Current Medicinal Chemistry - Anti-Cancer Agents - Volume 3, Issue 6, 2003

A major challenge for cancer treatment is the preferential and irreversible killing of tumor cells and minimal damage of normal tissues, both in the site of the malignancy and in the body. The agents used in boron neutron capture therapy (BNCT) are supposed to have the following advantages over many conventional chemotherapeutics: 1) when irradiated with thermal neutrons, an unstable isotope 11B is formed whose rapid decay yields local radioactivity and a thermal effect; 2) because the free path of the released particles is close to the cell diameter, the tissues outside the tumor should gain less damage; 3) local radioactivity and heat should be harmful for cells that, in the course of their natural history, acquired the determinants of altered response to many toxic stimuli. However, a higher specificity of damage would be achieved if the drugs accumulate mostly in cancer cells rather than in non-malignant counterparts. Therefore, optimization of agents for BNCT presumes the design of chemicals with improved accumulation / retention in cancer cells. In particular, carboranyl-substituted porphyrins, the stable conjugates of macrocyclic porphyrins with complex boron-containing polyhedra, are considered good candidates for BNCT due to their uptake by cancer cells and high boron content. Importantly, the proposed mechanisms of pharmacological effects of carboranylporphyrins make these compounds potentially appropriate for elimination of pleiotropically resistant tumor cells.

Recently treatment strategies in advanced malignant melanoma have significantly changed. Due to high response rates (e.g. more than 50% for the Dartmouth-regimen), combination chemotherapy has been the standard therapy in several oncological and dermatooncological centers in the USA and Europe. For the last three years different prospective randomized phase III trials failed to achieve similar results. There was no benefit in overall survival and in response duration in comparison to single agent chemotherapy. Currently, randomized clinical trials seem to be the best approach for the clinical treatment of metastatic melanoma. In this review several novel strategies against malignant melanoma are discussed with focus on the role of single agent chemotherapy and biochemotherapy.

Gonadotropin releasing hormone (GnRH) is a hypothalamic decapeptide that binds to GnRH receptors on pituitary gonadotrope cells to modulate the synthesis and secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These gonadotropins in turn regulate gonadal steroidogenesis and gametogenesis. Chemical characterization and structure-activity analysis of GnRH variants containing systematic amino acid substitutions led to the discovery of GnRH superagonists and antagonists. These peptides are widely used for the treatment of clinical conditions in which modulation of or interference with sex hormone production is beneficial to prevent development or progression of benign conditions (e.g. endometriosis, uterine fibroids) or malignant tumors (e.g. breast, ovarian, endometrial and prostate carcinoma). When compared to native GnRH, GnRH superagonists have increased potency for the short-term release of gonadotropins. However, they show paradoxical action in that chronic treatment with superagonists results in inhibition of gonadotropin production as a result of desensitization of the gonadotropes and down regulation of its receptor. In contrast, GnRH antagonists produce a rapid and dose-dependent suppression of gonadotropin release by competitive blockade of the GnRH receptors without any initial stimulatory effect as seen with superagonists. In recent years, a search for peptidomimetic compounds to replace peptides as therapeutic agents has been undertaken to find compounds with higher affinity for the GnRH receptor but do not have the disadvantages of peptides. Such efforts have resulted in the identification and development of small-molecule non-peptide compounds that are sufficiently stable in vivo and possess favorable pharmacological parameters comparable to peptide antagonists. Some of these compounds are being tested in human volunteers and the preliminary results are very encouraging.

Chartreusin and elsamicin A are structurally related antibiotics that bind to GCrich tracts in DNA, with a clear preference for B-DNA over Z-DNA. They inhibit RNA synthesis and cause single-strand scission of DNA via the formation of free radicals. Elsamicin A can also be regarded as the most potent inhibitor of topoisomerase II reported so far. It can inhibit the formation of several DNA-protein complexes. Elsamicin A binding to the P1 and P2 promoter regions of the c-myc oncogene inhibits the binding of the Sp1 transcription factor, thus inhibiting transcription. Despite the pharmacological interest in chartreusin, elsamicin A and their derivatives, there is no experimental data on the structure of their complexes with DNA. This shortcoming has been partially solved by a theoretical approach, which provided some details about the DNAelsamicin A interaction, and the thermodynamic characterization of the binding of chartreusin and elsamicin A to DNA. Elsamicin A but not chartreusin is being developed clinically as an anti-cancer agent. IST-622 (6-O-(3- ethoxypropylonyl)-3',4'-O-exo-benzylidene-chartreusin), a novel semi-synthetic derivative of chartreusin, which has shown a promising anti-cancer activity in a phase II study, appears to be a pro-drug with a more suitable pharmacokinetic profile than chartreusin.

Modern approaches to treatment of cancer seek to activate the internal suicide program in the malignant cells, and thereby effectively eliminate them without engaging most of other bodily systems. Many currently used cytostatics are known to induce apoptosis and efforts are being paid to develop new ones with better and more effective proapoptotic potential. Nevertheless, despite recent developments in this field, there are still numerous malignancies showing a varying degree of resistance to cell death due to the corrupted signaling pathways and genetic alterations, often in conjunction with expansive proliferation rate. It has been shown that topoisomerase inhibiting agents such as etoposide, camptothecin and others represent a powerful and dynamic group of cytostatic chemicals used in experimental and clinical conditions. So, it is a group of microtubule targeting poisons comprising classical colchicines on the one hand and new taxanes on the other hand. Since several members of both groups have been evidenced as apoptosis inducers operating via distinct mechanism, their combination should theoretically enhance the final therapeutic outcome. This minireview focuses on the possibilities of such a combinational approach with respect to possible benefits and hazards of this strategy.

A series of naturally occurring and synthetic novel oxapenam (4-oxa-1- azabicyclo[3.2.0] heptan-7-one) derivatives with their antitumor activity and the structure-activity relationship among this class of compounds is reported. Among the synthetic 4-oxa-1- azabicyclo[3.2.0]heptan-7-one having an ester, amide, ether derivatives of hydroxy group at C-3 position exhibited either no activity or reduced the antitumor activity in vitro. The 3-amino acid 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivatives showed better antitumor activity than naturally occurring 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivative G0069A. The trans isomers exhibited superior stability and activity over the cis isomers at the 3- and 5-position. Some of these compounds showed strong cytotoxicity against P388 and KB cells with IC50 value ranging from 0.004 to 0.6 μg / ml and they did not show any cross resistance against ADR, 5-FU and VCR resistant cell lines in vitro. Of these, 3-hydroxy methyl, 3-(2-amino-2-carboxy-1-benzyloxy ethyl) and 3-(2-amino-2-carboxy ethyl) 4-oxa-1-azabicyclo[3.2.0] heptan-7- one inhibited 71-84% in vivo tumor growth of colon 26 and S-180 cells subcutaneously implanted into mice at a varying dose between 0.625-15 mg / kg / day depending upon the compounds and the tumor cell lines.

The present review focuses on the structural modifications responsible for the transformation of an antibacterial into an anticancer agent. Indeed, a distinctive feature of drugs based on the quinolone structure is their remarkable ability to target different type II topoisomerase enzymes. In particular, some congeners of this drug family display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models. Hence, these cytotoxic quinolones represent an exploitable source of new anticancer agents, which might also help addressing side-toxicity and resistance phenomena. Their ability to bind metal ion cofactors represents an additional means of modulating their pharmacological response(s). Moreover, quinolones link antibacterial and anticancer chemotherapy together and provide an opportunity to clarify drug mechanism across divergent species.