1.2.6. The Anticancer Antibiotics

Analysis of the number and sources of anticancer and antiinfective agents, indicates that over 60% of the approved drugs and pre-approved candidates developed in the area of these diseases are of natural origin. Drugs of natural origin have been classified as original natural products, products derived semisynthetically from natural products, or synthetic products based on natural product models. Anticancer antibiotics are drugs derived from microbial sources. Data showed that of the new approved drugs reported between 1983 and 1994 antibacterial drugs of natural origin is 78%  while 61% of the 31 anticancer drugs  are naturally-derived  or are modeled on a parent natural product. Of the 87 approved anticancer drugs, 62% are of natural origin or are modeled on natural parent products-fifteen are the original natural product, and 25 are semisynthetic derivatives including steroids, nucleosides, microbial- and plant-origin, choline and peptide derivative. Approved rest 14 anticancer drugs may be classified natural product  models. Of the 299 pre-approved anticancer drug candidates which were in preclinical or clinical development for the period 1989-1995, 50 are the original natural product of  marine-,  microbial-, and  plant source and 48 are semisynthetic derivatives of nucleosides, aniimal-, microbial-, and plant origin, while 30 are based on natural product models and 88 are biologics. Among them enediyne class of natural products are newer anticancer antibiotics.

Over the past ten years there has been a rapid escalation in the discovery of molecular targets that may be applied to the discovery of novel tools for the diagnosis, prevention, and treatment of human diseases. With the sequencing of the human genome, there has been an explosion in the knowledge of combinatorial synthesis and screening to select the active drug candidates including anticancer agents.Therefore now a day many new drugs are coming up which are already approved or in clinical or pre-clinical trial. Some important examples of anticancer drugs are given below.

(a) Anthracyclines

• • First anthracycline antibiotics were isolated from Streptomyces peucetius in 1958

• • Mechanisms of action: Disrupt DNA

• • Intercalate into the base pairs in DNA minor grooves

• • Inhibits topoiosomerase II enzyme, preventing the relaxing of supercoiled DNA, thus blocking DNA transcription and replication

• • Cause free radical damage of ribose in the DNA

• • Some of the most effective cancer drugs available

• • Adramycin is used to treat acute leukemias, lymphoma, and a number of solid tumors

• • Common Anthracyclines (Figure 1)

• • Daunorubicin (Cerubidine, DaunoXome)

• • Doxorubicin (Adriamycin, Rubex, Doxil)

• • Epirubicin (Ellence, Pharmorubicin)

• • Idarubicin (Idamycin)

• • Daunomycin (DNR) for acute lymphocytic and myeloid leukenmia

• • Doxorubicin (DOX) for chemotherapy for solid tumors including breast cancer, soft tissue sarcomes, and aggressive lymphomas

• • Daunorubicin was isolated from Streptomyces coeruleorubidus and S. peucetius.  This significant discovery was made independently in France and Italy in 1963.

• • The most important member of the anthracycline, doxorubicin (adriamycin) was isolated from S. peucetius var. caesius in 1969 in Italy.

Figure 1. Chemical structures of anthracyclin class of anticancer drugs

(b) Dactinomycin (Cosmegen)

• • Actinomycin D intercalates DNA and thereby prevents DNA transcription and messenger RNA synthesis.

• • The drug is given intravenously, and its clinical use is limited to the treatment of trophoblastic (gestational) tumors and the treatment of pediatric tumors, such as Wilms’ tumor and Ewing’s sarcoma (Figure 2).

(c) Plicamycin (Mithramycin)

(d) Mitomycin (Mutamycin)  

Figure 2. Chemical structures of some anticancer agents.

(e) Platinum Compound 

• • Cisplatin:Mechanism of Action:

• • Cisplatin binds to guanine in DNA and RNA, and the interaction is stabilized by hydrogen bonding. The molecular mechanism of action is unwinding and shortening of the DNA helix (Figure 2).

(f) Bleomycin (Blenoxane)

• • Natural glycopeptidic antibiotics produced by bacterium Streptomyces verticillus.

• • Efficacy against tumors

• • Mainly used in therapy in a combination with radiotherapy or chemotherapy

• • Bleomycin refers to a family of structurally related compounds. Commonly administered as Blenoxane, a drug that includes both bleomycin A2 and B2.

• • Bleomycin was first discovered in 1962 when the Japanese scientist Hamao Umezawa found anti-cancer activity while screening culture filtrates of S. verticullus. Umezawa published his discovery in 1966. The drug was launched in Japan by Nippon Kayaku in 1969. In the US bleomycin gained Food and Drug Administration (FDA) approval in July 1973 (Figure 3).

• • Initially marketed by Bristol-Myers Squibb under brand name Blenoxance.

• • Mechanism:

• • Induction of DNA strand breaks

• • Medicate DNA strand scission of single and double strand breaks dependent on metal ions and oxygen

• • It is believed that bleomycin chelates metal ions (primarily iron) producing a pseudoenzyme that reacts with oxygen to produce superoxide and hydroxide free radicals that cleave DNA.

Figure 3. Chemical structure of Bleomycin.

(g) Enediynes

• •Enediyne anticancer antibiotics belong to the family of highly potent anticancer agents that bind to specific DNA sequences and cause double-stranded DNA lesions (Figure 4).

• •Their positioning within the minor groove is such that the active form of a drug can abstract two hydrogen atoms from the sugars of opposite strands.

Figure 4. Chemical structure of Enediyne-Calicheamicin.

Below is a schematic presentation of the A-T and G-C base pairs in the minor groove with designated sites of action of various anticancer drugs (Figure 5).

Figure 5. Schematic presentation of the A-T and G-C base pairs in the minor groove with designated sites of anticancer drug action.