peplomycin and Leukemia-P388

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 uptake of [3H]peplomycin-Cu(II) ([3H]PEP-Cu(II)) into various tumor cell lines was studied. The time course of [3H]PEP-Cu(II) uptake into AH66, AH66F, Ehrlich and P388 cells was biphasic. The first phase of uptake was completed within 5 minutes. The second, slower phase, of uptake into AH66, AH66F and Ehrlich cells increased linearly with incubation time, but that into P388 cells reached a plateau level. In L1210 cells, only the first rapid uptake was observed. The lower uptake into P388 and L1210 cells during the second phase may be related to their insensitivity to PEP. However, the uptake into AH66F cells was higher than that into AH66 cells, although AH66F cells were less sensitive to PEP than AH66 cells. Deamide PEP was detected in intact cells which had taken up [3H]PEP-Cu(II) during 4 hours. This confirmed that PEP-Cu(II) was transported into the cell, the copper removed and PEP metabolized to deamide PEP. [3H]PEP-Cu(II) uptake into AH66 and AH66F cells increased in proportion to the extracellular concentration of drug up to at least 200 micrograms/ml, suggesting that uptake was not mediated by a carrier system. Metabolic inhibitors such as NaN3 and 2,4-dinitrophenol enhanced [3H]PEP-Cu(II) uptake, but did not influence efflux. Uptake was also enhanced by membrane modifiers such as dibucaine and chlorpromazine which increase the fluidity of lipid membranes. The results suggest that PEP-Cu(II) was taken up into tumor cells by passive diffusion, controlled by an energy-dependent cell membrane barrier.

Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; Carcinoma, Ehrlich Tumor; Chlorpromazine; Chromatography, High Pressure Liquid; Colchicine; Dibucaine; Dose-Response Relationship, Drug; Leukemia L1210; Leukemia P388; Liver Neoplasms, Experimental; Peplomycin; Permeability; Time Factors; Tumor Cells, Cultured; Vinblastine

The in vitro cytotoxicity of etoposide against mouse P388 leukemia cells was kinetically studied and compared with those of podophyllotoxin, the parent compound, and other antitumor agents. When P388 cells were exposed to etoposide, surviving-cell fraction decreased with etoposide concentration and exposure time. Similar results were obtained with doxorubicin, peplomycin and cisplatin. The cytotoxicity of melphalan was dependent on concentration but scarcely on exposure time. From these data, n in Cn X T = K where T, C and K are exposure time, concentration required for killing 90% of P388 cells and a constant, respectively, was calculated. Etoposide gave an n value of 1.16. n values for doxorubicin, peplomycin and cisplatin, all belonging to the Shimoyama type Ib group where the cytotoxicity of the agent depends on both concentration and exposure time, were 1.29, 1.28 and 3.03, respectively. The n value for melphalan, belonging to the type Ia group where cytotoxicity depends only on concentration, was 54.0. From these results, it was concluded that etoposide is of type Ib. The cytotoxicities of podophyllotoxin, 5-fluorouracil, cytarabine and vinblastine were greatly dependent on exposure time. Podophyllotoxin may be an agent of type II whose cytotoxicity depends only on exposure time.

Topics: Animals; Bleomycin; Cell Cycle; Cell Survival; Cisplatin; Colony-Forming Units Assay; Cytarabine; Doxorubicin; Etoposide; Fluorouracil; Leukemia P388; Leukemia, Experimental; Melphalan; Mice; Peplomycin; Podophyllotoxin; Tumor Stem Cell Assay; Vinblastine