TY - JOUR
TI - COMPARATIVE DOSIMETRY OF O-6-METHYLGUANINE IN HUMANS AND RODENTS TREATED
WITH PROCARBAZINE
AU - SOULIOTIS, VL
AU - VALAVANIS, C
AU - BOUSSIOTIS, VA
AU - PANGALIS, GA and
AU - KYRTOPOULOS, SA
JO - Journal of Carcinogenesis
PY - 1994
VL - 15
TODO - 8
SP - 1675-1680
PB - Oxford University Press
SN - 1477-3163
TODO - 10.1093/carcin/15.8.1675
TODO - null
TODO - The accumulation of O-6-methylguanine (O-6-meG) in the DNA of blood
leukocytes of 21 Hodgkin’s lymphoma patients (followed for up to 12
cycles of treatment) treated in the context of MOPP combination
chemotherapy with 150 mg procarbazine daily for 10 days was examined and
compared to that observed in rats treated with different doses of
procarbazine as a single agent once per day for 10 days. In humans, the
adduct accumulated in a dose-related fashion and appeared to approach a
steady-state after 7-8 days of treatment. Adduct levels on day 10 of the
treatment cycle averaged 0.25 +/- 0.09 (mean +/- SD) mu mol/ molG and,
for different individuals, covered a 3-fold range. Intra-individual
variability between different treatment cycles was much more limited
than inter-individual variability, the two parameters accounting for
8.9% and 84.5% respectively of adduct variance at a constant
cumulative dose. Comparison of the dose-response relationships for
humans and rats indicates that, under conditions of no depletion of
O-6-alkylguanine-DNA alkyltransferase (AGT), O-6-meG accumulates in
blood leukocyte DNA of humans at a rate which is only approximately
2-fold lower than in rats, implying that, to the extent to which O-6-meG
contributes to the genotoxic activity of procarbazine, human
susceptibility to it is likely to be comparable to that of the rat. This
is likely to be true also of the bone marrow (the tissue of interest as
a target tissue for leukaemogenesis), since the tissue distribution of
O-6-meG induced by low doses of procarbazine in rats, mice and rabbits
indicated that blood leukocyte levels of this adduct closely reflect
those in the bone marrow. Based on these results, it is estimated that
by the end of a MOPP chemotherapy cycle O-6-meG reaches levels of the
order of 0.2-0.3 fmol/mu g DNA (0.3-0.5 mu mol/molG) in human bone
marrow (the target tissue of leukaemogenesis observed after such
treatment).
ER -