Bleomycin

Description

Bleomycin is a complex of no less than 16 glycopeptide antibiotics made from the family Streptomyces verticilus, which have different R groups. Bleomycines exhibit antitumor, antiviral, and antibacterial activity. When bound to DNA, they disturb the spiraling of both single and double strands of DNA. To a lesser degree, they inhibit RNA and protein synthesis. It is administered both intravenously and intramuscularly.

Originator

Bleomycin Hydrochloride,Nippon Kayaku, Co.,Japan

Uses

Bleomycin sulfate USP (Blenoxane)is used to traet squamous cell carcinoma of head, neck, esophagus, skin, GU tract; testicular tumor; Hodgkin’s lymphomas.

Uses

It is used for lymphomas, carcinomas, and sarcomas.

Uses

Antineoplastic for solid tumors.

Definition

A species of bleomycin noted for its adverse pulmonary effects in humans. It is a complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2.

Indications

The bleomycins are a group of glycopeptides that are isolated from Streptomyces verticillus. The clinical preparation, bleomycin sulfate (Blenoxane), is a mixture of several components. Bleomycin binds to DNA, in part through an intercalation mechanism, without markedly altering the secondary structure of the nucleic acid. The drug produces both single- and double-strand scission and fragmentation of DNA. It is thought that the bleomycins, which are avid metal-chelating agents, form a bleomycin–Fe ++ complex that can donate electrons to molecular oxygen, thus forming the superoxide and hydroxyl free radicals. It is these highly reactive intermediates that attack DNA and produce DNA strand breakage and maximum cytotoxicity in the late G2 and early M-phases of the cell cycle.

Manufacturing Process

To a medium having a composition of 6.4 % of millet jelly, 0.5 % of glucose, 3.5 % of soybean powder, 0.75 % of corn steep liquor, 0.3 % of sodium chloride, 0.1 % of potassium secondary phosphate, 0.05 % of zinc sulfate, 0.01 % of copper sulfate, 0.2 % of sodium nitrate and 0.01 % of Toho No. 1 (trade name for a surface active agent composed of polyoxyethylene manufactured by Toho Chemical Industry Co. Ltd., Japan) was added 3-aminopropyl- dimethylsulfonium bromide hydrobromate in a proportion of 0.4 mg/ml to adjust the pH of the medium to 6.5.
Each 100 ml of the thus treated medium was separately charged into a Sakaguchi flask and was then sterilized. Subsequently, Streptomyces verticillus (ATCC No. 15003) was inoculated in the medium and was cultured at 27°C for 8 days with stirring at 130 r.p.m. Thereafter, the culture liquors (4.5 L) were collected and filtered to obtain 3.0 L of a filtrate (potency 38.8 mg/ml, total potency 416.4 mg). This culture filtrate was passed through and adsorbed on a column packed with 200 ml of Amberlite IRC-50 and was washed with water and was eluted with 0.5 N hydrochloric acid. 1.0 L of the eluate was neutralized, was passed through and adsorbed on a column packed with 100 ml of active carbon, was washed and was then eluted by use of a 1:1 (by volume) mixture of acetone - 0.02 N aqueous hydrochloric acid solution, and fractions active to Mycobacterium 607 were collected and concentrated to dryness. The resulting residue was dissolved in 5 ml of an 80 % aqueous methanol solution and was charged into a column packed with 30 ml of neutral alumina, followed by elution with an 80 % aqueous methanol solution. Subsequently, bleomycin-containing fractions were collected and concentrated to dryness to obtain 195 mg of bleomycin hydrochloride (potency 650.7 mcg/mg, total potency 172 mg). The yield from the culture filtrate was 30.5 %.

brand name

Blenoxane (Bristol-Myers Squibb).

Therapeutic Function

Antibiotic

General Description

Bleomycin is a glycopeptide antibiotic complex isolatedfrom Streptomyces verticillus initially by Umezawa.Atleast 13 different fractions of bleomycin have been isolatedwith the clinically used product (Blenoxane) being a mixtureof predominantly A2₂ (55%–70%) and B₂ (25%–32%)fractions.Of these fractions, A₂ appears to possessthe greatest antineoplastic activity. Copper is found inthe naturally occurring material, and its removal is importantfor the material used clinically because it significantlyreduces activity.
Bleomycin is notable for its lack of myelotoxicity, andthis allows it to be combined with other myelosuppressantswithout a resulting additive effect. The acute toxicities seenwith bleomycin are erythema (reddening of the skin), hyperpigmentation(skin darkening) found predominately on theextremities, and pulmonary toxicity. The pulmonary toxicitymay first occur as pneumonitis (inflammation of lung tissue),which normally responds to glucocorticosteroid therapy.Chronic pulmonary toxicity is expressed as pulmonaryfibrosis, which is irreversible and limits utility of the agent.

General Description

Colorless or yellowish powder. Possible bluish color depending on copper content.

Air & Water Reactions

Water soluble

Hazard

Possible carcinogen.

Fire Hazard

Flash point data for Bleomycin are not available. Bleomycin is probably nonflammable.

Pharmaceutical Applications

The drug Bleomycin (BLM) is successfully used as an anticancer agent, and is known to cause fragmentation of the DNA. The drug is used for the treatment of testicular cancer, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma and cancers of the head and neck area (Cancer research UK). The name Bleomycin describes a family of water-soluble antibiotics that can be isolated from the bacterium Streptomyces verticillus. All family members contain the same core structure, a sulfur-containing polypeptide chain, and are only differentiated by a small side group and the sugar moiety.
BLM was discovered 1966 by Umezawa et al. when they screened the filtrate of S. verticillus for cytotoxic activity. The therapeutically active forms of BLM are BLM A₂ and B₂, which differ only in the side chain. BLM is believed to exhibit its anticancer activity by DNA degradation, a process that is dependent on the presence of molecular oxygen, and the binding of a metal to BLM to form the so-called ‘activated BLM complex’.
The structure of BLM consists of several biologically important units, each contributing to its anticancer activity. Two structural units of importance to highlight are the metal-binding site and the DNA-binding site. It is believed that the intercalation of DNA by BLM occurs via the C-terminus, which contains two thiazole rings and the positively charged sulfonium salt. The positive charges of the sulfur atom can interact with the negatively charged phosphate backbones of the DNA. The metal-binding site can be found at the N-terminus and contains deprotonated amide and histidine groups. The metal is coordinated in a square planar complex, where a primary amine group occupies the axial position. It can coordinate to a variety of metals such as Cu²⁺, Co²⁺, Zn²⁺ and Fe²⁺, but it shows the highest binding affinity to Fe²⁺. The metal chelation and subsequent activation of molecular oxygen is crucial to the antiproliferative activity of BLM. The carbohydrate core seems to be less involved in the direct anticancer activity. Nevertheless, it has been suggested that it regulates the cellular uptake and indirectly regulates the anticancer activity.

Mechanism of action

Bleomycin is poorly absorbed orally, but it can be given by various parenteral routes. Its plasma half-life is not affected by renal dysfunction as long as creatinine clearance is greater than 35 mL/minute. 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 toxicities are related to the persistence of relatively high local concentrations of active drug.

Clinical Use

Bleomycin, in combination with cisplatin or etoposide, 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.

Side effects

A potentially fatal lung toxicity occurs in 10 to 20% of patients receiving bleomycin. Patients particularly at risk are those who are over 70 years of age and have had radiation therapy to the chest. Rarely, bleomycin also may cause allergic pneumonitis. Bleomycin skin toxicity is manifested by hyperpigmentation, erythematosus rashes, and thickening of the skin over the dorsum of the hands and at dermal pressure points, such as the elbows. Many patients develop a low-grade transient fever within 24 hours of receiving bleomycin. Less common adverse effects include mucositis, alopecia, headache, nausea, and arteritis of the distal extremities.

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid clozapine, increased risk of agranulocytosis.
Cytotoxics: increased pulmonary toxicity with cisplatin and brentuximab, avoid with brentuximab; in combination with vinca alkaloids can lead to Raynaud’s syndrome and peripheral ischaemia.
Live vaccines: avoid concomitant use.

Metabolism

The mechanism for bio-transformation is not yet fully known. Inactivation takes place during enzymatic breakdown by bleomycin hydrolase, primarily in plasma, liver and other organs and, to a much lesser degree, in skin and lungs. About 60-70% of the administered drug is excreted unchanged in the urine, probably by glomerular filtration. Approximately 50% is recovered in the urine in the 24 hours following an IV or IM injection. The rate of excretion, therefore, is highly influenced by renal function; concentrations in plasma are greatly elevated if usual doses are given to patients with renal impairment with only up to 20% excreted in 24 hours.

Raw materials

Preparation Products