Current Pharmaceutical Design - Volume 8, Issue 19, 2002

This review describes gene therapy strategies that take advantage of defective signal transduction pathways to selectively kill cancer cells without adversely affecting normal cells. The distinctive features of cancer cells currently exploited by gene therapy include mitosis, cell permissiveness to infection, specific protease activity, and the activity of the p53, Rb / E2F and wnt / catenin signal transduction pathways. In most cases, proof of concept has been obtained in vitro and in vivo, but only a few approaches made it to the clinic. Overall, the clinical success rate has been disappointing and it is concluded that the gene therapy of cancer requires more innovation and hard work before its potential can be fully realized.

Colorectal cancer is one of the leading causes of cancer deaths in the Western world. More than 56,000 newly diagnosed colorectal cancer patients die each year in the United States. Available therapies are either not effective or have unwanted side effects. Epidemiological data suggest that dietary manipulations play an important role in the prevention of many human cancers. Curcumin the yellow pigment in turmeric has been widely used for centuries in the Asian countries without any toxic effects. Epidemiological data also suggest that curcumin may be responsible for the lower rate of colorectal cancer in these countries. Curcumin is a naturally occurring powerful anti-inflammatory medicine. The anticancer properties of curcumin have been shown in cultured cells and animal studies. Curcumin inhibits lipooxygenase activity and is a specific inhibitor of cyclooxygenase-2 expression. Curcumin inhibits the initiation of carcinogenesis by inhibiting the cytochrome P-450 enzyme activity and increasing the levels of glutathione-S-transferase. Curcumin inhibits the promotion / progression stages of carcinogenesis. The anti-tumor effect of curcumin has been attributed in part to the arrest of cancer cells in S, G2 / M cell cycle phase and induction of apoptosis. Curcumin inhibits the growth of DNA mismatch repair defective colon cancer cells. Therefore, curcumin may have value as a safe chemotherapeutic agent for the treatment of tumors exhibiting DNA mismatch repair deficient and microsatellite instable phenotype. Curcumin should be considered as a safe, non-toxic and easy to use chemotherapeutic agent for colorectal cancers arise in the setting of chromosomal instability as well as microsatellite instability.

The epothilones are a novel class of non-taxane microtubule-stabilizing agents obtained from the fermentation of the cellulose degrading myxobacteria, Sorangium cellulosum. Preclinical studies have shown that the epothilones are more potent than the taxanes and active in some taxane-resistant models. Similar to paclitaxel and other taxanes, the epothilones block cells in mitosis, resulting in cell death. The chief components of the fermentation process are epothilones A and B, with epothilones C and D found in smaller amounts. Trace amounts of other epothilones have also been detected. Pre-clinical studies have shown that epothilone B is the most active form, exhibiting significantly higher antitumor activity than paclitaxel and docetaxel. Several phase I and phase II clinical trials are ongoing with epothilone B and BMS 247550, an epothilone B analog. Preliminary reports indicate these agents are active against human cancers in heavily pretreated patients. The epothilones appear to be well tolerated, with a side effect profile that is similar to that reported with the taxanes. This article will review some basic aspects of epothilone chemistry and biology, and pre-clinical and preliminary clinical experience with epothilone B and its analog, BMS 247550.

Farnesyltransferase catalyzes the transfer of a farnesyl residue from farnesylpyrophosphate to the thiol of a cysteine side chain of proteins which carry at the C-terminus the so called CAAX-sequence. Although the exact cellular events affected by farnesyltransferase inhibiton remain to be determined, farnesyltransferase has become a major target in the development of potential anti-cancer drugs. Numerous farnesyltransferase inhibitors have been described from which the majority are CAAX-peptidomimetics possessing a free thiol group which coordinates the enzyme-bound zinc ion. The development of farnesyltransferase inhibitors is clearly directed towards the so-called non-thiol farnesyltransferase inhibitors because of adverse drug effects connected to free thiols. This review mainly deals with the efforts of the authers group towards the design of non-thiol-farnesyltransferase inhibitors. Our first step on the way to non-thiol farnesyltransferase inhibitors was the development of an CAAX-peptidomimetic based on a pharmacophore model. On the basis of this benzophenone core, bisubstrate analogues were developed as one class of non-thiol farnesyltransferase inhibitors. In most non-thiol farnesyltransferase inhibitors known in literature nitrogene containing heterocycles are used as cysteine replacements supposedly coordinating the enzyme bound zinc. However, we and others have shown that nitrogen heterocycles can be replaced by aryl residues lacking the ability to coordinate metal atoms, an observation which let to the postulation of two hitherto unknown aryl binding sites. Using flexible docking of model compounds and GRID analysis we were able to locate these postulated aryl binding sites. Subsequently, we used one of this aryl binding sites for the structure based design of highly active non-thiol farnesyltransferase inhibitors.

Therapeutic management of cancer has undergone tremendous conceptual advance over the last couple of decades. Not only are we better acquainted with the intricate mechanisms leading to oncogenic transformation, but also the strategies to intercept and disturb these command and control pathways are becoming more specific and target-selective. One critical change is the realization that despite the existence of diverse mechanisms for the development of different sub-sets of cancers, there may indeed be central regulatory networks that serve as a common denominator in all forms of neoplasia. These critical events could endow cells with the potential for unabated proliferation, insensitivity to death inducing signals, and enhanced metastatic potential. Thus, developing strategies to target these critical events or pathways should significantly improve the outcome of cancer chemotherapy. The purpose of this review is to briefly discuss the complexities of the disease, highlight the current therapeutic strategies, and more importantly provide a mechanistic approach for future drug design aimed at targeting the traits of the disease and for favorably tailoring the response of cancer cells to drug therapy.

After more than 100 years since the first adjuvant for a cancer vaccine was described and more than a decade since the first tumor antigen has been molecularly cloned, it seems possible that cancer vaccines might be integrated into the standard care of cancer patients. Exciting new technologies concerning tumor antigen discovery, vaccine delivery and formulation define the basis for enormous efforts in academia as well as in the pharmaceutical and biotech industry. With the unveiling of the human genome additional targets will emerge that could further enhance vaccine efficacy, specificity and clinical applicability. Most likely therefore, tumor antigen targets which are widely expressed in cancer will be of advantage over patient-oriented approaches due to their favorable cost-to-benefit ratio. Some widely expressed candidate tumor antigens and methods to discover additional widely expressed tumor antigens are discussed here. While the armamentarium of potential tools to cancer vaccine development seems to be endless, only those that are scientifically sound yet economically reasonable will - in the end - have a chance to become clinically useful cancer vaccines.

Treatment of patients with unconjugated MAb such as rituximab (Rituxan) the anti-CD20 MAb or trastuzumab (Herceptin) the anti-Her2 MAb, have shown efficacy in clinical trials and have gained approval from the Food and Drug Administration (FDA) has a result. Likewise, an anti-CD33 MAb conjugated with the antibiotic calicheamicin (Mylotarg) has proven efficacious in the treatment of patients with acute myeloid leukemia and has also been approved by the FDA. This overview presents some of the monoclonal antibody (MAb)-guided strategies with a focus on some of the experiences reported for MAb evaluated in clinical trials.

Ionizing radiation exhibits immunomodulatory properties, which could portend a future collaboration of cancer immunotherapy with radiation therapy. The “danger” model of immunity describes antigen-specific cellular immunity engendered by an inflammatory milieu. Dendritic cells (DCs) are attracted to this microenvironment, undergoing maturation after internalizing apoptotic and necrotic cellular debris. Mature DCs mediate antigen-specific cellular immunity via presentation of processed antigen to T cells. Administration of radiation has been utilized in vitro and in vivo to create an inflammatory setting, via induction of apoptosis, necrosis, cell surface molecules, and secretory molecules. Caspase-mediated cellular apoptosis is induced by radiation thro ugh multiple signaling pathways. Radiation upregulates expression of immunomodulatory surface molecules (MHC, costimulatory molecules, adhesion molecules, death receptors, heat shock proteins) and secretory molecules (cytokines, inflammatory mediators) in tumor, stromal, and vascular endothelial cells. Results of animal studies indicate possible radiation-mediated modulation of tumor antigen-specific immunity. Experimental data could indicate that the radiation-induced “danger”microenvironment engenders a DC-mediated antigen-specific immune response. Further enhancement of radiation-mediated inflammation and cell death can be achieved via administration of radiosensitizing pharmaceuticals. Radiation-mediated immune modulation currently remains unquantified and poorly understood. A major research effort will be required to elucidate mechanisms of action. With a thorough understanding of this phenomenon, we believe that ionizing radiation could be optimized for use with cancer vaccines and generate tumor antigen-specific cellular immunity.