Current Medicinal Chemistry - Anti-Cancer Agents - Volume 4, Issue 6, 2004

The role of peroxisome-proliferator activated receptor (PPAR)γ in tumor growth inhibition has been extensively studied during last seven years but still remains debated. Many in vitro and xenograft studies have demonstrated that PPARγ ligands are anti-tumorigenic due to anti-proliferative, pro-differentiation and anti-angiogenic effects. In animal models, PPARγ ligands have shown preventive effects against chemical carcinogenesis. On the other hand, evidences are accumulating against the possible use of this ligand activated nuclear receptor in molecular targeting for cancer therapy. The growth inhibitory effects of certain PPARγ ligands have recently been shown to be independent of PPARγ-activation. Studies have also come up with results indicating the growth promoting effects of PPARγ-activation, particularly in certain animal models genetically predisposed to cancer development. Loss-of-function mutations of PPARγ in tumors and increased susceptibility of PPARγ heterozygote knockout mice to carcinogenesis suggested a tumor-suppressing role of PPARγ. However, recent findings do not support PPARγ as a tumor suppressor gene. Although initial clinical trials with PPARγ ligand troglitazone reported promising results in liposarcoma and prostate cancers, recent studies failed to show the expected therapeutic values in advanced colorectal and breast cancers. In this review, we have addressed these controversies on potential use of PPARγ ligands in cancer therapy.

Bioprospecting and natural products drug development for cancer treatment has become an important area. Most of the cancer chemotherapeutic agents are associated with toxicity towards normal cells and tissues. Optimal dosing of cancer chemotherapeutic agents is often limited because of severe non-myelosuppressive and myelosuppressive toxicities. It is a continuing challenge to design therapy that is safer, effective and selective. Cytoprotective agents offer opportunities to reduce treatment related toxicity of anticancer therapy without diminution of efficacy. None of the available agents satisfy criteria for an ideal cytoprotection. This has stimulated research for discovering natural resources with immunomodulatory and cytoprotective activities. This article describes chemical agents presently employed in clinical practice and reviews ethnopharmacological agents reported to have chemoprotective, radioprotective, immunomodulating, adaptogenic and antitumour activities.

Tamoxifen is a well-known antiestrogen used for the hormonotherapy of estrogen receptor positive breast cancer. In addition to its high affinity binding to the estrogen receptor (ER), tamoxifen binds with comparable affinity to the microsomal antiestrogen binding site (AEBS), and inhibits with a micromolar efficiency, protein kinase C (PKC), calmodulin (CaM)-dependent enzymes and Acyl CoenzymeA: Cholesterol Acyl Transferase (ACAT). Each of these tamoxifen targets might explain the genomic as well as non-genomic effects of tamoxifen. In this review, we will report current knowledge about the structural features of tamoxifen involved in this multiple targeting. These data provide a useful guide for the conception of selective ligands of ERs, AEBS, PKC, CaM or ACAT based on the chemical structure of tamoxifen.

Natural and synthetic indolocarbazole compounds have triggered considerable interest since the discovery in 1986 of the inhibitory properties of staurosporine toward protein kinase C (PKC). Later, it has been shown that indolocarbazole compounds may inhibit various kinases, such as cyclin dependent-kinases and / or topoisomerase I, someones behave only as DNA intercalators. In this review are presented various indolocarbazole compounds bearing a sugar moiety and their biological targets. The relevance of these targets to develop indolocarbazole compounds as potential antitumor agents is discussed.

Microsomal cytochrome P450 (CYP 450) enzyme aromatase belongs to CYP 19 super family. It is involved in the conversion of androgens to estrogens. In postmenopausal women the main sites of aromatisation are skin, adipose tissue and breast. Aromatase localized in breast tumor produces sufficient estrogen for its proliferation. Hence it is an important target for the treatment of hormone dependent breast cancer in postmenopausal women. There are mainly two types of aromatase inhibitors, one is steroidal another is nonsteroidal type. The first and second generation aromatase inhibitors encounter the undesirable drug- drug interactions besides being not very specific and plagued with pharmacokinetic problems. Third generation aromatase inhibitors developed recently are more potent and specific with a greater capacity to annihilate circulating estrogen levels. These agents have satisfactory pharmacokinetic profiles and are devoid of major drug-drug interactions. Third generation aromatase inhibitors became drugs of choice for both first and second line treatment of advanced breast cancer. Aromatase inhibitors can also be used for neoadjuvant therapy of breast cancer in which they have achieved better therapeutic efficacy than tamoxifen. Early results of ATAC (Armidex Tamoxifen Alone or Combination) trial suggest that anastrozole is superior to tamoxifen in adjuvant setting for disease free survival, particularly in receptor positive patients, and in reducing the incidence of contralateral breast cancer. Therapeutic potential of aromatase inhibitors stretches beyond the postmenopausal breast cancer treatment as they also play a role in the treatment of estrogen dependent benign and malignant conditions such as gynaecomastia, prostate cancer, fibroadenomata and the induction of ovulation. By virtue of their ability to reduce estrogen levels they pose problems like demineralization of bone, hot flushes and anti-implantation effects.

Acethlycholine (Ach), one of the most important examples of a neurotransmitter, represents a phylogenetically old molecule, widely distributed from bacteria to humans. The finding that neuronal Ach receptors (nAChRs) are present in non-neuronal cells raised some interesting issues related to their specific activity. In humans, different studies have showed that many lung cancer cells expressed nAchRs and that low concentrations of nicotine blocked the induction of apoptosis in these cells. A recent study presents data that SCLC express a cholinergic autocrine loop that can regulate cell growth. Such work demonstrates that SCLC cells have a cholinergic phenotype and that ACh exerts as an autocrine growth factor in human lung tumors. Recently it has been shown that human malignant pleural mesothelioma express a cholinergic system, involved in cell growth regulation. Hence, mesothelioma cell growth as well as normal mesothelial cells growth is modulated by the cholinergic system in which agonists (i.e. nicotine) has a proliferative effect and antagonists (i.e. curare) has an inhibitory effect. Furthermore apoptosis mechanisms in mesothelioma cells are under the control of the cholinergic system (nicotine antiapoptotic via induction of NF-κB complexes and phosphorilation of Bad at Serine112, curare proapoptotic via G0-G1 arrest p21waf-1-dependent, but p53-independent). The involvement of the non-neuronal cholinergic system in lung cancer and mesothelioma appears reasonable and open up new therapeutic strategies.

Salivary gland cancers are a rare malignancy accounting for less than 1% of all cancers and 3-6% of cancers of the head and neck region. The classification of salivary gland tumors is traditionally based on morphology and the different subtypes exhibit various clinical behaviors. The low grade and biologically indolent cell types include the adenoid cystic, acinic cell and adenocarcinoma while the salivary duct, squamous and mucoepidermoid are more active and high grade. The initial management of salivary gland malignancies is to assess resectability and possible adjuvant radiation therapy. Those with locoregional recurrence or metastatic disease are treated with systemic therapy. Numerous studies with small sample sizes have assessed the activity of different cytotoxic agents. Both single agent and combination chemotherapy have been used for the treatment of this disease. For these agents, the response rates are generally modest with objective response rates ranging from 15-50%. Duration of response is typically cited in the range of 6-9 months. Clinicopathological data have demonstrated correlations between poor clinical outcomes and the expression of molecular markers such as mutated p53 protein and vascular endothelial growth factor (VEGF) in salivary gland cancers. Recent studies have also evaluated the epidermal growth factor receptor family including erbB1 / EGFR and erbB2 / HER2 as potential therapeutic targets. While the prognostic significance of EGFR overexpression has not been well defined, overexpression of the HER2 oncoprotein has been associated with biological aggressiveness and poor prognosis in most series. Given the suboptimal response rates, duration of response, and toxicity of conventional chemotherapy, a better understanding of the biology of salivary gland malignancies will lead to improved prognostication and treatment. With the emergence of molecular targeted therapy, these tumors become an optimal candidate for trials of investigational drugs and established drugs for new indications.