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PubMed1976

Intracellular distribution of (14C)bleomycin and the cytokinetic effects of bleomycin in the mouse tumor.

The differential effects (BLM) on cycling and noncycling cells were investigated with a mouse ascites tumor in vivo. An i.p. injection of 37.0 or 111.1 mug BLM per g caused a decrease in tumor cell number but an increase in percentage of tumor cells in mitosis. There are no significant differences between the percentage labeled mitoses at various times after pulse labeling by tritiated thymidine of BLM-treated tumor cells and by that of an untreated control, except that the height of the second peak was significantly lower in the treated cells. Hence BLM may be cell cycle nonspecific, and the BLM-induced decrease in cell number, i.p., may stimulate some nondividing cells to reenter the division cycle. However, the fact that percentage of cells in mitosis versus time after the administration of BLM showed two peaks indicates the possibility that another cause of the increase in mitotic figures might be a relative increase of cycling cells due to higher sensitivity of noncycling cells to the agent. Autoradiographic studies on the intracellular distribution of [14C]BLM revealed the following. (a) There were few necrotic cells in mitosis that incorporated much [14C]BLM into the cytoplasm at each time point and the mitotic figures gradually increased with time after i.p. injection of the isotope, while necrotic cells other than in mitosis, most of which were heavily labeled, increased in number with time. These findings seem to be related to the possibility that cycling cells may be less sensitive to BLM. The mode of intracellular distribution of [14C]BLM in mitotic cells changed with time and appeared to reflect the drug susceptibility depending on the cell cycle phase when labeled.

Animals↗
PubMed1977

Inhibition of bleomycin-induced [3H] thymidine 5'-triphosphate incorporation into liver and hepatoma nuclei by N-ethyl maleimide and daunomycin.

The addition of bleomycin to a nuclear incorporating system results in an increased incorporation of 3H-thymidine 5'-triphosphate (3H-TTP) into the DNA of liver and hepatoma nuclei. Bleomycin added to the nuclear incorporating system also produces scissions of DNA as determined by sucrose density gradient centrifugation of the extracted DNA. The action of bleomycin is dependent on the presence of sulfhydryl agents in the incubation mixture. Two compounds, N-ethyl maleimide and daunomycin, inhibit the bleomycin-induced incorporation of 3H-TTP preferentially. N-Ethyl maleimide inhibits bleomycin-induced activity in liver and hepatoma 7777 nuclei equally. Lower levels of daunomycin inhibit the bleomycin-induced activity in the hepatoma 7777 nuclei than are required to inhibit the activity in liver nuclei. The two compounds inhibit the bleomycin effect by different mechanisms. The addition of N-ethyl maleimide to bleomycin in the incubation system prevents bleomycin from causing breaks in the DNA. The addition of daunomycin, despite inhibition of bleomycin-induced 3H-TTP incorporation, does not affect the bleomycin-produced breaks in the DNA. N-Ethyl maleimide acts by binding to the DNA and by competing with a sulfhydryl agent for bleomycin-sensitive sites on the DNA. Daunomycin apparently inhibits a repair enzyme that is responsible for the increased incorporation following bleomycin treatment.

Animals↗
PubMed1977

Radioimmunoassay of bleomycin in plasma and urine.

Antibodies to bleomycin were raised by immunization of sheep and rabbits with bleomycin-albumin conjugates. The combination of a high-titre, high-avidity sheep antiserum and iodinated bleomycin produced a radioimmunoassay sensitive to 8 ng of bleomycin per ml of plasma or urine. Untreated specimens (100 microliter) of plasma or urine could be added directly to the assay tubes. The antiseerum was specific for bleomycin and showed no cross-reaction with other anticancer agents used in combination chemotherapy. Over a concentration range of 20-100 ng/ml, recovery of bleomycin from plasma was 110% and from urine, 93%. Repeated assay of plasma samples showed a decrease in bleomycin levels unless the samples were kept at 4 degrees C or below. Assay of bleomycin levels in plasma and urine from patients under treatment with bleomycin showed similarities with results reported using a microbiological assay. The radioimmunoassay offers a more reliable, rapid and sensitive method for the measurement of bleomycin.

Animals↗
PubMed1976

Molecular interactions of the combined effects of bleomycin and x-rays on mammalian cell survival.

The interactions between bleomycin and X-ray damage and repair have been examined in rat and human tumor cells. Bleomycin itself indices extensive DNA single-strand breaks but does not appear to inhibit the repair of X-ray-induced DNA single-strand breaks. Quantitative analysis of these interactions is complicated by the retention of active bleomycin within cells that remains capable of further DNA degradation even under the conditions of alkaline sucrose gradient cell lysis. DNA double-strand breaks and/or disruptions of DNA-lipid complexes also occur following bleomycin exposure. X-ray-induced excision repair replication is only minimally influenced by even high concentrations of bleomycin. A small amount of excision repair is demonstrable in nonirradiated cells treated with high concentrations of bleomycin consistent with repair of bleomycin-induced nucleotide damage in cellular DNA by a "cut and patch" repair mechanism. Repair of bleomycin-induced DNA single-strand breaks also occurs. The data indicate that bleomycin and X-ray damage are quite similar both in their induction and repair, but that lesions occur and are repaired independently. The enzymatic mechanisms appear similar in the two cell types despite substantial differences in their sensitivity to bleomycin.

Animals↗
PubMed1976

Effect of bleomycin on [3H]Thymidine 5'-Triphosphate incorporation into host liver and hepatoma nuclei.

The effect of bleomycin on [3H]thymidine 5'-triphosphate ([3H]TTP) incorporation into isolated sucrose nuclei from host liver and Morris hepatomas has been compared. Bleomycin stimulates [3H]TTP incorporation 13-fold in host liver and hepatoma 16 nuclei, 8-fold in hepatoma 7800 nuclei, and 3-fold in hepatoma 7777 nuclei. Differences in the nuclear membranes are not responsible for the different response of the nuclei. Nuclei, denuded of their membranes by Triton X-100 treatment, give similar results to sucrose nuclei. Analysis of DNA extracted from liver or hepatoma nuclei incubated with bleomycin indicates that bleomycin produces scissions in the nuclear DNA and that some repair synthesis takes place. Incubation of nuclei with 111indium-labeled bleomycin shows an equal binding capacity of liver and hepatoma nuclei for bleomycin. Bleomycin also stimulates incorporation of [3H]TTP in a system using chromatin or calf thymus DNA as primer. Host liver or hepatoma chromatin incubated with a DNA polymerase extracted from normal rat liver nuclei is stimulated approximately to the same extent by bleomycin. When DNA polymerase extracts from host liver and hepatoma nuclei are assayed with calf thymus DNA as primer, bleomycin has a greater stimulatory effect on [3H]TTP incorporation with host liver DNA polymerase than with hepatoma DNA polymerase in the system. We suggest that a defect in the repair system in hepatoma nuclei is responsible for the relatively lower response to bleomycin.

Animals↗
PubMed1976

Radioimmunoassay of bleomycin.

A radioimmunoassay for bleomycin has been produced using 125l-labeled bleomycin and antisera raised in rabbits against a carbodiimide-catalyzed bleomycin-bovine serum albumin conjugate. 125l-Labeled bleomycin was synthesized by direct iodination of the drug using the chloramine-T technique. The standard curve of the assay was linear on a logit-log plot and the lower limit of sensitivity was 250 pg bleomycin sulfate. A mean recovery of 102.6% (+/- 3.3% S.E.) was obtained using bleomycin added to normal sera. No significant decrease in bleomycin immunoreactivity was observed following 24 hr incubation of the drug in serum at 37 degrees. The radioimmunoassay was also suitable for measuring bleomycin in the presence of other drugs since the assay was not significantly affected by the other antineoplastic agents tested. The sensitivity and specificity of the radioimmunoassay for bleomycin should provide a new means for pharmacokinetic and toxicity studies of bleomycin.

Animals↗
PubMed1976

Structure and action of bleomycin.

The structures of bleomycins and of other bleomycin-phleomycin group of antibiotics were described. The activity of bleomycins and their derivatives in causing strand scission of SV40 viral DNA suggests that the beta-aminoalanine amide moiety and the carbamoyl group are involved in this reaction. More than one guanido group in the terminal amine of bleomycin-phleomycin group antibiotics caused irreversible renal toxicity in dogs. Pulmonary toxicity varied depending on the terminal amines. A bleomycin-inactivating enzyme which distributes widely in animal cells was shown to be a new aminopeptidase B which hydrolyzes beta-aminoalanine amide group. At least one of the reasons for activity against squamous cell carcinoma was shown to be due to the lower content of this enzyme. The inhibitor of this enzyme was synergistic to bleomycin in inhibiting growth of cells, thus suggesting the intracellular action of this enzyme. Selected for further study from the bleomycins containing various terminal amines, bleomycin 5033 which showed the same activity against squamous cell carcinoma in mouse skin as the bleomycin used at present and lower toxicity than the latter, and bleomycin A5196 which showed stronger activity and stronger toxicity but lower lung toxicity than the latter.

Aminopeptidases↗
PubMed1977

Comparison of radiolabeled bleomycins and gallium citrate in tumor-bearing mice.

Radioiodinated bleomycin is a chemically stable radiopharmaceutical that can be prepared with high specific activity using 123I. Its pharmacokinetics were compared with those of 99mTc,- 111In-, and 57Co-bleomycin, and 67Ga citrate in mice bearing a transplanted KHJJ tumor. The in vivo kinetics and stability of 123I- and 57Co-bleomycin were similar: both were acceptable, although not equivalent, tags for bleomycin and, along with 67Ga citrate, both had biologic properties suitable for tumor detection. Both 99mTc- and 111In-bleomycin dissociated rapidly in vivo and hence do not represent legitimate tags for bleomycin. However, 111In-bleomycin may have tumor-localizing properties related to its biochemical properties after the indium and chelate separate in vivo. Iodine-123 is superior to either 57Co or 55Co. Tumor-to-blood and tumor-to-liver ratios were higher for I-bleomycin than for 67Ga or Co-bleomycin. The nearly ideal nuclear properties of 123I should complement the biologic properties of bleomycin and lead to a useful tumor radiodiagnostic agent.

Adenocarcinoma↗