Bleomycin hydrolase

Newer bleomycins such as peplomycin and especially liblomycin, are more resistant to bleomycin hydrolase. This results in less lung toxicity but more bone marrow toxicity, and allows for a different spectmm of antitumor action. Bleomycin is inactive orally it is given intravenously, intramuscularly, subcutaneously, or directiy into a cavity such as the pleural cavity. The majority of dmg is excreted unchanged in the urine. 

CA C1 C01.084 Bleomycin hydrolase (animal) Destroys chemotherapeutic bleomycin... 

Gener ally, a family of peptidases contains either exopeptidases or endopeptidases, but there are exceptions. Family Cl contains not only endopeptidases such as cathepsin L, but also the aminopeptidase bleomycin hydrolase. Some members of this family can act as exopeptidases as well as endopeptidases. For example, cathepsin B also acts as a peptidyl-dipeptidase, and... 

P-450 / Metallothione ins Glutathione-S-Transferase Dl-1. r.phofos Cylidine Deaminase Thymidylate Synthase Bleomycin Hydrolase... 

Fig. 2. Mechanisms causing resistance to antitumor treatment. ATM. ataxia telangiectasia gene, (Westphal et al., 1998 Xu and Baltimore, 1996), bcl-2/bax (Farrow and Brown, 1996, Zunino et al., 1997 Haq and Zanke, 1998), bcr/abl (McGahon et al., 1994), BCRP, breast cancer resistance protein (Doyle et d., 1998 Ross et al, 1999) bleomycin hydrolase (El-Deiry, 1997), BRCAl (Husain et al., 1998 Chen et al., 1998), BRCA2 (Chen et al., 1998 Chen et 1999), c-abl (White and Prives, 1999), c-jun (Sanchez-Perez and Perona, 1999), cytidine deaminase (El-Deiry, 1997), DNA poip, DNA polymerase p (Ochs et al., 1999), dihydrofolate reductase (Schimke, 1986), DT-diaphorase (Riley and Workman, 1992 Fitzsimmons et al., 1996 El-Deiry, 1997), EGR-1 (Ahmed et al., 1996), fos (Niimi et al., 1991), glucosylceramide synthase...

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. 

Bleomycin hydrolase, which inactivates bleomycin, is an enzyme that is abundant in liver and kidney but virtually absent in lungs and skin the latter two organs are the major targets of bleomycin toxicity. It is thought that bleomycin-induced dermal and pulmonary toxici-ties are related to the persistence of relatively high local concentrations of active drug. 

Resistance These mechanism(s) have not been elucidated, although experimental systems have implicated increased levels of bleomycin hydrolase (or deamidase), glutathione-S-transferase, and possibly increased efflux of the drug. DNA repair also may contribute. 

Clan CA is composed of twenty families. Family Cl within clan CA is divided into two subfamilies that consist of CIA (papain subfamily) and CIB (bleomycin hydrolase subfamily) groups. The larger subfamily CIA consists of secreted and lysosomal proteases that include the animal cysteine cathepsin proteases cathepsins B, H, and L as well as the plant proteases papain, chymopapain, and actinidain. 

Re.sistancc to bleomycin is afforded by the cytosolic cn-xyme bleomycin hydrolase, which removes an amide group from the molecule. This is especially problematic with sarcomas. which have high levels of the hydrolase. 

BLM is also metabolized by bleomycin hydrolase, which is an enzyme catalyzing the hydrolysis of the (3-amino-alanine carboxamide (upper left of structure). The carboxylic acid obtained shows decreased DNA affinity. Several hydrolase-resistant BLMs, where the carboxamide nitrogen carries a 3-(a-methyl-benzylamino) propylamine group, exhibited lower pulmonary toxicity. 

Sebti, S. M., Mignano, J. E., Jani, J. P., Srimatkandada, S., Lazo, J. S. (1989 Aug 8). Bleomycin hydrolase Molecular cloning, sequencing, and biochemical studies reveal membership in the cysteine proteinase family. Biochemistry, 25(16), 6544—6548. 

No. Bone marrow contains high levels of bleomycin hydrolase, which converts the drug to an inactive form. 

Species- and strain-related differences in susceptibility (high expression of bleomycin hydrolase)... 

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