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PubMed1997

The cysteine-peptidase bleomycin hydrolase is a member of the galactose regulon in yeast.

Bleomycin hydrolase is a cysteine peptidase discovered through its ability to detoxify the anti-cancer glycopeptide, bleomycin. Although found in all tissues in mammals and in both eukaryotes and prokaryotes, the normal cellular function of this peptidase is not known. We had previously reported the purification of bleomycin hydrolase from yeast based on its unexpected ability to bind DNA. Recently we collaborated in solving the crystal structure of this protein, revealing a hexameric ring organization. We now report that the molecular characterization of the gene encoding yeast bleomycin hydrolase is also surprising. The transcription of the gene is regulated by galactose. Furthermore, this regulation is conveyed by a binding site for the Gal4 regulatory protein in its promoter, prompting the designation of this gene as GAL6. Gal6p also appears to have a negative effect on the GAL system as a deletion of the gene leads to a 2-5-fold higher expression of the GAL1, GAL2, GAL7, and MEL1 genes. The GAL6 deletion does not affect the expression of another inducible gene, HSP26. Neither the peptidase nor the nucleic acid binding activity of Gal6p as assayed is apparently required to convey this regulation, implying yet another function for this new member of the GAL regulon.

Base Sequence↗
PubMed1977

Scintigraphic evaluation of lymphoma: a comparative study of 67Ga-citrate and 111In-Bleomycin.

Sequential whole-body scans with both 67Ga-citrate and 111In-bleomycin were performed for 14 patients undergoing staging for Hodgkin's disease or other lymphomas. A comparison or these scans gave a sensitivity in detecting the pathologically-proved tumor sites of 84% for 67Ga-citrate and only 56% for 111In-bleomycin. In 12 patients, the gallium scan demonstrated the lesions more clearly; in the others, the uptake of the two radionuclides was equal. In no case was a clinically diagnosed or histologically proved lesion identified by 111In-bleomycin that was not also demonstrated by 67Ga-citrate. 111In-bleomycin does not complement the 67Ga-citrate scan in the scintigraphic evaluation of lymphomas.

Adolescent↗
PubMed1977

Tallysomycin, a new antitumor antibiotic complex related to bleomycin. II. Structure determination of tallysomycins A and B.

The structures of tallysomycins A and B, two major components of a new antitumor antibiotic complex, have been determined. They are glycopeptide antibiotics structurally related to bleomycin: four amino acid moieties and a disaccharide fragment which are the constituents of bleomycin molecule are also present in the tallysomycins. Tallysomycins A and B contain two new amino acids and a unique amino sugar, 4-amino-4,6-dideoxy-L-talose, which have not been hitherto found in the phleomycin-bleomycin group of antibiotics. In addition tallysomycin A has an additional amino acid, L-beta-lysine, and thus a longer peptide chain than bleomycin or tallysomycin B. Tallysomycins A and B have the same terminal amine moiety, spermidine.

Amino Acids↗
PubMed2003

Flagellate hyperpigmentation following intralesional bleomycin treatment of verruca plantaris.

BACKGROUND: Flagellate hyperpigmentation is a well-documented complication of systemic bleomycin sulfate therapy when using doses of 100 U or more as an antineoplastic agent. Two cases occurred after using systemic doses from 15 to 30 U injected intravenously or intrapleurally; however, it has not been described as a complication following intralesional treatment of verruca plantaris. OBSERVATIONS: We report a case of flagellate hyperpigmentation after intralesional injection of 14 U of bleomycin for verrucae plantaris and review the literature associated with this cutaneous complication. CONCLUSIONS: Flagellate hyperpigmentation from extremely low doses of intralesional bleomycin is a previously undescribed complication. Although the mechanisms of reaction are not clearly understood, the clinician should be mindful of this uncommon complication.

Abdomen↗
PubMed1998

Treatment of cutaneous and subcutaneous tumors with electrochemotherapy using intralesional bleomycin.

BACKGROUND: Electrochemotherapy (ECT) is performed by locally administering a chemotherapeutic agent in combination with electric pulses. Previous clinical studies have demonstrated the effectiveness of ECT. In these initial trials, the drug was administered intravenously, followed by administration of electric pulses directly to the tumor. This study was initiated to determine whether an intralesional injection of the drug in combination with electric pulses could provide an improved result. A group of 34 patients was studied. METHODS: The dose of intralesional bleomycin was based on tumor volume. This was followed 10 minutes later by 6 or 8 99-microsec pulses of electricity at an amplitude of 1.3 kV/cm. Both the bleomycin and the electric pulses were administered after 1% lidocaine with epinephrine solution was injected around the treatment site. RESULTS: All patients responded to the treatment. Responses were observed in 142 (99%) of 143 metastatic nodules or primary tumors within 12 weeks, with complete responses observed in 130 (91%) of the nodules. No complete responses were observed in nodules treated with bleomycin only or electric pulses only. Random biopsies confirmed the clinical findings. All patients tolerated the procedure well, and no significant side effects were noted. Muscle contraction was evident during administration of each electric pulse but promptly subsided after the pulse. CONCLUSIONS: ECT was shown to be an effective local treatment for cutaneous malignancies. The results suggest that ECT may have a tissue-sparing effect and result in minimal scarring. ECT may be a suitable alternative therapy for the treatment of basal cell carcinoma, local or regional recurrent melanoma, and other skin cancers.

Adult↗
PubMed1996

Cell-specific expression of the alpha 1 (I) collagen promoter-CAT transgene in skin and lung: a response to TGF-beta subcutaneous injection and bleomycin endotracheal instillation.

Transgenic mice containing a rat collagen alpha 1 (I) promoter (3.6 kilobases) fused to the reporter gene chloramphenicol acetyl transferase (CAT) express the reporter gene parallel to endogenous gene in most connective tissues other than vascular tissue [Pavlin et al. (1992): J Cell Biol 116:227-236; Bedalov et al. (1994): J Biol Chem 269:4903-4909]. We have challenged transgenic mice with subcutaneous injections of transforming growth factor-beta (TGF-beta) or intratracheal instillation of bleomycin. In situ hybridization studies of skin revealed increased CAT expression in the papillary dermis of TGF-beta treated animals. In contrast, alpha 1 (I) collagen mRNA was expressed throughout the dermis including granulation tissue and reticular dermis. Therefore, the transgenic promoter responds to TGF-beta in a subset of dermal fibroblasts. Endotracheal instillation of bleomycin induces lung fibrosis which is thought to be mediated in part by TGF-beta. CAT gene expression in lungs was increased 6-8-fold at 2 weeks post bleomycin treatment. In situ hybridization studies revealed focal areas of cells expressing both CAT and collagen genes in the interstitium. However, most regions, especially around airways, contained a subset of cells expressing the endogenous gene with little or no CAT expression as judged by in situ hybridization. These cells could be myofibroblasts that require additional cis-acting elements to activate alpha 1 (I) collagen gene expression similar to smooth muscle cells.

Animals↗
PubMed1975

Bleomycin combination chemotherapy in the management of testicular neoplasia.

Eighty-three patients with Stage II or Stage III germinal neoplasia of the testis and 7 patients with extragonadal primary tumors were treated with bleomycin plus vinblastine, or a five-drug program, bleomycin plus cyclophosphamide, vincristine, methotrexate, and 5-fluorouracil. Of the 70 Stage III patients, there were 53 responses (75%), 22 complete and 31 partial. The mean survival of the complete responders is 100+ weeks, with 3 dead. The mean survival of the partial responders and nonresponders is 38 weeks and 33 weeks, respectively. There is a highly significant difference between complete responders vs. partial and nonresponders (p less than 0.01). Thirteen patients with nonmeasurable disease (Stage II and Stage III postresectional status) but at great risk to develop widespread metastasis were treated prophylactically after conventional therapy. Nine continue in complete response to 36 months. The 7 extragonadal primary patients showed 4 partial responses, none complete. Major toxicity was myelosuppression and also bleomycin pneumonitis in 5 of the 90 evaluable patients.

Abdominal Neoplasms↗
PubMed1976

Enhanced pulmonary toxicity with bleomycin and radiotherapy in oat cell lung cancer.

In a recently completed study, combination chemotherapy consisting of bleomycin, adriamycin, cyclophosphamide, and vincristine was given to 29 patients with oat cell lung cancer. There were no cases of pulmonary fibrosis in these 29 patients. Although several of these patients had prior radiotherapy, none had concomitant radiotherapy and chemotherapy. This same four-drug chemotherapy regimen was combined with concomitant radiotherapy in 13 patients with oat cell lung cancer. There were three cases of fatal pulmonary fibrosis and two other cases of clinically significant pulmonary fibrosis. All five cases of pulmonary fibrosis occurred several weeks after completion of a six-week course of bleomycin (total dosage 90 units). It is concluded that bleomycin cannot be safely administered while patients are receiving radiotherapy to the lung.

Bleomycin↗
PubMed1976

Intracavitary bleomycin in the management of malignant effusions.

Instilled bleomycin and thoracostomy were utilized in 38 patients with malignant pleural effusions; the therapy produced a complete or partial response rate of 63%. Toxicity was minimal. In patients with intraperitoneal effusions, bleomycin instillation after drainage produced a complete or partial response in 36%. One patient had severe hypotension and fever. Patients with ovarian and breast carcinoma responded best, among them, effusions were controlled in greater that 70%. Because of its low systemic toxicity, absence of marrow toxicity, and virtual absence of discomfort, we think that the local instillation of bleomycin is indicated in the management of malignant effusions.

Ascites↗
PubMed1978

Treatment of recurrent Paget's disease of the vulva with topical bleomycin.

Seven patients with recurrent Paget's disease of the vulva underwent treatment with topical bleomycin (NSC 125066-Blenoxane, Bristol Laboratories) ointment. None had an associated invasive carcinoma. Four patients experienced a complete, objective response to this therapy, and one of these has responded completely to treatment of a subsequent recurrence. In two patients the response could not be evaluated. All patients experienced pain in the treated area; one, developed systemic toxicity to bleomycin requiring cessation of therapy. Topical bleomycin appears to benefit selected patients with recurrent Paget's disease of the vulva.

Administration, Topical↗
PubMed1979

Cobalt-57 bleomycin for imaging head and neck tumors.

Cobalt-57 bleomycin imaging was performed in 11 patients with a history of head and neck cancer. Clinical and scan findings concurred on the presence and extent of tumor in 9 patients (82%); tumor was present in 7 and absent in 2 of the 9. In 2 patients (18%) the scan demonstrated tumor in the neck but failed to show metastatic sites. Cobalt-57 bleomycin images were of good technical quality, with remarkably low background activity at 24 hours after administration. Cobalt-57 bleomycin imaging appears to be a promising technique for evaluating patients with head and neck tumors.

Adult↗
PubMed1979

Induction chemotherapy in advanced squamous head and neck carcinoma with high-dose cis-platinum and bleomycin infusion.

Forty patients with advanced head and neck cancer were treated with combined Cis-platinum-Bleomycin chemotherapy. Cis-diammine dichloroplatinum (DDP) 120 mg/m2 iv was given after prehydration, with mannitol diuresis on Day 1. On Day 3, an initial loading dose of Bleomycin 15 mg/m2 was given by rapid iv push followed by continuous 24 hour intravenous infusion of Bleomycin 15 mg/m2 Day 3 through Day 10. DDP 120 mg/m2 iv was administered again on Day 22. The patients were evaluated for tumor response and resectability between Day 29 to Day 35. Of 39 patients who were evaluable, there were 8 complete responses or CR (20%) and 22 partial responses or PR (56%), for a major response rate of 76%. Nineteen patients had surgery (14 patients whose lesions were initially inoperable and 5 patients who were initially operable). Chemotherapy toxicity in 40 patients included alopecia (40), vomiting (39), mucositis (11), skin rash (10), fever (17), weight loss of more than 5 lbs. (25), WBC less than 3,000 (2), platelets less than 100,000 (1), peak serum creatinine of 2 mg% (3), severe-hearing loss (1), hypersensitivity reaction (2). Surgical complication in 19 patients were pharyngocutaneous fistulae (2), wound dehiscence (1), meningitis and brain abscess (1). There was one death secondary to nephrotoxicity. This particular combination chemotherapy when given as initial treatment, appears very effective in reduction of tumor bulk. Long-term follow-up and randomization is necessary to determine effect upon survival.

Aged↗
PubMed1980

The adjuvant treatment of inoperable stage III and IV epidermoid carcinoma of the head and neck with platinum and bleomycin infusions prior to definitive radiotherapy: an RTOG pilot study.

Twenty-nine previously untreated patients with advanced unresectable Stage III or IV epidermoid carcinoma of the oral cavity, oropharynx, hypopharynx, or nasopharynx were entered on a pilot protocol to evaluate the effectiveness and toxicity of platinum-bleomycin infusion chemotherapy administered prior to definitive radiotherapy. Platinum was given by 24-hour continuous I. V. infusion (in an attempt to decrease gastrointestinal and renal toxicity) without mannitol diuresis at a dose of 80--100 mg/m2 on day 1 and repeated on day 22. Bleomycin was administered 15 U/m2 I. V. push on day 3 and was then followed by a five-day continuous I. V. infusion of 15 U/m2/day. Fourteen of 29 (48%) patients achieved an objective partial response on chemotherapy alone (an additional 5 patients or 17% had a minor response). Chemotherapy was well tolerated with 10/29 experiencing no nausea, 4/29 mild nausea alone, and 14/29 experiencing controllable nausea/vomiting. Transient reversible azotemia was noted in 4, skin rash in 3, and anemia in 9 patients. All 29 patients began radiotherapy on day 28; 25 completed radiotherapy and 12/25 (48%) achieved complete tumor clearance; all 12 are currently free of disease with short follow-up. The radiotherapy was well tolerated, completed on schedule, and no unexpected toxicities were encountered. This combined modality approach demonstrated substantial antitumor activity and was able to reduce the significant morbidity from platinum-bleomycin chemotherapy for the treatment of unresectable head and neck carcinoma.

Anemia↗
PubMed1981

Phase II trials of Baker's antifol, bleomycin, CCNU, streptozotocin, tilorone, and 5-fluorodeoxyuridine plus arabinosyl cytosine in metastatic breast cancer.

A total of 202 patients with advanced breast cancer were entered into two prospectively randomized Phase II trials conducted by the Eastern Cooperative Oncology Group, in an effort to identify promising agents and combinations for previously treated cases. Patients in Study 1 received bleomycin, CCNU, or streptozotocin and those in Study 2 received tilorone, Baker's antifol, or a combination of 5-fluorodeoxyuridine plus arabinosyl cytosine. Partial responses were seen only with bleomycin, Baker's antifol, and 5-fluorodeoxyuridine plus arabinosyl cytosine. The median times to treatment failure ranged from 3.6 weeks to 5.7 weeks, and the median survival times, from 8 weeks to 25 weeks for tilorone and bleomycin, respectively. Toxic reactions was primarily hematologic and gastrointestinal, but skin, neurologic, respiratory, and renal abnormalities were noted in some treatment arms. The treatment schedules outlined and the toxic effects noted provide background information that might prove useful in designing complex new chemotherapeutic programs, since there is pharmacological rationale for incorporating some of the agents tested into present standard combination chemotherapy regimens.

Antineoplastic Agents↗
PubMed1984

Treatment of bladder cancer with a combination of hyperthermia, radiation and bleomycin.

The treatment of urinary bladder cancer with hyperthermia in combination with radiation and bleomycin was investigated. Immediately following a daily course of external bladder irradiation (150-200 rad; total 4 week exposure of 3500-4000 rad), patients diagnosed with transitional cell carcinoma of the bladder were irrigated with a solution of warmed saline (intravesical temperature, 42 degrees C-43 degrees C), containing 30 micrograms/ml bleomycin. Of a total of 33 patients, complete responses were observed in 14 patients, and partial responses were observed in 10. The side effects of the combined treatment were limited to local symptoms of bladder and urethral irritation. These preliminary results suggest that the combined use of hyperthermia, radiation, and bleomycin may represent an effective conservative therapy for the management of bladder cancer in humans.

Adult↗
PubMed1985

Vinblastine, bleomycin, and cisplatin in malignant germ cell tumors of the ovary.

Fourteen patients with malignant ovarian germ cell tumors were treated with vinblastine, bleomycin, and cisplatin. A complete clinical response was achieved in all 14 patients; however, 1 patient had small macroscopic disease present at second-look laparotomy. One patient died of bleomycin pulmonary toxicity. The remaining 13 patients are alive and free of disease from 20 months to 8 years and 8 months after initial diagnosis. Serum alpha-fetoprotein and beta-human chorionic gonadotropin levels were monitored in all patients and were found to be reliable indicators of response to treatment and disease status. The uninvolved ovary was preserved in seven patients without compromising the response to treatment, and one patient subsequently became pregnant. Vinblastine, bleomycin, and cisplatin chemotherapy appears to be a safe, effective combination and is recommended as the primary treatment of choice in the management of patients with malignant ovarian germ cell tumors.

Adolescent↗
PubMed1987

Combination chemotherapy with methotrexate, bleomycin, and vincristine with or without cisplatin in advanced squamous cell carcinoma of the head and neck.

A total of 185 eligible patients with advanced inoperable squamous cell carcinoma of the head and neck were randomized into two groups; the cisplatin, methotrexate, bleomycin, and vincristine (CABO) group received cisplatin (50 mg/m2; day 4), methotrexate (40 mg/m2; days 1, 15), bleomycin (10 mg; days 1, 8, and 15), and vincristine (2 mg; days 1, 8, and 15) and the ABO group received methotrexate, bleomycin and vincristine in the same doses on days 1, 8, and 15. After three courses, patients in both arms received weekly methotrexate as maintenance therapy; those 34 patients with previously untreated locoregional disease went off the study because of subsequent locoregional treatment in form of radiotherapy +/- surgery. The complete response rate was 16% in patients receiving CABO, compared with 5% among patients given ABO. The corresponding overall response rates were 50% and 28%, respectively (P = 0.003). Among patients with recurrent or metastatic disease, progression was delayed in patients receiving CABO (median, 18 weeks) compared to those receiving ABO (median, 14 weeks) (P = 0.07), but there was no difference in survival time. Myelosuppression consisted mostly of leukopenia, which was seen in 67% of the CABO patients versus 47% in the other arm. Myelosuppression-associated infection and hemorrhage led to death in two patients in the CABO treatment group and six patients in the ABO treatment group. Nausea and vomiting, mostly of grades 1 or 2, occurred in 93% of the patients given CABO and 44% of those receiving ABO. Other toxic effects--neuropathy, alopecia, stomatitis, constipation, fever/chills, diarrhea, cutaneous alterations, and renal impairment--occurred equally in the two treatment groups. This study underlines the role of cisplatin in head and neck cancer, although no impact on survival could be demonstrated. It also supports indirectly the superiority of combination chemotherapy over single-agent treatment for this disease.

Adult↗
PubMed1989

Treatment of oral leukoplakia with topical bleomycin. A pilot study.

Leukoplakia is a clinical diagnosis with the potential for malignant transformation. This pilot study tested the use of bleomycin a as topical agent for the treatment of leukoplakia. Twelve patients were enrolled in this study, each for 2 weeks of daily topical application of bleomycin in dimethylsulphoxide (DMSO) painted over the lesion. Two patients were excluded from analysis due to excessive dilution of the medication by local saliva production. Five patients were treated with a 0.5% solution that caused a decrease in the thickness of all of the lesions clinically. One lesion also had a sharp decrease in size. Five patients were treated with a 1.0% solution that caused a complete resolution of the lesions in three patients. Two lesions demonstrated maturation of parakeratosis to keratosis only. All patients tolerated the treatments well. Topical bleomycin may play a role in the treatment of leukoplakia and warrants further investigation.

Administration, Topical↗