Cytotoxicity bleomycin

Mizuno S (1981) Ethanol-induced cell sensitization to bleomycin cytotoxicity and the inhibition of recovery from potentially lethal damage. Cancer Res 41 4111-4114... 

The biochemical basis for bleomycin cytotoxicity and pulmonary toxicity may involve the generation of reactive oxygen species by a complex of bleomycin with iron. This complex has been shown to catalyse the formation of 02 and HO capable of causing DNA strand excision (Sausville et al. 1978) and lipid peroxidation (Kameda et al. 1979). 

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-3] interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabohtes, interfering with complex metaboHc pathways in the cell, include methotrexate [59-05-2] 5-fluorouracil [51-21-8] and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxombicin [23214-92-8] h.a.ve been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

Petering, D. Xiao, J. Nyayapati, S. Fulmer, P. Antholine, W. Oxidation Damage by Bleomycin, Adriamycin and Other Cytotoxic Agents that Require Iron or Copper Farrell, N., Ed. The Royal Society of Chemistry Cambridge,... 

Manabe, Y., Tsubota, T., Haruta, Y., Okazaki, M., Haisa, S., Nakamura, K., and Kimura, I. (1983) Production of monoclonal antibody-bleomycin conjugate utilizing dextran T40 and the antigen-targeting cytotoxicity of the conjugate. Biochem. Biophys. Res. Comm. 115, 1009. 

The current was applied in the form of electrical pulses in order to permeabilize the membranes of the tumor cells for the entry of the chemotherapeutic agent bleomycin which is a very potent cytotoxic molecule. Clinical complete responses were achieved in 56.4% of the tumors and partial responses were observed in 28.9% of the tumors. This work is thus not strictly electrochemical treatment in the sense of Nordenstrom18 and Xin32 but is rather chemotherapy aided by electrochemical-driven movement of ions, molecules and drugs etc. (e.g., by electroosmosis, electrophoresis) into the tissue regions targeted for necrosis, as in several studies28,51,93 94 described earlier within this chapter. 

Ciclosporin, a calcineurin inhibitor, is a potent immunosuppressant useful in the prevention of rejection in organ transplants and grafting procedures. Ciclosporin is markedly nephrotoxic. Vincristine is a vinca alkaloid cytotoxic agent fluorouracil and methotrexate are both antimetabolite cytotoxic agents and bleomycin is a cytotoxic antibiotic. 

The biosynthetic pathway described above indicates the possible involvement of multifunctional enzyme con5>lexes in the biosynthesis of the peptide part of bleomycin. The peptide peurt of bleomycin has no cytotoxicity. Probably, in the final step of the biosynthesis, the disaccharide peirt is transferred to the B-hydroxyl group of the B-l droxylhistidyl moiety and the bleomycin thus synthesized is rapidly released extracellularly. 

The classic example of schedule dependency is cy-tarabine, a drug that specifically inhibits DNA synthesis and is cytotoxic only to cells in S-phase. Continuous infusion or frequent administration of cytarabine hydrochloride is superior to intermittent injection of the drug. Bleomycin is another drug for which continuous infusion may increase therapeutic efficacy. 

A. Carmustine and mechlormethamine kiU both normal and malignant cells to the same extent. Hydroxyurea and bleomycin kiU cells preferentially in specific phases of the cell cycle. Hydroxyurea is specific for S-phase, while bleomycin is most toxic to cells in Gj- and early M-phase. Flurouracil is cytotoxic in Gi and Gj phases. 

Various cytotoxic antibiotics bleomycin sulfate mitomycin mitotane... 

Anionic polyelectrolytes have been shown to enhance resistance to bacteria and fungi, enhance immune response, inhibit adjuvent arthritis and either depress or stimulate phagocytic activity of the reticuloendothelial system [458,459]. Carboxylic acid polymers have shown interferon induction, antiviral activity, and tumor growth inhibition [460]. The effects include inhibition of sarcoma, leukemia, polyoma and vesicular stomatitis virus. In one application, the cytotoxicity of bleomycin toward cultured mammalian cells was synergisti-cally enhanced by stirring in the presence of high molecular weight polyfacrylic acid) [461]. 

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. 

The antitumor antibiotic bleomycin (BLM) is believed to cause cytotoxicity through its ability, in the combined presence of dioxygen and a metal ion cofactor (204), to bind to and degrade DNA (205). Iron complexes of BLM have aroused special attention, as such complexes are the first (vide supra concerning the discussion of hemerythrin and hemocyanin) non-heme-iron complexes with a significant capacity for dioxygen activation (206). 

Stillman MJ, Shaw CF III, Suzuki KT (1992) Metallothioneins. Synthesis, structure, and properties of metallothioneins, phytochelatins and metal-thiolate complexes. VCH Publishers, New York Stratford IJ, Hoe S, Adams GE, Hardy C, Williamson C (1983) Abnormal radiosensitizing and cytotoxic properties of ortho-substituted nitroimidazoles. Int J Radiat Biol 43 31-43 Stubbe J, Kozarich JW (1987) Mechanisms of bleomycin-induced DNA degradation. Chem Rev 87 1107-1136... 

In addition to the direct cytotoxic effect of PDT on the cells in the tissues and the vasculature targeting there are substantial documentation from in vivo models and some clinical documentation that immunological effects contribute to the therapeutic effect of PDT, in particular for cancer therapy [36-38]. Both attraction of inflammatory cells and other immune reactions have been observed after PDT, but this is beyond the scope of this review. However, the immune response and antitumor immunity induced by PDT as well as PCI of bleomycin has been described in several reviews [39, 40]. 

Oxidative stress reduces the rate of cell proliferation, and that occurring during chemotherapy may interfere with the cytotoxic effects of antineoplastic drugs, which depend on rapid proliferation of cancer cells for optimal activity. Antioxidants detoxify ROS and may enhance the anticancer effects of chemotherapy. For some supplements, activities beyond their antioxidant properties, such as inhibition of topoisomerase II or protein tyrosine kinases, may also contribute. ROS cause or contribute to certain side effects that are common to many anticancer drugs, such as gastrointestinal toxicity and muagenesis. ROS also contribute to side effects that occur only with individual agents, such as doxorubicin-induced cardiotoxicity, cisplatin-induced nephrotoxicity, and bleomycin-induced pulmonary fibrosis. Antioxidants can reduce or prevent many of these side effects, and for some supplements the protective effect results from activities other than their antioxidant properties. Certain side effects, however, such as alopecia and myelosuppression, are not prevented... 

In vitro studies with several tumor cell lines have shown vitamin C to enhance the cytotoxic activity of doxorubicin, cisplatin, paclitaxel, dacarbazine, 5-FU, and bleomycin. Vitamin C has also been shown to increase drug accumulation and to partially reverse vincristine resistance of human nonsmall-cell lung cancer cells. 

P-Carotene has been shown to enhance the cytotoxicity of melphalan and BCNU on human squamous carcinoma cells and of cisplatin and dacarbazine on melanoma cells. In mice with transplanted mammary carcinoma, P-carotene enhanced the antitumor effect of cyclophosphamide, and in mice transplanted with Fsall fibrosarcoma or SCC VII carcinoma, p-carotene enhanced the antitumor effect of melphalan, BCNU, doxorubicin, and etoposide. p-Carotene (5 to 50 mg/kg) has been shown to reduce the genotoxicity of cyclophosphamide in mice and of mitomycin C, methyl methanesulfonate, and bleomycin in cultured cells. P-Carotene also reduced the rate of tumor induction in animals receiving chronic low doses of cyclophosphamide. 

Cytotoxic antibiotics depress the bone marrow, cause gastrointestinal upsets and stomatitis, alopecia, cardiomyopathy (daunorubicin and doxorubicin) and pulmonary fibrosis and skin rashes (bleomycin). Some of these effects are dose-dependent, for example, doxorubicin-induced cardiomyopathy. Others may be potentiated by concomitant use of radiotherapy. 

It has been suggested that handhng cytostatic agents can insidiously cause hepatic damage and possibly irreversible fibrosis. Three case reports of hepatic injnry in nurses after years of handling cytotoxic dmgs (bleomycin, vincristine, cyclophosphamide, doxornbicin, dacarbazine, fluoronracU, and methotrexate) have been described (99). All had nenrological sjmptoms associated with raised semm alanine transaminase and alkahne phosphatase... 

Cytotoxic antibiotics produce their effect mainly by direct action on DNA. Anthracyclines include the important drugs doxorubicin, aclarubicin and idarubicin. Related compounds are mitozantrone and epirubicin. Some others are the Streptomyces antibiotic dactinomycin. and the metalchelating glycopeptides especially bleomycins. Mitomycin effectively is a prodrug that is converted in the body to an alkylating agent. 

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