TY - JOUR
T1 - Pharmacologically Directed Design of the Dose Rate and Schedule of 2′,2′-Difluorodeoxycytidine (Gemcitabine) Administration in Leukemia
AU - Grunewald, Ralf
AU - Kantarjian, Hagop
AU - Keating, Michael J.
AU - Abbruzzese, James
AU - Tarassoff, Peter
AU - Plunkett, William
PY - 1990/11/15
Y1 - 1990/11/15
N2 - The objective of this study was to determine the dose rate of 2′,2′-difluorodeoxycytidine (dFdC) that maximizes the accumulation of the active 5′-triphosphate (dFdCTP) in circulating leukemia cells during therapy. The investigational approach was to evaluate the relationship between plasma dFdC and the accumulation of dFdCTP by circulating leukemia cells during infusion of different dFdC dose rates in the same individuals. Four patients with relapsed leukemia were treated weekly with two or three consecutive infusions of 800 mg/m2, the first administered over 1 h, the second over 2 h, and the third over 3 h. Two patients, one with acute myelogenous leukemia and one with acute lymphocytic leukemia, received all three infusions, but thrombocytopenia prohibited infusion of the third dose to two patients with chronic lymphocytic leukemia. The average steady-state plasma dFdC levels, achieved within 15 min after the infusion began, were 43.8 pM during infusion of 800 mg/m2/h, 9.4 [M during infusion of 400 mg/m2/h, and 5.6 [M at 267 mg/ m2/h. The median area under the concentration times time curve of dFdCTP in leukemia cells during infusion was increased 23- and 5.1-fold for the 2- and 3-h infusions, respectively. In vitro incubations of leukemia cells from the four patients with 2.5–100 [M dFdC for 1 h showed that the maximum cellular accumulation of dFdCTP was produced by 15–20 [M dFdC. We conclude that a dose rate of >400 mg/m2/ h was required to achieve plasma dFdC levels that supported the maximum rate of dFdCTP accumulation in leukemia cells.
AB - The objective of this study was to determine the dose rate of 2′,2′-difluorodeoxycytidine (dFdC) that maximizes the accumulation of the active 5′-triphosphate (dFdCTP) in circulating leukemia cells during therapy. The investigational approach was to evaluate the relationship between plasma dFdC and the accumulation of dFdCTP by circulating leukemia cells during infusion of different dFdC dose rates in the same individuals. Four patients with relapsed leukemia were treated weekly with two or three consecutive infusions of 800 mg/m2, the first administered over 1 h, the second over 2 h, and the third over 3 h. Two patients, one with acute myelogenous leukemia and one with acute lymphocytic leukemia, received all three infusions, but thrombocytopenia prohibited infusion of the third dose to two patients with chronic lymphocytic leukemia. The average steady-state plasma dFdC levels, achieved within 15 min after the infusion began, were 43.8 pM during infusion of 800 mg/m2/h, 9.4 [M during infusion of 400 mg/m2/h, and 5.6 [M at 267 mg/ m2/h. The median area under the concentration times time curve of dFdCTP in leukemia cells during infusion was increased 23- and 5.1-fold for the 2- and 3-h infusions, respectively. In vitro incubations of leukemia cells from the four patients with 2.5–100 [M dFdC for 1 h showed that the maximum cellular accumulation of dFdCTP was produced by 15–20 [M dFdC. We conclude that a dose rate of >400 mg/m2/ h was required to achieve plasma dFdC levels that supported the maximum rate of dFdCTP accumulation in leukemia cells.
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M3 - Article
C2 - 2208147
AN - SCOPUS:0025089191
SN - 0008-5472
VL - 50
SP - 6823
EP - 6826
JO - Cancer Research
JF - Cancer Research
IS - 21
ER -