peplomycin and Carcinoma--Ehrlich-Tumor

We have been studying the resistance mechanisms of various antitumor drugs and screening substances from natural and synthetic products which overcome resistance. In this paper, we described compounds mainly obtained from our screening systems. I. Circumvention of multidrug resistance (MDR). Lactoquinomycin was discovered from the culture broth of a strain of Streptomyces sp. and it showed preferential growth inhibition against multidrug-resistant L5178 Y cells. The mechanism of action of lactoquinomycin was studied. Another novel antibiotic, resorthiomycin, exhibited not only preferential inhibition against MDR tumor cells but also augmentation of cytotoxicity of several antitumor drugs. As synthetic potentiators, dipyridamole, cepharanthine, AHC-52 and analogs of dihydropyridines were described; all of them were thought to interact with a P-glycoprotein and inhibit active efflux of drugs from tumor cells. SDB-ethylenediamine was unique because it overcame MDR and also potentiates a wide range of antitumor drugs including 5-FU and bleomycin. II. E-64 was found to inhibit the activity of a bleomycin-inactivating enzyme. It potentiated the activity of peplomycin in vitro and in vivo. III. Cadeguomycin was discovered from the culture filtrate of a Streptomyces sp. and it potentiated Ara-C by inhibition of the activity of dCMP deaminase, an Ara-C-inactivating enzyme.

Topics: Animals; Antineoplastic Agents; Bleomycin; Carcinoma, Ehrlich Tumor; Cytarabine; Drug Resistance; Drug Screening Assays, Antitumor; Drug Synergism; Leukemia, Experimental; Mice; Peplomycin

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

Topics: Animals; Bleomycin; Carcinoma, Ehrlich Tumor; Cell Survival; Cysteine Endopeptidases; Drug Synergism; Female; Glycoside Hydrolases; Leucine; Leupeptins; Mice; Oligopeptides; Peplomycin

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Ehrlich Tumor; Cisplatin; Combined Modality Therapy; Mice; Peplomycin

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Ehrlich Tumor; Cisplatin; Male; Mice; Mice, Inbred ICR; Peplomycin

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Ehrlich Tumor; Carcinoma, Squamous Cell; Cisplatin; Drug Synergism; Head and Neck Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Peplomycin

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Ehrlich Tumor; Cisplatin; Drug Synergism; Interphase; Mice; Mice, Inbred ICR; Peplomycin

The cytokinetic response of Ehrlich ascites tumor (EAT) cells in vivo upon chronic treatment at low dosage levels with cytarabine (1-beta-D-arabinofuranosylcytosine, ara-c) bleomycin (BLM) and peplomycin (PEP) was estimated. Bivariate DNA histograms allow the simultaneous evaluation of the cell cycle status of living and killed cells. It could be confirmed that ara-C is cytostatic on cells in S phase. Pronounced cytotoxicity was observed in G1 and G2+M phase. BLM and PEP showed no (or neglectable ) accumulation of vital cells in any cycle phase. Both drugs, however, are cytotoxic on cells, regardless their position within the cell cycle. A successive application of ara-C and BLM (or PEP) in a cell kinetics-directed therapy schedule may be taken into account.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Ehrlich Tumor; Cell Survival; Cytarabine; Female; Mice; Peplomycin; Time Factors

Topics: Animals; Bleomycin; Carcinoma, Ehrlich Tumor; Combined Modality Therapy; Male; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Neoplasms, Experimental; Peplomycin

The effect of peplomycin by three different treatment schedules was studied in mice bearing Ehrlich Effeit of carcinoma. continuous i.p. infusion of peplomycin via an osmotic minipump was compared to those by intermittent injection and daily injection. Equivalent total doses of the drug were administered in all three schedules. Continuous infusion for 7 days produced marked inhibition of tumor growth, which was significantly better than intermittent injection or daily injection of the same total dose. The effect of bleomycin by continuous infusion was significantly better than that by intermittent injection, but was as equally effective was daily injection. The results indicate that the continuous infusion of peplomycin is a useful treatment method.

Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; Body Weight; Carcinoma, Ehrlich Tumor; Mice; Mice, Inbred ICR; Peplomycin