Chemotherapeutic agents, possessing

The development of chemotherapeutic agents for the treatment of cancer has resulted in a significant number of once fatal neoplasia to become classified as curable, or at the very least, treatable. However, despite the great advances in the synthesis of new anti-cancer compounds, these compounds tend to possess nonspecific toxicity restricting their efficiency in vivo. Furthermore, multidrug tumor cell resistance is fairly common. 

Actinomycin D has been clinically used for the treatment of many cancers and is known to be a DNA intercalator. The structure of actinomycin D is based on a phenoxazine ring bound to two cyclic pentapeptides [33]. The presence of the phenoxazine ring in the structure of actinomycin D suggests that phenoxazine derivatives may possess anticancer activity. Phenoxazine derivatives are known to be effective multidrug resistance (MDR) modulators in cancer cells [34], potent inhibitors of Akt signaling in cells [35], inhibitors of human plasma cholinesterase [36], and photo-chemotherapeutic agents in cancer cells [37]. Recent studies also show that the relatively water-soluble phenox-azines, such as 2-amino-4,4a-dihydro-4a,7-dimethyl-2H-phenoxazine-3-one and 2-aminophenoxazine-3-one, exert antitumor effects on various cancer cells in vitro and in vivo. [38]. We have investigated 24 phenoxazines [23,39] (Fig. 4). 

Polyanhydrides degrade primarily by surface erosion and possess excellent in vivo compatibility. In 1996 the FDA approved a polyanhydride-based drug delivery system to the brain of chemotherapeutic agent BCNU, which is currently being manufactured by Guilford Pharmaceutical, Inc. 

The definition of receptors as specific sites for drug action owes much to the work of John Newton Langley [ 1852-1925 ] and Paul Ehrlich [ 1854-1915 ]. Their separate work on the autonomic nervous system and toxins and chemotherapeutic agents led to the concept of a receptor that possesses both recognition and transduction components and of chemotherapeutic molecules possessing discrete molecular features subserving specific functions ... 

Enough evidence, we consider, has now been assembled to show that penicillin is a new and effective type of chemotherapeutic agent, and possesses some properties unknown in any antibacterial substance hitherto described. 

From his extensive work on immunology and the chemotherapy of parasitic infections, Ehrlich argued that cells must possess specific and defined protoplasmic side chains that, because of their unique chemistry and steric architecture, could interact specifically with the complementary groups of a chemotherapeutic agent, toxin or antibody (Parascondola, 1981 Ehrlich, 1900) ... 

Nonclassical 2,4-diaminoquinazoline analogues of folic acid have been of interest as potential chemotherapeutic agents since the early 1970s. Some possess interesting levels of antibacterial activity and remarkable antimalarial effects. The drug trimetrexate (693) displays potent anti-malarial, antibacterial, and antitumor activities, and has been through clinical trials as an anticancer... 

The rifamycins act on the sensitive bacteria, blocking the synthesis of all cellular RNA, because they are potent inhibitors of all bacterial DNA-directed RNA polymerases. Most rifamycins are not effective on the mammalian RNA polymerase. Therefore, they possess the necessary requisite for ideal chemotherapeutic agents, that is, selective toxicity against pathogens. Detailed studies on the mechanism of action of rifamycins revealed that they inhibit the initiation of RNA synthesis by inactivating the enzyme before the incorporation of the first purine nucleotide of the RNA chain. Rifamycins form a rather stable equimolecular complex with the bacterial RNA polymerase, binding with the subunit of the enzyme [201-203]. 

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