Current Medicinal Chemistry - Anti-Cancer Agents - Volume 2, Issue 3, 2002

The importance of folylpoly-γ-glutamate synthetase (FPGS) in cancer chemotherapy arises from its function of adding g-L-glutamate moieties to classical antifolates which contain an L-glutamate. Polyglutamylation of classical antifolates used in cancer chemotherapy have certain advantages. The polyglutamylated antifolates are trapped within the cell and hence are retained for a longer duration. In addition some polyglutamylated forms of classical antifolates also inhibit the target folate-dependent enzyme to a greater extent than those monoglumate form. There are however certain drawbacks to this enzymatic transformation of classical antifolates. For those analogs which need polyglutamylation for activation either for retention within tumor cells or to increase inhibitory activity against the target folate-dependent enzyme(s) (both of which could contribute to the antitumor activity of the analog), resistance to the antifolates can be manifested by reduction in the level of FPGS activity. In addition retention of polyglutamate forms of antifolates within normal cells may be a cause of toxicity. Thus the structural requirements for substrate activity for FPGS are of critical importance in the design of classical antifolates as cancer chemotherapeutic agents. In addition classical antifolates which lack the necessity of polyglutamation could circumvent the resistance due to a decrease in the level and activity of FPGS. FPGS activity on natural folate is essential to cell proliferation and survival. Thus inhibition of FPGS activity itself has been suggested as a chemotherapeutic strategy. Structural requirement for inhibition of FPGS have also been studied extensively. This review highlights the synthesis and the structural requirement for substrate and inhibitory activity of classical antifolates for FPGS and their relevance to cancer chemotherapy.

Curcumin, an active yellow pigment of turmeric and curry, possesses anti-inflammatory, antioxidative and anticarcinogenic properties. Analysis of its structure revealed the presence of b-diketone moiety and phenolic hydroxy groups that were believed to contribute to antioxidation. And vanillin, ferulic acid and a dimer of curcumin were identified as the curcumin-derived radical reaction products. In addition to antioxidation, curcumin could also induce apoptosis by targeting mitochondria, affecting p53-related signaling and blocking NF-kB activation. To further dissect its anticarcinogenic mechanisms, a number of curcumin targets were identified. These included the aryl hydrocarbon receptor, cytochrome P450, glutathione S-transferase, serine / threonine kinases, transcription factors, cyclooxygenase, ornithine decarboxylase, nitric oxide synthase, matrix metalloproteinases and tyrosine kinases. This review will summarize our current knowledge on how these important proteins are affected by curcumin, and hopefully, may provide a whole picture illustrating how the chemopreventive and antitumorigenic effect of curcumin is achieved.

Data from all parts of the world show a rising incidence of cutaneous malignant melanoma. The latter is one of the most difficult malignancies to treat. Early stage melanoma is curable but once metastatic it is almost uniformly fatal.Systemic therapy for advanced melanoma includes chemotherapy, either with dacarbazine alone or a multiagent combination chemotherapy, and biological therapy with recombinant interferon-alpha and / or interleukine-2. However none of these treatments options has produced long-term control of the disease except on rare occasion.In the present review, new strategies in the treatment of malignant melanoma that are now under investigations are discussed. Such new strategies might could be open new perspectives avoiding the toxicity of the conventional treatments too. In particular, possible agents acting on signal transduction pathways, such as Protein Kinase C modulators, and on the cell cycle are reviewed.Melanoma is the most immunogenic tumor among all tumor neoplasia. The feature has led to test several immunological strategies for manipulating immune responses in order to induce tumor growth control in vivo. Thus, the most interesting and recent strategies in this field and in particular the possibility to use specific vaccines are also considered.

Modulation of multidrug resistance (MDR) has been extensively studied in vitro and in vivo. However, several clinical trials have failed to show any important benefits in terms of response to chemotherapy or the length of survival using MDR reversing agents. This may be due to the expression or co-expression of other drug resistance mechanisms in malignant cells. Several studies have shown that most, if not all, chemotherapeutic agents exert their anticancer activity by inducing apoptosis; therefore, resistance to apoptosis may be a major factor limiting the effectiveness of anticancer therapy. In the last few years, effort has been made to understand the biochemical alterations of apoptotic pathways in cancer. Many of these alterations confer a multidrug resistant phenotype to malignant cells. In this context, the new recently developed anticancer therapies based on drugs that modulate apoptosis may have importance for the treatment of tumors that are scarcely responsive to the conventional anticancer chemotherapy. In this review, we discuss the current knowledge about drug resistance, apoptosis and cancer and report the recently developed apoptosis modulating strategies that have potential therapeutic implications for the drug resistant tumors.

Angiogenesis, defined as the generation of new blood vessels from pre-existing vessels, is one of life7's essential processes. Inflammation and angiogenesis, while distinct and separable, are closely related processes. One of the hallmarks of chronic inflammation is granulation tissue, a prominent feature of which is neovascularization. Whenever tissue constituents proliferate, repair, or hypertrophy, such change must be accompanied by a proportional increase in capillary blood supply to assure delivery of nutrients, and removal of metabolic waste. This absolute dependence suggests two characteristics of angiogenesis. First, under normal conditions the process must be tightly controlled. Second, in the absence of such strict control, abnormal physiology, or disease is likely to result.The role of angiogenesis in solid tumor growth has attracted a great deal of attention as a potential therapeutic target. Lung cancer is a particularly devastating disease in industrialized countries. The majority of patients with lung cancer are faced with very poor therapeutic options, and gaining insight to the mechanism of angiogenesis in this disease has obvious implications for the design of therapeutic agents. Research in our laboratories has demonstrated that chemokines (chemotactic cytokines) are pivotal determinants of the angiogenic activity of non-small cell lung cancer (NSCLC). This review will focus on the evidence supporting the central role of these molecules in lung cancer angiogenesis, and focus on potential novel means of targeting this family of angiogenic regulators.

Cancer chemotherapy started with the discovery of the cytostatic effect of N-mustard and its derivatives more than five decades ago. This observation opened the way for the synthesis of various alkylating agents, antimetabolites and antimitotics expliciting antitumour activity against several human malignancies. The considerable toxicity of these drugs however, limited their application and only hormone-active products were relatively well tolerated. Besides, the majority of human malignant tumours proved to be chemoresistant. Consequently, there was still an urgent need for finding less toxic compounds possessing broader antitumour spectrum.Therefore, it became obvious that better understanding of the cellular metabolism - due to revolution in molecular biology - yielded new targets for cancer chemotherapeutic agents. Key enzymes active in signal transduction pathways could be blocked by new substances. Cell cycle control could be influenced by apoptosis inducers. Mitotic division could be inhibited by antitubulin agents. Multidrug resistance (MDR) could be modified by revertants.New concepts also emerged: a) chemoprevention, which is based on the principle, that since carcinogenesis is a genetically determined, progressive multistep process it can timely be reconverted into the direction of normal cellular metabolism by redifferentiating agents b) antimetastatic therapy: originally performed postoperatively as an adjuvant therapy nowadays before surgical intervention, in order to block vascular dissemination of tumor cells (neoadjuvant therapy) c) antiangiogenic therapy: substances capable to hinder the vessel production essential for the development of metastasis d) antitelomerase molecules inhibiting the immortal division capacity of DNA in malignant cells.All these new research approaches necessitate to review the existing drugs which are in clinical use or are investigational agents against human malignancies.