charleston SC USA 29425 arm, Charleston, SC 29425 USA NCI, Mol Biol Lab, NIH, Bethesda, MD USA NCI Bethesda MD USANCI, Mol Biol Lab, NIH, Bethesda, MD USA
Titolo Testata:
TOXICOLOGY AND APPLIED PHARMACOLOGY
fascicolo: 2, volume: 158, anno: 1999,
pagine: 152 - 160
SICI:
0041-008X(19990715)158:2<152:TAPODA>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACUTE MYELOID-LEUKEMIA; A CHAIN IMMUNOTOXIN; FACTOR GM-CSF; CELL LYMPHOMAS; PHASE-I; THERAPY; PROTEIN; PROGENITORS; MODULATION; RECEPTORS;
Keywords:
diphtheria toxin; fusion toxin; acute myeloid leukemia; GM-CSF;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
30
Recensione:
Indirizzi per estratti:
Indirizzo: Frankel, AE Wake Forest Univ, Sch Med, Dept Canc Biol, Hanes 4046, WinstonSalem, NC 27157 USA Wake Forest Univ Hanes 4046 Winston Salem NC USA 27157157 USA
Citazione:
C.E. Hotchkiss et al., "Toxicology and pharmacokinetics of DTGM, a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human granulocyte-macrophage colony-stimulating factor, in cynomolgus monkeys", TOX APPL PH, 158(2), 1999, pp. 152-160

Abstract

We developed a fusion toxin consisting of the catalytic and translocation domains of diphtheria toxin linked to human granulocyte-macrophage colony-stimulating factor (GM-CSF) (DTGM) for the treatment of patients with acute myeloid leukemia (AML), Our goal in this study was to determine the toxicity and pharmacokinetics of DTGM in cynomolgus monkeys (Macacca fascicularis), which possess cross-reactive GM-CSF receptors. Four groups of young adultmonkeys (6 males and 12 females) were treated with five daily bolus iv infusions of 1, 5, 7.5, and 10 mu g/kg DTGM. Monkeys (2 males and 2 females) treated at 1 mu g/kg/day showed no significant side effects. Monkeys (2 males and 2 females) treated at 5 mu g/kg/day showed Grade 1-2 thrombopenia (NCI common toxicity criteria) on day 9. In contrast, monkeys (6 females) treated at 7.5 mu g/kg/day developed Grade 3 neutropenia, Grade 1-2 thrombopenia, Grade 1-3 anemia, and Grade 1-3 hypoalbuminemia. The neutropenia developed by day 4 in the 7.5 mu g/kg/day monkeys and by day 3 or 5 in the 10 mu g/kg/day monkeys and resolved in both groups by day 9, but the thrombopenia,anemia, and hypoalbuminemia persisted until day 16. Monkeys (2 male and 2 female) treated with 10 mu g/kg/day showed Grade 4 neutropenia that resolved by day 8 and Grade 2-3 anemia, hypoalbuminemia, and thrombopenia. Three of the animals developed sepsis, DTGM plasma half-life was 30 min with a peak concentration of 0.1 mu g/mL or 2 nM (1000-fold higher than the IC50 in vitro for AML blasts). Immune responses were minimal in all animals tested at 14 and 28 days with anti-DTGM levels <1 mu g/mL. All four animals at 10 mu g/kg died or were euthanized, and necropsies were performed. Animals necropsied on days 4 and 6 showed marked apoptasis and hypoplasia in the marrow, which was completely resolved for animals necropsied on day 9. No injury to other organs, including kidney, heart, liver, central nervous system, orlung, was seen. The drug was selectively toxic to malignant or differentiated myeloid cells with little toxicity to myeloid progenitors or other organs. Minimal effects in nontarget tissues make DTGM a promising candidate chemotherapeutic agent. (C) 1999 Academic Press.

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Documento generato il 04/12/20 alle ore 03:34:21