Current Medicinal Chemistry - Anti-Cancer Agents - Volume 2, Issue 2, 2002

Cancer chemotherapy is associated with severe side effects which may be reduced by selective liberation, at the tumour site, of a cytotoxic agent from a non-toxic prodrug. Several strategies are used to achieve the required selective activation : with enzymes which are present in higher concentration in, or close, to the tumour (β-glucuronidase, plasmin), with enzymes covalently linked to a macromolecular carrier able to recognize antigen positive cancer cells (ADEPT : Antibody Directed Enzyme Prodrug Therapy) or with reductive processes which are favoured in an hypoxic environment. Most of the prodrugs include a linker (or spacer) between the trigger and the drug (or effector). The design of such linkers is crucial in order to achieve a fast drug liberation under physiological conditions. The linker groups may be classified in two categories based on elimination or cyclization processes. The advantages and the limitations of each strategy are discussed.

The utility of light as a therapeutic agent can be traced back over thousands of years when it was used in Ancient Egypt, India and China to treat a variety of skin diseases like psoriasis, vitiligo, rickets, cancer and psychosis. The isolation of porphyrins and their inherent tumor localizing properties coupled with its ability to generate reactive singlet oxygen when activated by light of particular wavelength which in turn results in cytotoxicity led to the emergence of a new modality namely, photodynamic therapy (PDT) as a therapeutic tool. The higher degree of selectivity offered by this modality and fewer side effects when compared to chemotherapy and radiotherapy has prompted the researchers around the globe to generate new photosensitizers. Porphyrins and expanded porphyrins are one class of molecules under intense investigation due to their photosensitizing ability for PDT application. Expanded porphyrins result from the expansion of the π electron conjugation by increasing the number of heterocyclic rings or bridging carbons of the existing porphyrin framework. These chromophores show strong absorptions in the red region (650-800 nm) compared to that of normal 18πporphyrins. The strong absorption of light by a water soluble nontoxic photosensitizing molecule in the therapeutic window resulting in maximum penetration of light into the tissues coupled with high singlet oxygen production will conceptualize an ideal photosensitizer. This review highlights various porphyrinoid sensitizers reported till date and their photosensitizing ability both in vitro and in vivo studies. Furthermore, the urgent need for developing ideal photosensitizer for PDT will also be highlighted.

Many of the classes of phytochemicals in herbal medicine are finding therapeutic use. In particular, cancer patients are reported to benefit from treatment with herbal medicine and survivability in many cases is significantly enhanced. Recent studies showed the anti-oxidative and superoxide scavenging activities of individual active components of herbal medicine for their inhibitory activities on lipid peroxidation and anti-cancer properties. Individual herbal medicines show antipyretic, analgesic and anti-inflammatory and anti-cancer effects. In addition to sharing many therapeutic activities, herbal medicine is also used in nutrient supplement for anti-cancer and anti-inflammatory activity. Numerous in vitro studies of herbal medicine on different cell lines and in vivo study of herbal medicine have been reported. However, the mechanisms of actions remain unclear. This review aims to give an overview on the recent development of herbal medicine in the prevention and treatment of cancer. The report covers the possible mechanism of action of some of the herbal medicine. In addition, the common properties of herbal medicine are described. Finally, the study sheds lights on the pharmacological applications of herbal medicine in the treatment of cancer and its potential use as anti-cancer agents.

Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are naturally occurring compounds isolated from various Streptomyces species. The PBDs exert their biological activity through covalent binding and exhibit cytotoxicity. Extensive studies have been carried out on the synthetic strategies of PBDs, and a sound understanding of structure activity relationships within this class of compounds has been developed. The PBDs have shown to interfere with the interaction of endonuclease enzymes of DNA and block the transcription by inhibiting RNA polymerase in a sequence specific manner. These processes have been thought to account for the biological activity of PBDs. The PBDs have also been used as a scaffold to attach different type of moieties leading to novel sequence selective DNA cleaving and cross-linking agents. The design and synthesis of C8-linked PBD dimers and other hybrids of PBDs has given a new insight towards the development of molecules with enhanced DNA binding affinity and sequence specificity compared to the naturally occurring PBDs. This improvement in the biological profile has been explained on the basis of certain factors like DNA cross-linking and doubling of DNA binding sites. There seems to be enough potential for further changing the substitution pattern and to design structurally modified PBDs by retaining the PBD core intact. In this review both the synthetic strategies and the structure-activity relationships, particularly the DNA binding and cytotoxicity studies of PBDs have been discussed.

A fermentation directed product search for potential anticancer drugs conducted by Bristol-Myers in the 1970s and early 1980s resulted in the identification of a novel indolocarbazole (IC) rebeccamycin (RBM) as a potential drug development candidate. Subsequently, an analog program designed to impart distal site in vivo antitumor activity resulted in the discovery of diethylaminoethyl analog of RBM (DEAE-RBM), which is presently undergoing clinical evaluation as NSC 655649 and BMY-27557. Strong DNA intercalation is the primary mechanism of action of DEAE-RBM resulting in the potent catalytic inhibition of both topoisomerases I and II. Precursor feeding fermentation experiments with fluorine-substituted tryptophans yielded novel fluoroindolocarbazoles (FICs). These FICs were identified as targeting topoisomerase (topo) I in a mechanism-based screen and their action on topo I was confirmed by production of topo I-mediated single-strand breaks in DNA at sites essentially identical to those induced by camptothecin. Topo I dependent cytotoxicity was demonstrated for specific FICs using a P388 and camptothecin-resistant P388 / CPT45 pair of cell lines, the latter expresses little or no functional topo I. For example, topo I selectivity was greatest with 3,9-difluoro substituted FIC and was least significant and least cytotoxic with 4,8-difluoro substituted FIC. The review focuses on the discovery of the rebeccamycin class of compounds and their structure-activity relationships leading to the development of the clinical candidate BMY-27557 (NSC 655649), as well as the lead identification of the fluoroindolocarbazole class of compounds.

Although 5-fluorouracil (FU) was first introduced in 1957, it remains an essential part of the treatment of a wide range of solid tumors. FU has antitumor activity against epithelial malignancies arising in the gastrointestinal tract, breast as well as the head and neck, with single-agent response rates of only 10-30%. Although FU is still the most widely prescribed agent for the treatment of colorectal cancer, less than a third of patients achieve objective responses. Recent research has focused on the biomodulation of FU to improve the cytotoxicity and therapeutic effectiveness of this drug in the treatment of advanced disease. As all the anticancer agents, FU leads to several toxicities. The toxicity profile of FU is schedule dependent. Myelotoxicity is the major toxic effect in patients receiving bolus doses. Hand-foot syndrome (palmar-plantar erythrodysesthesia), stomatitis, neuro- and cardiotoxicity are associated with continuous infusions. Other adverse effects associated with both bolus-dose and continuous infusion regimens include nausea and vomiting, diarrhea, alopecia and dermatitis. All these reasons explain the need of more effective and less toxic fluoropyrimidines. In the first part of the review, we briefly present the metabolic pathways of FU responsible for the efficacy and toxicity of the drug. This knowledge is also necessary to understand the target(s) of the biomodulation. The second part is devoted to a review of the literature on the various prodrugs of FU, including 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, ftorafur, UFT, and S-1. The promising approach of gene directed enzyme-prodrug therapy is also presented. A brief survey of antibody directed enzyme-prodrug therapy and some new FU prodrugs concludes the paper. The pharmacological principles that have influenced the development of these new drugs and our current knowledge of the clinical pharmacology of these new agents, focusing on antitumor activity and toxicity, are presented.

Protein-Protein (P-P) interactions play a pivotal role in determining cellular structure and in all cellular processes. The nature of P-P interactions is complex, and despite the large amount of research that has occurred in the field, is still poorly understood. Abnormal P-P interactions are particularly important because of their association with a variety of diseases, including cancer. This review examines P-P interactions with particular emphasis on the discovery of new anti-tumor drugs, including underlying physical forces that determine affinity and specificity and discusses classical and newer strategies used to discover inhibitors of P-P interactions, providing a number of recent cancer-related case studies and commentary.