Tetrandrine achieved plasma concentrations capable of reversing MDR in vitro and had no apparent effect on doxorubicin pharmacokinetics in mice.

PURPOSE: Tetrandrine (Tet), a multidrug resistant (MDR) modulator, was a potential candidate for use in cancer therapy and exhibited potent biological activity in vitro and in vivo when combined with anticancer agents such as doxorubicin, paclitaxel. Our aims were to determine whether serum concentration of Tet, which was capable of blocking P-gp in vitro, could be safely achieved in mice and whether Tet induced pharmacokinetic alterations in serum doxorubicin disposition in mice. METHODS: Tet of 30 mg/kg dose used to reverse MDR was administrated intraperitoneally in mice. Plasma Tet and serum doxorubicin concentration were analyzed by HPLC. CYP 3A4 activity was examined by HPLC with the substrate of nifedipine. RESULTS: More than 1 micromol/L of Tet could at least tenfold reverse MDR in vitro. The plasma peak concentration of Tet was about 2 micromol/L and not less than 1 micromol/L until 18 h following Tet administration (i.p.) at 30 mg/kg. These suggested that the concentrations of Tet that were sufficient to inhibit P-gp might be achieved in mice receiving 30 mg/kg of Tet. Importantly, no significant difference was demonstrated between the doxorubicin pharmacokinetic parameters obtained in mice received doxorubicin only and doxorubicin plus Tet. This implied that Tet of 30 mg/kg did not alter the profiles of pharmacokinetics of doxorubicin including the clearance and AUC of doxorubicin. Furthermore, Tet did not significantly affect on CYP 3A4 activity in human liver microsomes until more than 25 micromol/L. CONCLUSIONS: Tet at the tested dose of combination treatment could achieve plasma concentrations that reversed MDR in experimental models and it had no apparent effect on doxorubicin pharmacokinetics in mice and CYP 3A4 activity in human liver microsomes.

Experimental chemotherapy against xenografts derived from multidrug resistant KBv200 cells and parental drug-sensitive KB cells in nude mice by annonaceous acetogenin 89-2.

AIM: Annonaceous acetogenin 89-2 was obtained from atemoya plant. To investigate the effect of 89-2 on experimental chemotherapy against xenografts derived from multidrug resistant KBv200 cells and parental drug-sensitive KB cells. METHODS: Cytotoxicity was determined by tetrazolium (MTT) assay. The models of KB and KBv200 xenografts in nude mice were established to investigate the effect of 89-2 on experimental chemotherapy against cancer in vivo. Mechanistic experiments were conducted to examine the function of P-gp by Fura 2-AM assay. RESULTS: The compound 89-2 showed potent cytotoxicity in KBv200 and KB cells, and the mean IC50 of 89-2 to KBv200 and KB cells was 48.7 and 64.6 nmol.L-1, respectively. The IC50 of 89-2 to multidrug resistant (MDR) cells was similar to that to the parental drug-sensitive cells (P < 0.05). In the models of KBv200 and KB cell xenografts in nude mice, 89-2 (0.90 mg.kg-1, q2d x 6) exhibited 52.3% and 56.5% in inhibiting the growth of xenografts, respectively. The toxicity was endurable. The intracellular accumulation of Fura-2 in KBv200 cells increased to 1.66, 2.03, and 2.74-fold, respectively, by addition of 12.8, 64 and 320 nmol.L-1 of 89-2. CONCLUSION: Both MDR KBv200 cells and parental drug-sensitive KB cells were sensitive to the treatment of 89-2 in vitro and in vivo. The mechanism of overcoming MDR was associated with the decrease of P-gp function MDR cells.

[Experimental studies on treatment of nasopharyngeal carcinoma with combination regimen of hydroxycamptothecin and etoposide].

BACKGROUND & OBJECTIVE: Many studies showed that there is complementary effect between topoisomerase I inhibitor and topoisomerase II inhibitor. Combination of them showed synergistic action. This study was designed to investigate the experimental therapeutic effect of the combination of topoisomerase I inhibitor hydroxycamptothecin (HCPT) with topoisomerase II inhibitor etoposide (VP-16) on nasopharyngeal carcinoma (NPC), the effect of the combination of HCPT with VP-16 against NPC was studied in vitro and in vivo. METHODS: Cytotoxicity of HCPT alone, VP-16 alone, and combination of HCPT and VP-16 on NPC cell strain CNE2 were measured by MTT assay. The models of nude mice xenografts were established for investigating the effect of the combination regimen against NPC in vivo. RESULTS: HCPT alone and VP-16 alone have potent cytotoxicity to CNE2 cells. The IC(50) values were 13.5+/-1.2 micromol/L and 13.5+/-1.0 micromol/L, respectively. The combination of HCPT with VP-16 (1:1) showed synergistic cytotoxicity to CNE2 cells in vitro (CI< 1). In vivo experiment showed that HCPT alone (1.5 mg/kg, i.p., q2d) exhibited 13.6% inhibition growth rate;VP-16 alone (10 mg/kg, i.p., q2d) exhibited 27.3% inhibition growth rate; the combination regimen exhibited 50% inhibition growth rate. CONCLUSION: The combination of HCPT with VP-16 had significant synergistic effect against NPC in vitro and in vivo. These results suggested that the combination of HCPT with VP-16 is a promising regimen to treat NPC in clinic.