Bleomycin lymphomas

MACOP-B Methotrexate, daunomycin, cyclophosphamide, vincristine, prednisone, bleomycin Lymphoma... 

Bleomycin (BLM) was first isolated as a copper complex from a culture of Streptomyces verticillus. Since then numerous analogs have been prepared by modifying the conditions of fermentation. Bleomycins (114, bleomycin A2) are used clinically in combination cancer chemotherapy for the treatment of head and neck cancer, certain lymphomas, and testicular cancer (555). 

This was the first report of the successful screening of antibiotics for antitumor activity. Antibiotic research was thus expanded to also cover antitumor research. The term antitumor antibiotics was coined to include those compounds that are produced by microorganisms and inhibit the growth of tumor cells and tumors. Since that time, I have been continuing the study of new antitumor 2Uitlbiotics. Up to now with my collaborators I discovered eibout 65 antitumor antibiotics and elucidated structures of about 50 of them. Among them, bleomycin which we discovered in 1966 (76,79) has been used in the treatment of Hodgkin s lymphoma, tumors of the testis, and carcinomas of the skin, head, neck, and cervix. 

Bleomycin is partially inactivated by bleomycin hydrolase present in various tissues. Some bleomycin-resistant cells contain high levels of hydrolase activity. Bleomycin is used in combination regimens for the treatment of lymphomas and in treating testicular, ovarian cancers and other solid tumors. 

Hodgkin s disease accounts for 1% of all new cancers diagnosed in Western countries and for 15% of all malignant lymphomas. In patients with early stage lA-IIA disease without B-symptoms or bulky adenopathy, therapy consists of either extended field radiotherapy or limited duration chemotherapy, e.g. ABVD (anthracycline, bleomycin, vinblastine, dacarbazine) for 3-4 cycles followed by involved field radiotherapy. Radiation alone results in a 10-year relapse free survival of 70-75% and, because of the efficacy of salvage chemotherapy for those who relapse, an overall survival of 80-85%. The combined modality approach results in fewer relapses but overall survival is similar. In order to reduce the long term morbidity of radiation current trials are exploring combined modality treatment with lower radiation doses versus chemotherapy alone. 

Bleomycin, in combination with cisplatin or etopo-side, is important as part of the potentially curative combination chemotherapy of advanced testicular carcinomas. Bleomycin is used in some standard regimens for the treatment of Hodgkin s and non-Hodgkin s lymphomas, and it is useful against squamous cell carcinomas of the head and neck, cervix, and skin. 

The anthracycline antibiotics, which include doxorubicin, daunorubicin, bleomycin, and mitomycin C, inhibit DNA and RNA synthesis. Doxorubicin also interfers with topoisomerase II (a DNA gyrase), the activity of which is markedly increased in proliferating cells. Structurally related to doxorubicin are epirubicin and mitozantrone. The cytotoxic antibiotics are used to treat leukaemias and lymphomas and also for solid tumours in the breast, lung, thyroid and ovary. Cardiotoxicity is the major dose-limiting factor, with arrhythmias and myocardial depression (Bacon and Nuzzo 1993). The chronic phase of cardiotoxicity is a dose-dependent cardiomyopathy that leads to congestive heart failure in 2-10% of patients. Myocardial injury is the result of oxygen free radical formation. Children are particularly sensitive to these cardiotoxic reactions and may require a heart transplant in their later years. Epirubicin is less cardiotoxic than doxorubicin. 

Bleomycin Oxygen free radicals bind to DNA causing single- and double-strand DNA breaks Hodgkin s and non-Hodgkin s lymphoma, germ cell cancer, head and neck cancer Allergic reactions, fever, hypotension Skin toxicity, pulmonary fibrosis, mucositis, alopecia... 

Generic Name Bleomycin Trade Name Blenoxane Primary Antineoplastic Indication(s) Carcinoma of head, neck, cervical region, skin, penis, vulva, and testicle Hodgkin disease non-Hodgkin lymphomas Common Adverse Effects Pulmonary toxicity [interstitial pneumonitis] skin disorders [rash, discoloration] mucosal lesions fever Gl distress general weakness and malaise... 

Diffuse histiocytic lymphoma Cyclophosphamide, Adriamycin (doxorubicin), vincristine, and prednisone (CHOP) bleomycin, Adriamycin (doxorubicin), cyclophosphamide, Oncovin (vincristine), and prednisone (BACOP) or cyclophosphamide, Oncovin (vincristine), methotrexate, and cytarabine (COMA). 

Bleomycin (Blenoxane) causes chain scission and fragmentation of DNA. With the exception of the skin and lungs, most tissues can enzymatically inactivate bleomycin. Bleomycin is used in the management of squamous cell carcinoma of the head, neck, and esophagus in combination with other drugs in patients with testicular carcinoma, and in the treatment of Hodgkin s disease and other lymphomas. Bleomycin causes stomatitis, ulceration, hyperpigmentation, erythema, and pulmonary fibrosis. 

Non-Hodgkin s lymphoma Combination chemotherapy cyclophosphamide, doxorubicin, vincristine, prednisone Bleomycin, lomustine, carmustine, etoposide, interferon, mitoxantrone, ifosfamide, rituximab... 

Five of thirty-two patients treated with the alternating drug regimen CAMBO-VIP (cyclophosphamide, doxorubicin, methotrexate, bleomycin, vincristine, etoposide, ifosfamide, and prednisolone) for non-Hodgkin s lymphoma developed blisters under the thickened skin of the palms and/or soles, followed by desquamation (28). 

Acute febrile interstitial pneumonitis occurred within less than 48 hours after the second to fourth cycles of chemotherapy (doxorubicin, cyclophosphamide, bleomycin, methotrexate, plus methylprednisolone) in five patients with non-Hodgkin s lymphoma who were receiving prophylactic G-CSF n — 3) or GM-CSF (n = 2) (23). Lymphocytic alveolitis was confirmed in four of these patients and all three patients tested had an increased number of CD8+ T cells. Even though all the patients received high-dose methylprednisolone, two died as a result of diffuse and extensive interstitial pulmonary fibrosis, demonstrated at postmortem. Although both G-CSF and GM-CSF can cause acute pneumonitis in patients with cancers, it is still unknown to what extent hemopoietic growth factors are involved in this complication. 

The long-term prognosis for sperm counts after chemotherapy with and without radiation in 71 males treated for non-Hodgkin s lymphoma on the CHOP-Bleomycin combination has been studied (262). Pelvic radiotherapy and cumulative cyclophosphamide dosages of greater than 9.5 g/m are associated independently and in combination with a greater risk of permanent sterility. 

Combination chemotherapy with mycin), bleomycin, vinblastine, and is the primary treatment for patients Hodgkin s lymphoma. Patients who sponse do not require consolidative patients who only achieve a partial from involved-field radiation. 

MACOP-B methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin MALT mucosa-associated lymphoid tissue M-BACOD methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), and dexamethasone MCL mantle cell lymphoma... 

Etoposide is used primarily in treatment of testicular tumors in combination with bleomycin and cispiatin, and in combination with cispiatin and ifosfamide for small-cell carcinoma of the lung. It also is active against non-Hodgkin s lymphomas, acute nonlymphocytic leukemia, and Kaposi s sarcoma associated with AIDS. Etoposide has a favorable toxicity profile for dose escalation in that its primary acute toxicity is myelosuppression. In combination with ifosfamide and carboplatin, it is frequently used for high-dose chemotherapy in total doses of 1500 to 2000 mg/m. ... 

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