A. Gabr et al., CELLULAR PHARMACOKINETICS AND CYTOTOXICITY OF CAMPTOTHECIN AND TOPOTECAN AT NORMAL AND ACIDIC PH, Cancer research, 57(21), 1997, pp. 4811-4816
pH-mediated conversions in the structure of the topoisomerase (topo) I
inhibitors camptothecin (CPT) and its analogues have strong implicati
ons for the pharmacokinetics and pharmacodynamics of these novel antic
ancer agents, Because the cell-penetrating and biologically active lac
tone isomers predominate at acidic conditions, we have tested if low p
H potentiates the cytotoxic and antitumor effects of CPT and its water
-soluble derivative topotecan (TPT). In L1210 leukemia cells, rapid in
itial uptake of radiolabeled CPT and TPT was followed by a gradual rel
ease from cells at physiological pH 7.4, whereas high drug levels were
maintained in cells at pH 6.2. Steady-state uptake levels of CPT incr
eased proportionally, up to 5-fold, with decreasing pH of the incubati
ng medium (from 7.4 to 6.0). With TPT, a maximum 3-fold increase was o
bserved at pH 6.8 to 6.4. By contrast, the cellular pharmacokinetics o
f the topoisomerase II inhibitor etoposide (ETP) were independent of t
he ambient pH, The large increases in intracellular CPT and TPT levels
caused only moderate potentiation of cytotoxicity in short-term incub
ations, Conditions of very low pH less than or equal to 6.2 even antag
onized the cytotoxicity of the topo I and topo II inhibitors, due to i
nhibition of DNA synthesis by Intracellular acidification, However, in
clinically relevant schedules of prolonged exposures at low drug conc
entration, low pH potentiated the cytotoxicity of CPT and TPT by 2-3-f
old. To investigate the effect of local pH in vivo, the basal intersti
tial pH of 6.8 of RIF-1 tumors was selectively lowered by i.p. injecti
on of the host animals with the mitochondrial inhibitor meta-iodobenzy
lguanidine (32 mg/kg) and glucose (1.5 g/kg). In accordance with the p
H optimum for TPT uptake at pH 6.8 to 6.4, tumor acidification had no
effect on the antitumor effect of this analogue, By contrast, the inte
rvention significantly potentiated the response of tumors to CPT, The
results indicate that local pH is an important determinant of the cell
ular pharmacokinetics and the antitumor activity of CPT and analogues.