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PubMed1975

Kinetics of 111In-bleomycin and 111 In-chlorides in mice.

Indium-111 as the chloride and chelated to bleomycin has been reported useful as a tumor-scanning agent. This report of the kinetics of these compounds compared in Yale-Swiss mice bearing a transplantable, in situ brain sarcoma. Indium-111-chloride, pH 1.5, gave a maximum tumor uptake of 18.5% dose per gram tumor, a maximum tumor-to-brain ratio of 17.0, and a maximum tumor-to-blood ratio of 4.4. Its renal blood clearance was a slow 0.0022 ml/min. Indium-111-bleomycin showed a maximum tumor uptake of 3.0% dose per gram tumor, a maximum tumor-to-brain ratio of 13.5, a maximum tumor-to-blood ratio of 6.8, and renal blood clearance of 0.254 ml/min. The labeling of bleomycin with 111In results in a tracer with localizing properties in this tumor model which are quite different from those obtained with 111In as chloride or that labeled to bleomycin would appear to have significant potential as agents for imaging tumors.

Animals↗
PubMed1975

[Urocytogram in the treatment with bleomycin].

Even though Bleomycin is excreted in the urine in high concentrations, side effects in the urinary tract due to the chemical nature of this compound are seldom observed. With respect to treatment of gynecological carcinomas, it is, therefore, important to examine the effect that Bleomycin when treatment involves the use of Endoxan. Cytologically, one finds an increase in desquanmation of the transitional epithelium and an increase in degenerate cell forms. The homogenous eosinophilic cellular inclusions which are observed, are specific for neither Endoxan nor for Bleomycin treatment. The antibiotic effect of Bleomycin results in an aseptic cystitis. The urocytogramm is suitable for examining the epithelial changes of the urinary tract in context with the gynecological carcinoma treatment and also for determing tumor breakthough into the bladder.

Bleomycin↗
PubMed1976

Large-dose bleomycin therapy and pulmonary toxicity. A possible role of prior radiotherapy.

Bleomycin sulfate pulmonary toxicity was encountered in nine of 101 patients receiving high-dose therapy for widespread testicular cancer. The pulmonary presentation was separable into two categories: (1) an early or minimal from with dyspnea on exertion, minimal roentgenographic findings, and normal arterial partial pressure of oxygen at rest and (2) a severe form, with prominent roentgenographic findings and hypoxemia at rest. All five patients with the severe form died, while the remaining four patients with the minimal presentation recovered. Prior thoracic radiotherapy appeared to predispose to bleomycin pulmonary toxicity, as this complication developed in five of 12 patients receiving prior chest radiotherapy vs four of 89 not receiving radiotherapy (p less than .001). The fatality rate of 5% with high-dose bleomycin therapy is acceptable in view of the 75% response rate and substantially improved survival achieved with bleomycin combination chemotherapy in metastatic testicular cancer.

Adolescent↗
PubMed1976

Effects of bleomycin on human tongue carcinoma cells as revealed by electron microscopy.

Five patients with tongue carcinoma were treated for 20 days with bleomycin, 15 mg/day, given by one-shot infusion through the superficial temporal artery. Specimens were taken 7, 14, and 20 days after the initial administration for light and electron microscope observations. The first alterations observed were the decrease of electron-dense chromatin clumps in nuclei and, simultaneously, the segregation of nucleolar components, i.e., amorphous protein component segregated from fibrillar and granular components. Subsequently, numerous nuclear bodies appeared in the nucleoplasm, which were observed for the first time in human tongue carcinoma cell nuclei in cases of bleomycin treatment. On the other hand, the cytoplasmic alterations were recognized by the decrease in number of mitochondria and by the appearance of numerous free ribosomes followed by the formation of tonofilaments. The cells enlarged because tonofilaments flocked together to make cancer cell nests, which were gradually together to make cancer cell nests, which were gradually transformed into a keratinic structure showing the so-called cancer pearl pattern. Finally, cancer cells were degenerated nearly to necrosis; there was no evidence of recurrence of cancer. Although the precise mechanism of the effect of bleomycin on nuclear activities of human tongue cancer cells remains unsettled because of the lack of cytochemical analysis, it is believed that bleomycin inhibits DNA synthesis and might also activate ribosomal RNA synthesis.

Bleomycin↗
PubMedDate not supplied

Sequential combination chemotherapy with vinblastine-bleomycin and doxorubicin-cis-dichlorodiammineplatinum(II) in disseminated nonseminomatous testicular cancer.

Forty-two patients with disseminated nonseminomatous testicular cancer were randomly entered to receive a two-armed chemotherapy regimen with mandatory crossover, consisting of either vinblastine-bleomycin or doxorubicin-cis-dichlorodiammineplatinum(II) (DDP) as initial therapy. Forty of these patients received at least four courses and were considered evaluable. Twenty-five of these patients received vinblastine-bleomycin and 15 received doxorubicin-DDP as initial treatment. The overall remission rate was 88%, with a complete remission rate of 68%. Thirty-two patients remain alive and 20 (50%) remain disease-free at 3+ to 18+ months, with a median duration of complete remissions of 9+ months. The response rate was not affected by prior chemotherapy or radiotherapy. Either treatment arm proved equally effective. However, response with doxorubicin-DDP therapy occurred in nine of 19 treatment courses when vinblastine-bleomycin therapy had failed, while response with vinblastine-bleomycin therapy occurred in only two of 11 treatment courses when doxorubicin-DDP therapy had failed. Thus, different patterns of cross-resistance between these alternative regimens may exist.

Adolescent↗
PubMedDate not supplied

Bleomycin alone or combined with mitomycin C in treatment of advanced or recurrent squamous cell carcinoma of the vulva.

Twenty patients with advanced and/or recurrent vulvar carcinoma were treated with bleomycin alone or combined with mitomycin C. Five of 11 patients in the bleomycin-treated group showed objective response (two complete and three partial) and five of nine patients in the bleomycin-mitomycin C-treated group showed objective response (one complete and four partial). No severe side effects were seen. Now that activity against this disease has been demonstrated for bleomycin, alone or combined with mitomycin C, attention should be directed to treating those patients not cured by surgery and radiation therapy alone.

Adult↗
PubMedDate not supplied

Bleomycin-induced scleroderma.

Two men are reported who developed cutaneous fibrosis indistinguishable from that encountered in progressive systemic sclerosis (PSS, scleroderma) after treatment with the antitumor agent, bleomycin. In vitro study of the dermal fibroblasts of 1 patient showed that these cells synthesized increased quantities of collagen and therefore resembled cells derived from individuals with naturally occurring PSS. Bleomycin was shown to stimulate collagen production by cultured normal skin fibroblasts. Also, in 1 of the patients, bleomycin stimulated a lymphoproliferative response in vitro. These effects of bleomycin may be responsible for certain toxic reactions to this drug in the skin and lung.

Adult↗
PubMedDate not supplied

Fatal pulmonary bleomycin toxicity in cisplatin-induced acute renal failure.

A 53-year-old male being treated for a metastatic squamous cell carcinoma had fatal pulmonary toxicity as a result of bleomycin therapy. The toxic reaction was observed when the conventional dose regimen of bleomycin was given to the patient who had unrecognized cisplatin-induced acute renal failure. Bleomycin dosage should be reduced in patients with established acute renal failure and the combination of cisplatin and bleomycin should be carefully followed.

Acute Kidney Injury↗
PubMed1980

Studies on the effect of bleomycin on Trypanosoma gambiense.

The antibiotic bleomycin inhibits nuclear duplication and causes deformation of the nucleus without any effect on the kinetoplast of Trypanosoma gambiense. Consequently it induces the anucleate form, not the dyskinetoplastic form. Studies showed that in many respects the effect of bleomycin on trypanosomes was very similar to that of neocarzinostatin. Analysis of DNA by CsCl density gradient centrifugation indicated that bleomycin inhibits DNA synthesis in the nucleus but not that in the kinetoplast. Bleomycin also induced excess formation of pellicular microtubules and disorderly arrangement of the axonemal and pellicular microtubules.

Animals↗
PubMed1980

[Repair of bleomycin-induced damage to Escherichia coli DNA. II. Participation of inducible processes].

The role of inducible cell functions in repair and mutagenesis after bleomycin-induced DNA damages was studied in Escherichia coli. Influence on these processes of some rec genes as well as sbcB, the structural gene for exonuclease I, was investigated. The data obtained suggest that this enzyme plays a negative role in the repair of DNA damaged by bleomycin. The hypersensitivity of recA mutant to bleomycin and recAlexA-dependence of bleomycin-induced mutagenesis do not suggest any principal differences between UV-induced pyrimidine dimers and apyrimidinic sites in the case of post-replication repair.

Bacterial Proteins↗
PubMed1980

Evaluation of antifibrotic drugs in bleomycin-induced pulmonary fibrosis in hamsters.

Endotracheal administration of bleomycin to hamsters causes severe pulmonary fibrosis. We have examined the utility of this response as a model for the screening of pulmonary antifibrotic agents. The time course of collagen synthesis after bleomycin administration was examined in neutral salt soluble and insoluble fractions by in vitro incubation of minced lung with [14C] proline. Collagen synthesis increased to approximately 250% above control in both neutral salt soluble and insoluble collagen fractions by day 6 after bleomycin. Noncollagenous protein synthesis was also increased but to a lesser amount. The early rise in collagen synthesis leads to accumulation of collagen that can be biochemically quantitated within 1 week. This time course is advantageous for short-term testing of antifibrotic agents. In the present study, beta-aminopropionitrile, D-penicillamine, and p-aminobenzoic acid were examined. All three agents were found to reduce significantly the accumulation of neutral salt insoluble collagen in bleomycin-treated animals.

4-Aminobenzoic Acid↗
PubMed1981

Preferential damage of active chromatin by bleomycin.

Preferential sensitivity of specific genes in chromatin to the action of bleomycin in different cell types was investigated using restriction enzyme digestion of DNA from drug-treated nuclei in combination with the Southern blotting procedure. The results show that the highly active ovalbumin gene in laying hen oviduct nuclei is more sensitive than the inactive globin gene to the digestion by bleomycin. Conversely, in red blood cells, bleomycin preferentially destroys the globin gene but not the ovalbumin gene. Therefore, bleomycin, like nucleases, can preferentially destroy DNA sequences in chromatin with open configuration, although the mode of action of this drug on DNA is drastically different from those of known nucleases.

Animals↗
PubMed1980

Therapeutic effect of bleomycin on experimental infection of mice with Trypanosoma gambiense and Trypanosoma evansi.

Intraperitoneal injection of 10 mg/Kg bleomycin into mice 24 h after inoculation with Trypanosoma gambiense or Trypanosoma evansi, reduced the incidence of infection 62.1%, and 95.2%, respectively. No parasitemia was not found in these mice. Treatment of mice with parasitemia with 30 mg/Kg of bleomycin decreased the number of parasites within about 5 h and caused complete cure without relapse in 45% and 75% of mice infected with T. gambiense and T. evansi, respectively. Treatment of mice infected with T. gambiense with bleomycin in combination with ethidium bromide was highly effective and resulted in a high incidence of complete cure, even in heavily infected mice. The mode of action of bleomycin and ethidium bromide on trypanosomes in relation to p-rosaniline resistance is discussed.

Animals↗
PubMed1981

Ethanol-induced cell sensitization to bleomycin cytotoxicity and the inhibition of recovery from potentially lethal damage.

The cytotoxic effect of bleomycin toward mouse mammary carcinoma FM3A cells in culture was markedly potentiated by exposure of the cells to ethanol either before or after treatment with bleomycin. Ethanol-induced cell sensitization to bleomycin cytotoxicity produced a decrease in cell survival which became dependent on dose and time of drug treatment. The sensitizing effect of ethanol after drug treatment was maximum when ethanol exposure immediately followed drug treatment, and it rapidly decreased as the time interval between the two treatments was increased. Ethanol did not sensitize cells to the cytotoxic effects of cis-diamminedichloroplatinum(II) and macromomycin. These results are discussed in terms of the ability of ethanol to inhibit cell recovery from potentially lethal damage after bleomycin treatment.

Animals↗
PubMed1981

Synergistic enhancement of bleomycin cytotoxicity toward tumor cells in culture by a combination of ethanol and moderate hyperthermia.

Bleomycin cytotoxicity toward mouse mammary carcinoma FM3A cells and human carcinoma HeLa S3 cells in culture was greatly potentiated by exposing the cells to a combination of a low concentration of ethanol and moderate hyperthermia. For example, the exposure of FM3A cells to a combination of 4.3% ethanol and 39 degrees, 2.4% ethanol and 41 degrees or 1.5% ethanol and 42 degrees induced a marked sensitization which was almost equivalent to that induced by exposure to 6% ethanol at 37 degrees and was greater than that induced by exposure to 43 degrees hyperthermia alone. However, when the cells were exposed to 3% ethanol at 37 degrees and then treated with bleomycin at 41 degrees, sensitization was hardly induced, indicating a requirement for simultaneous exposure to ethanol and hyperthermia to produce a synergistic increase in bleomycin cytoxicity. A possible application of these findings to cancer treatment with bleomycin is discussed.

Animals↗
PubMed1982

Comparison of the sequences at specific sites on DNA cleaved by the antitumor antibiotics talisomycin and bleomycin.

We have investigated the site-specific cleavage of DNA by the antitumor antibiotics talisomycin and bleomycin by using 5'- or 3'-terminal 32P-labeled restriction fragments of pBR 322 DNA. Both drugs cleaved DNA preferentially at G-C and G-T sequences. However, the relative amounts of cleavage at particular cleavage sites differed between talisomycin and bleomycin at concentrations of the drugs which produced similar extents of total cleavage. In addition, talisomycin produced specific cleavages at G-A sequences which were relatively resistant to cleavage by bleomycin. Within a preferred sequence group (i.e., G-C sequences), some sites were cleaved to a greater extent relative to others by both talisomycin and bleomycin, suggesting that a greater degree of specificity than that provided by only two nucleotides is involved in the site-specific recognition and cleavage of DNA by these drugs.

Antibiotics, Antineoplastic↗
PubMed1982

Inhibition of bleomycin-induced pulmonary fibrosis by cobra venom factor.

A single dose of cobra venom factor, a known, potent depletor of serum complement, has recently been reported to be highly effective in inhibiting lung collagen deposition at 7 days after bleomycin treatment. The present study shows that this is associated with suppression of the bleomycin-induced increase in collagen synthesis, down to virtually normal levels. There is also a concomitant reduction in tissue free proline pool size. No significant effects are noted in noncollagenous protein synthetic rates. This inhibitory effect is not seen at 30 days after bleomycin and is correlated with a return to normal levels of serum complement hemolytic activity. These data suggest an important role for complementary activity in the lung's fibrotic response to bleomycin.

Animals↗
PubMed1982

Oxygen transfer from bleomycin-metal complexes.

Both Fe(III) and Cu(II) complexes of bleomycin (BLM), but not N-acetyl BLM . Fe(III), mediated the transfer of oxygen from iodosobenzene to organic substrates. In analogy with results obtained using certain cytochrome P-450 analogs, cis-stilbene was converted cleanly to the respective oxide, while no more than traces of trans-stilbene oxide were formed from trans-stilbene under identical conditions. The possible relevance of these observations to the degradation of DNA by bleomycin was also studied. In both the presence and absence of O2, BLM . Cu(II) . C6H5IO effected DNA degradation, as judged by the release of [3H]thymine from radiolabeled Escherichia coli DNA. These findings provide a valuable new assay system for the study of bleomycin analogs and suggest the possibility that bleomycin may function as an "oxygen transferase" in its degradation of DNA in situ.

Bleomycin↗