*4.3.3. Platinum compounds*

*4.3.2. Cytotoxic antibiotics*

56 Drug Discovery

A number of cytotoxic antibiotics that have been derived from natural sources such as grampositive bacteria in soil and water, belonging to genus *Streptomyces* (phylum *Actinobacteria*) [4,119]. They produce secondary metabolites, many of which have been successfully isolated and used as antifungals, antibiotics and anticancer drugs. The large-scale screening of fermentation products by the pharmaceutical industry which resulted in the discovery of antibiotics to treat wound infections is one more example of finding anticancer drugs by serendipity. Although penicillin, which was the basic compound for the above mentioned studies has no antitumor properties itself, but the chromo oligopeptide actinomycin D, isolated from *Streptomyces antibioticus* by Selman Abraham Waksman (1888-1973) and Boyd Woodruff in the 1940s as a result of search for drugs to treat tuberculosis, has significant antitumor properties and was applied in the 1950/1960s in paediatric oncology. This antibiotic was approved by the U.S. Food and Drug Administration (FDA) in 1964. In 1950, the search for anticancer compounds from soil-based microbes in the area of Castel del Monte, Italy, resulted in the discovery of an antibiotic - Daunorubicin (red pigment) - independently by Aurelio di Marco, Arpad Grein and Celestino Spalla from bacterium *Streptomyces peucetius* and by M. Dubost from *Streptomyces caeruleorubidus.* It was found to be active against murine tumours (Yoshida sarcoma). Although clinical trials which began in the 1960s suggested its significant activity against acute leukaemia and lymphoma, but shortly after, in 1967, it was recognized that daunorubicin had significant cardiac toxicity. In general, many antibiotics produced by *Streptomyces* are too toxic for use as antibiotics in humans, but their activity towards specific cells lines makes them useful in chemotherapy. The search for more effective antitumor antibiotics over 2,000 analogues of slightly modified structures yielded in a series of com‐ pounds, some of which are in common use till today. In 1969, Federico Arcamone developed a derivative of Doxorubicin which in the same year was tested against animal tumours by di Marco. Daunroubicin and Doxorubicin belongs to inhibitors of the topoisomerase II, one of two enzymes that regulate overwinding/underwinding of DNA. Inhibition of the topoiso‐ merase II block cleavage of both strands of the DNA which ultimately leads to cell death. An important antibiotic of a wide spectrum of anticancer activity is Mitomycin C isolated from *Streptomyces caespitosu* in 1955 and *Streptomyces lavendulae*in 1958 and clinically used since the first successful trials against childhood leukaemia reported by Charlotte Tan in 1965. Mito‐ mycin C belongs to bifunctional alkylating agents, whose biological activity mode is DNA alkylation and cross-linking. It has a broad activity against a range of tumours. In 1966 Hamao Umezawa discovered an important unique antibiotic in this group - bleomycin - a glycopeptide showing anticancer activity, while screening a culture filtrates of *Streptomyces verticullus.* Bleomycin is used to treat many types of cancer, including testicular cancer, non Hodgkin's lymphoma, Hodgkin's lymphoma and cancers of the head and neck. Anticancer antibiotics, apart from Bleomycin, act on a cancer cell in every phase of its life cycle and prevent cell divisions, but Bleomycin is considered as cell cycle agent specifically working in G2 and M phase, Fig. 2. However, the risk connected with the use of cytotoxic antibiotics classified as group 2 or 3 agent in IARC classification is smaller than that related to alkylating agents [3].

Cisplatin was synthesized in 1845 but its potential as an antitumour agent was not recognized until 1965 when its capabilities were discovered by Barney Rosenberg, Loretta van Camp and Thomas Krigas. The inhibition of growth caused by platinum complex of ammonia and chloride (Peyrone's salt i.e. Cis-platinum) was discovered by serendipity during the studies of the influence of electric current on bacterial growth. The positive result during the studies of murine tumours in vivo confirmed its antitumor activity and prompted the studies of other compounds from this class [4,56,119]. It was introduced into clinical practice one decade later in the 1970s [120]. By 1978 about 1,000 platinum complexes had been screened, but only seven were selected for detailed pharmacological evaluation on rats and only two - Carboplatin and Oxaliplatin - were non-toxic at effective antitumour dose. Although Cisplatin belongs to three most commonly used chemotherapeutics, progress made to improve its use since its discovery is in fact limited. The mechanism of action of Cisplatin and other platinum compounds resemble that of the alkylating agents. They interact covalently with DNA and form intrastrand (within the same DNA molecule; >90%) or interstrand (between two different DNA molecules; <5%), cross links between adjacent guanine molecules [121]. The formation of DNA adducts results in an inhibition of DNA synthesis and transcription. Platinum compounds act on a cancer cell in every phase of its life cycle, Fig.2. Their use is widespread and includes the treatment of bladder and colorectal cancer, upper gastrointestinal disease, germ cell tumours, head and neck malignancies, lung and ovarian cancer. Their ability to induce secondary cancers reflected by their classification as definite carcinogens by IARC is high [3].
