ABSTRACT
In clinical practice, glucocorticoids are often used with the aim of modulating the efficacy and toxicity of chemotherapeutic agents. However, how glucocorticoids modulate the pharmacological action of chemotherapeutic agents remains to be clarified. In this study, we generated glucocorticoid receptor (GR)-deficient rat-1 cells to investigate the role of GR in the regulation of cellular sensitivity to irinotecan hydrochloride (CPT-11). Treatment of wild-type rat-1 cells with dexamethasone (DEX) significantly enhanced the cytotoxic effect of CPT-11, whereas the treatment had little effect on the cytotoxicity of CPT-11 in GR-deficient cells. Topoisomerase-I activity in wild-type cells after concomitant treatment with DEX and CPT-11 was significantly lower than that after treatment with CPT-11 alone. DEX treatment also enhanced the inhibitory action of CPT-11 on the phosphatidylinositol 3-kinase-Akt signaling pathway in wild-type cells, accompanied by facilitating caspase-3 activity. These modulatory effects of DEX on the CPT-11-induced cytotoxicity were not observed in GR-deficient cells. Our present findings reveal the underlying mechanism by which GCs enhance the chemotherapeutic effect of CPT-11 and indicate the possibility that the dosage of CPT-11 could be reduced by the combination treatment with GCs, which may attenuate the adverse effect without decreasing anti-tumor activity.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Camptothecin/analogs & derivatives , Cell Survival/drug effects , Receptors, Glucocorticoid/physiology , Animals , Antineoplastic Agents, Phytogenic/pharmacokinetics , Camptothecin/pharmacokinetics , Camptothecin/pharmacology , Dexamethasone/pharmacology , Drug Synergism , Irinotecan , Phosphoinositide-3 Kinase Inhibitors , Rats , Receptors, Glucocorticoid/drug effects , Receptors, Glucocorticoid/genetics , Topoisomerase I Inhibitors , TransfectionABSTRACT
Influence of hydroxyurea (HU) on the antitumor effect of irinotecan hydrochloride (CPT-11) was investigated in ICR male mice transplanted with sarcoma 180 cells (S-180). A single dose of CPT-11 (100 mg/kg) was injected at various times after a single dose of HU (300 mg/kg). The relative tumor weight varied significantly depending on the timing of CPT-11 injection after HU injection (P < 0.01). The higher antitumor effect of CPT-11 was observed when DNA synthesis of S-180 cells increased (20 hr), and the lower effect was observed when the DNA synthesis decreased (0 hr). The loss of body weight also varied significantly depending on the timing of CPT-11 injection after HU injection (P < 0.01). The toxicity of CPT-11 was higher when the inhibitory effect of HU on DNA synthesis of bone marrow cells was stronger (15 hr), and the lower toxicity was observed when the inhibitory effect was not observed (0 hr). The plasma SN-38 concentration at 2 hr after CPT-11 injection was higher at 20 hr after HU injection than at 0 hr after HU injection. The difference in plasma esterase activity between 0 hr and 20 hr after HU injection was regarded as the mechanism underlying the dosing time-dependent difference of the SN-38 concentration. These experiments suggest that HU can produce a different phase of cell cycle between tumor cells and normal cells. This leads to increase the antitumor effect of CPT-11 without increasing the adverse effect of the drug. It is essential to consider the dosing time in the two-drug combination therapy.
