Cellular pharmacodynamics and plasma pharmacokinetics of parenterally infused hydroxyurea during a phase I clinical trial in chronic myelogenous leukemia.
OBJECTIVE
To determine the maximum-tolerated dose (MTD), toxicities, and antileukemic activity of hydroxyurea (HU) administered intravenously to patients with advanced-phase chronic myelogenous leukemia (CML). Further objectives were to analyze pharmacodynamic effect on deoxynucleotides (dNTPs) and to seek relationships between the decrease in dNTP pools and inhibition of DNA synthesis in CML blasts.


METHODS
HU (8, 12, 18, 27, and 40 g/m2) was administered intravenously by a 24-hour continuous infusion to 19 adults with CML in blastic or accelerated phase. Plasma levels of HU were analyzed in all patients. To determine the role of HU in inhibiting ribonucleotide reductase, dNTP pools in the leukemia cells were quantitated. Correlations were sought with these parameters and DNA synthesis inhibition measured ex vivo by [3H]thymidine incorporation.


RESULTS
The MTD of HU given as a 24-hour infusion was 27 g/m2. The dose-limiting toxicity was mucositis. There was a significant but transient myelosuppression, with nadir counts generally seen 3 to 4 days after the dose. The steady-state concentration of HU in plasma was achieved by 6 hours, and was proportional to the dose. There was a median 57% decrease in the deoxyadenosine triphosphate (dATP) pool in circulating blasts. In contrast, deoxyguanosine triphosphate (dGTP) and pyrimidine dNTPs were not significantly affected. The extent of DNA synthesis inhibition was related to the residual concentrations of intracellular dATP.


CONCLUSIONS
A 24-hour infusion of HU results in significant but transient myelosuppression in advanced-phase CML. The specific decrease of intracellular dATP correlated with the inhibition of DNA synthesis in CML blasts. This pharmacodynamic action of HU provides a rationale for combination with other chemotherapeutic agents, the effects of which could be augmented by the decline in dATP pools.
Gandhi
V
V
Department of Clinical Investigation, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. vgandhi@notes.mdacc.tmc.edu
Plunkett
W
W
Kantarjian
H
H
Talpaz
M
M
Robertson
L E
LE
O'Brien
S
S
D000255:Adenosine Triphosphate / Q000097:blood; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D008452:Maximum Allowable Concentration; D008875:Middle Aged
D000970:Antineoplastic Agents; D000255:Adenosine Triphosphate; D006918:Hydroxyurea