pirarubicin and Leukemia-P388

The effect of the anti-tuberculosis drug rifampicin on pirarubicin activity was investigated in multidrug-resistant cells overexpressing P-glycoprotein. Rifampicin increased the sensitivity of pirarubicin to anthracycline-resistant mouse leukemic P388 cells and significantly enhanced the cytotoxicity and intracellular accumulation of pirarubicin in resistant cells, but had no effect in parent cells. By contrast, two other rifamycins, rifamycin B and SV, had no effect on pirarubicin accumulation in resistant cells. Rifampicin also enhanced pirarubicin-induced apoptosis and G2/M blockade on the cell cycle in resistant cells. These results show that rifampicin enhances the cytotoxic action of pirarubicin in resistant cells, at least partly via the inhibition of cellular pirarubicin efflux.

Topics: Animals; Antibiotics, Antineoplastic; Antibiotics, Antitubercular; Apoptosis; Cell Cycle; Doxorubicin; Drug Resistance, Multiple; Drug Synergism; Gene Expression Regulation, Neoplastic; Genes, MDR; Leukemia P388; Mice; Rifampin; Tetrazolium Salts; Thiazoles

In vivo antitumor activity of pirarubicin (THP) and epirubucin (EPI) in combination with doxifluridine (5'-DFUR) and cisplatin (CDDP) were examined using mouse P388 leukemia. THP (1.25-7.5 mg/kg) or EPI (1.25-15 mg/kg) was given intravenously on day 1, and then 5'-DFUR (125 or 250 mg/kg/day) and CDDP (4 mg/kg) were given orally on days 1-4 and intravenously on day 5 after tumor inoculation, respectively. Both THP and EPI enhanced the antitumor of a combination of 5'-DFUR and CDDP. The enhancement by THP was additive or synergistic, while that by EPI was additive. Cured animals were observed in the combination of THP with the two drugs, but not in that of EPI. Thus, in combination with 5'-DFUR and CDDP, THP was more effective against P388 leukemia than was EPI. The combination therapy using THP, 5'-DFUR and CDDP may be a novel chemotherapeutic approach to a variable type of tumors in clinical trials.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Doxorubicin; Drug Screening Assays, Antitumor; Epirubicin; Female; Floxuridine; Leukemia P388; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA

We have examined the therapeutic effects of combination therapy of pirarubicin ((2"R)-4'-O-tetrahydropyranyladriamycin, THP) with various antitumor agents against P388 murine leukemia. THP showed a high antitumor activity in combination with various antitumor drugs, especially with cyclophosphamide (CPM), cisplatin (CDDP), mitomycin C (MMC), enocitabine (BHAC), vindesine (VDS) or methotrexate (MTX). The effects of combination therapy depended on the order of administration of THP and combined drugs. THP-preceding treatment gave more synergistic effects in combination with 5-fluorouracil (5-FU) or MTX. THP-preceding or simultaneous treatment with etoposide (ETP) indicated the higher synergistic activity than ETP-preceding one. Moreover, THP showed much higher synergistic effects in any order of the combination with CPM, CDDP, MMC, BHAC, VDS or MTX. These results suggest that THP possesses a therapeutic usefulness clinically in combination with various antitumor drugs, if the selection of drugs combined with THP and the order of administration are suitable.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Screening Assays, Antitumor; Fluorouracil; Leukemia P388; Male; Mercaptopurine; Methotrexate; Mice; Mice, Inbred BALB C; Mitomycin; Peplomycin; Vindesine

The effect of sodium chloride on the cytotoxicity of 4'-O-tetrahydropyranyldoxorubicin (pirarubicin), a novel anthracycline derivative, was investigated on P388 mouse leukemia cells in vitro. The modifications in efficiency of uptake and killing action of pirarubicin were found to be dependent on the ionic strength of the medium. The relationship between intracellular drug accumulation into cells and cell killing was pointed out.

Topics: Animals; Doxorubicin; Leukemia P388; Mice; Sodium Chloride; Tumor Cells, Cultured

The activity of reserpine and a possible mechanism by which it reverses the resistance to both doxorubicin and pirarubicin in doxorubicin-resistant P388 leukemia (P388/DOX) cells were examined in vitro. During 48 hr drug-exposure, the sensitivity of doxorubicin and pirarubicin were potentiated markedly when reserpine was present at the concentration of 1 microgram/ml, which is not toxic to P388 leukemia (P388/S) cells. However, reserpine had little effect on the cytotoxicity of doxorubicin and pirarubicin in the sensitive parent cell. Reserpine at 0.5-20 micrograms/ml increased intracellular accumulation of doxorubicin and pirarubicin in the drug-resistant cells. The potentiating action of reserpine was stronger when the cells were preincubated with reserpine within 30 min. Efflux of doxorubicin and pirarubicin was greater in drug-resistant cells compared to sensitive cells. This enhanced efflux of drug resulted in a decrease in the intracellular accumulation of doxorubicin in the drug-resistant cells. When the resistant cells were exposed to 2 micrograms/ml of reserpine, this enhanced efflux was blocked. A similar effect of reserpine on doxorubicin was seen with the efflux pattern of pirarubicin. From the measurements of drug uptake and efflux, it seems that like other multiple drug resistance modifiers, reserpine modulates anthracycline resistance by increasing intracellular accumulation of drug.

Topics: Animals; Doxorubicin; Drug Resistance; Drug Screening Assays, Antitumor; Leukemia P388; Mice; Reserpine; Tumor Cells, Cultured

The activity of dipyridamole and its possible mechanisms which reverse the resistance of pirarubicin were studied in a P388 mouse leukemia cell lines. Dipyridamole alone was minimally cytotoxic in both of the doxorubicin-resistant cell line (P388/DOX) and the sensitive parent cell line (P388/S), but reversed pirarubicin-resistance in a dose-related manner in P388/DOX cells. A similar dose-response relationship was observed for dipyridamole by increasing net intracellular pirarubicin accumulation. The increase was a result of secondary blocking of enhanced pirarubicin efflux from P388/DOX cells. In contrast, dipyridamole did not affect cytotoxicity and transport in the drug-sensitive cell line. It is suggested that dipyridamole is a useful drug for modulation of the multidrug-resistance of cells.

Topics: Animals; Cell Survival; Dipyridamole; Doxorubicin; Drug Resistance; Drug Synergism; Leukemia P388; Tumor Cells, Cultured

Chlorpromazine enhanced the cytotoxicity of pirarubicin against doxorubicin-resistant P388 leukemia cells in colony forming assays. Chlorpromazine also prolonged the survival of mice bearing doxorubicin-resistant P388 leukemia, when given in combination with pirarubicin.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chlorpromazine; Doxorubicin; Drug Evaluation, Preclinical; Drug Synergism; Leukemia P388; Mice

The intracellular uptake, retention and cytotoxicity of pirarubicin, an anthracycline derivative, combined with chlorpromazine were investigated in doxorubicin-resistant mouse P388 leukemia (P388/DXR) cells. The number of viable cells was determined by the dye exclusion method. Chlorpromazine increased the cytotoxicity of pirarubicin in a dose-related manner in P388/DXR cells. A similar dose-response relationship was observed for chlorpromazine in increasing net intracellular pirarubicin accumulation. The accumulation was based on block of enhanced pirarubicin efflux from resistant cells by chlorpromazine. However, chlorpromazine did not affect cytotoxicity or transport of pirarubicin in the drug-sensitive cell line. The possible mechanisms of the restoration of pirarubicin sensitivity in P388/DXR cells by chlorpromazine are discussed.

Topics: Animals; Antineoplastic Agents; Chlorpromazine; Doxorubicin; Drug Resistance; Drug Synergism; Leukemia P388; Tumor Cells, Cultured

The preparation and antitumor effects of 3'-deamino-3'-morpholino derivatives of pirarubicin are described. Di-N-alkylation of pirarubicin with bis(2-iodoethyl)ether gave 3'-morpholino-pirarubicin, which was converted into its 13-tosylhydrazone, 13-deoxy derivative and 13-(S)- and 13-(R)-dihydro derivatives. Intraperitoneal administration to murine tumors indicated that the effective dose ranges of the compounds having sp3 carbon at C-13 position were broader than those of the compounds having sp2 carbon. By oral administration, 13-(S)-dihydro isomer was more effective than 13-(R)-dihydro isomer.

Topics: Administration, Oral; Animals; Chromatography, Thin Layer; Dose-Response Relationship, Drug; Doxorubicin; Female; Injections, Intraperitoneal; Leukemia L1210; Leukemia P388; Magnetic Resonance Spectroscopy; Mice; Molecular Structure; Morpholines; Tumor Cells, Cultured

The preparation and biological evaluation of N-salicylidene derivatives of pirarubicin are described. Pirarubicin was treated with various kinds of aryl aldehydes. Most of compounds synthesized here were more active than pirarubicin in vitro. Some of them showed significant prolongation of the survival period in experimental mice by oral administration. Interestingly, a derivative containing forphenicine exhibited the broadest dose-response range by intraperitoneal administration.

Topics: Animals; Antibiotics, Antineoplastic; Chemical Phenomena; Chemistry; Chromatography, Thin Layer; Dose-Response Relationship, Drug; Doxorubicin; Female; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Mice; Molecular Structure; Tumor Cells, Cultured

Cellular accumulation of daunorubicin (DNR), N-trifluoroacetyl-adriamycin-14-valerate, and THP-Adriamycin (THP-ADR) in doxorubicin sensitive and resistant murine leukemic P388 cells was studied with laser excited flow cytometry. Appearance of DNR fluorescence in P388/S cells was rapid in contrast to that of P388/R cells. A comparison of P388/S and P388/R cells incubated for 20-30 min showed that DNR fluorescence in P388/R cells was one-sixth that of P388/S cells. In contrast, the difference between fluorescence value of P388/S and P388/R cells similarly incubated with N-trifluoroacetyl-adriamycin-14-valerate or THP-ADR was less than 2-fold. Chlorpromazine, verapamil, and trifluoperazine increased the cellular accumulation and cytotoxicity of DNR and THP-ADR but had no major effect on N-trifluoroacetyl-adriamycin-14-valerate fluorescence or cytotoxicity in P388/R cells. Fluorometric and soft agar assays confirmed the data on the effect of these modulators on drug accumulation obtained by the more rapid method of laser flow cytometry.

Topics: Animals; Biological Transport; Cell Line; Chlorpromazine; Daunorubicin; Doxorubicin; Flow Cytometry; Fluorometry; Leukemia P388; Leukemia, Experimental; Mice; Monitoring, Physiologic; Trifluoperazine; Tumor Stem Cell Assay; Verapamil

(2''R)-4'-O-Tetrahydropyranyladriamycin (THP), a new anthracycline antibiotic, showed stronger inhibition of the growth of L1210, CCMT (mouse mammary adenocarcinoma) and Yoshida sarcoma in rats than did adriamycin (ADM). The antitumor activity of THP against P388 and Meth-A (mouse fibrosarcoma) was equal or slightly superior to that of ADM. Moreover, THP was active against an ADM-resistant subline of P388. THP at the optimal effective dose against experimental tumors had no toxic effect on the cellular immune system in normal and tumor-bearing mice.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Doxorubicin; Immunity, Cellular; Leukemia L1210; Leukemia P388; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred Strains; Neoplasms, Experimental; Sarcoma, Yoshida

Chemotherapy with 4'-O-tetrahydropyranyladriamycin (THP-ADM), a new derivative of Adriamycin, was equally or more effective against several experimental mouse tumors than it was with Adriamycin (ADM). When mice with P388 leukemia were given i.p. injections of THP-ADM or ADM daily for 9 consecutive days, the maximum increases in life span (ILSs) of the mice were 190 and 175%, respectively. Eight of 24 mice treated with THP-ADM were free of tumor, while one of 24 mice treated with ADM was free of tumor. A single i.p. injection of either drug was also effective; maximum ILS was 170% for mice treated with THP-ADM and 240% for those treated with ADM. Nine of 12 mice were found to be free of tumor. THP-ADM was equally or slightly more effective against P388 leukemia than was ADM when either drug was given i.v. The maximum ILS was 106% with THP-ADM and 77% with ADM when the drug was given for 9 consecutive days. Single i.v. injections of THP-ADM or ADM were almost equally (ILS, 100%) effective. Chemotherapy with THP-ADM was also very effective against L1210 leukemia. THP-ADM administered i.p. five times, every other day starting from Day 1, was more effective than ADM was against Lewis lung carcinoma, B16 melanoma, and colon adenocarcinoma 38 inoculated s.c. In the study with Lewis lung carcinoma, metastasis to the lungs was well suppressed by THP-ADM. ADM was more effective than was THP-ADM against colon adenocarcinoma 26. Because THP-ADM was more cytotoxic than or almost equally as cytotoxic as ADM against the established cell lines from the above mouse tumors, we suggest that THP-ADM is more efficiently transported into cultured cells.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cell Line; Colonic Neoplasms; Doxorubicin; Leukemia P388; Lung Neoplasms; Melanoma; Mice; Mice, Inbred Strains; Neoplasms, Experimental