Current Cancer Drug Targets - Volume 6, Issue 5, 2006

Breast cancer, the most common form of cancer among women in North America and almost all of Europe, is a significant health problem in terms of both morbidity and mortality. It is estimated that each year this disease is diagnosed in over one million people worldwide and is the cause of more than 400,000 deaths. Although chemotherapy forms part of a successful treatment regime in many cases, as few as 50% patients may benefit from this, as a result of intrinsic or acquired multiple drug resistance (MDR). Through the use of in vitro cell culture models, a number of mechanisms of MDR have been identified; many, if not all, of which may contribute to breast cancer resistance in the clinical setting. This phenomenon is complicated by the likely multi-factorial nature of clinical resistance combined with the fact that, although apparently studied extensively in breast cancer, reported analyses have been performed using a range of analytical techniques; many on small sub-groups of patients, with different clinicopathological characteristics and receiving a range of therapeutic approaches. Larger defined studies, using standardised genomic and proteomics profiling approaches followed by functional genomics studies, are necessary in order to definitively establish the degree of complexity contributing to drug resistance and to identify novel therapeutic approaches - possibly involving chemotherapy, drug resistance modulators, and novel targeted therapies - to combat this disease.

The oxazaphosphorines including cyclophosphamide (CPA), ifosfamide (IFO) and trofosfamide are one important group of alkylating agents. However, resistance is the major hindrance for success of oxazaphosphorine chemotherapy. The mechanism of resistance to oxazaphosphorines is not fully identified, but recently some novel insights into these aspects have been generated by using sensitive analytical techniques and powerful pharmacogenetic techniques. Potential mechanisms for oxazaphosphorine resistance include decreased activation by cytochrome P450s (e.g. CYP3A4, CYP2C9 and CYP2B6), increased deactivation of the agents by deactivating enzymes such as aldehyde dehydrogenases (ALDHs), increased cellular thiol level, increased DNA repair capacity, and altered cellular apoptotic response to DNA repair, e.g. deficient apoptosis due to lack of cellular mechanisms to result in cell death following DNA damage. In addition, decreased cellular accumulation of cytotoxic species of oxazaphosphorines may also play a role in the resistance. This review highlights the pharmacology of oxazaphosphorine anticancer drugs and possible agents that reverse the resistance to these agents. Possible agents that can overcome oxazaphosphorine resistance include inducers of CYPs, modulators of GSTs and ALDHs, modulators of DNA repair process, antisense oligonucleotides against genes encoding various enzymes and signalling proteins, and novel gene delivery systems. Most of these agents have been investigated in preclinical studies and promising results have been observed. To date, several types of these agents are being evaluated in Phase III trials in cancer patients. Further studies are needed to identify the molecular targets associated with resistance to oxazaphosphorines.

Ribonucleotide reductase (RR) is a multisubunit enzyme responsible for the reduction of ribonucleotides to their corresponding deoxyribonucleotides, which are building blocks for DNA replication and repair. The key role of RR in DNA synthesis and cell growth control has made it an important target for anticancer therapy. Increased RR activity has been associated with malignant transformation and tumor cell growth. Efforts for new RR inhibitors have been made in basic and translational research. In recent years, several RR inhibitors, including Triapine, Gemcitabine, and GTI-2040, have entered clinical trial or application. Furthermore, the discovery of p53R2, a p53-inducible form of the small subunit of RR, raises the interest to develop subunit-specific RR inhibitors for cancer treatment. This review compiles recent studies on (1) the structure, function, and regulation of two forms of RR; (2) the role in tumorigenesis of RR and the effect of RR inhibition in cancer treatment; (3) the classification, mechanisms of action, antitumor activity, and clinical trial and application of new RR inhibitors that have been used in clinical cancer chemotherapy or are being evaluated in clinical trials; (4) novel approaches for future RR inhibitor discovery.

Malignant gliomas are frequently chemoresistant and this resistance seems to depend on at least two mechanisms. First, the poor penetration of many anticancer drugs across the blood-brain barrier (BBB), the blood-cerebrospinal fluid barrier (BCSFB) and blood-tumor barrier (BTB), due to their interaction with several ATP-binding cassette (ABC) drug efflux transporters that are overexpressed by the endothelial or epithelial cells of these barriers. Second, resistance may involve the tumor cells themselves. Although ABC drug efflux transporters in tumor cells confer multidrug resistance (MDR) on several other solid tumors, their role in gliomas is unclear. This review focuses on astrocytes and summarizes the current state of knowledge about the expression, distribution and function of ABC transporters in normal and tumor astroglial cells. The recognition of anticancer drugs by ABC transporters in astroglial cells and their participation in the multidrug resistance phenotype of human gliomas is discussed.

A major problem in the search for new cancer drug targets is that the drugs are often toxic to normal tissues and require high doses to kill tumor cells. Therefore cellular targets which appear to involve low dose responses to cancer therapy are especially interesting since they could selectively target normal tissues which are not targeted by the treatment and thus may be responsible for unpleasant side effects or may be amenable to exploitation in order to improve the therapeutic ratio. One such target, which is the subject of this review, is radiation-induced bystander effects [RIBE], which result in the observation of radiation like responses in cells which have not been irradiated. RIBE is a novel phenomenon which indicates that at low doses, cell signaling is more important than direct DNA damage. Historically, DNA has always been considered to be the target for radiation therapy. The growing realization that signaling is important opens up several important therapeutic strategies which will be discussed in this review. RIBE appears to be the result of a generalized stress response in tissues or cells which is expressed at the level of the tissue, organ or organism rather than at the level of the individual cell. The signals may be produced by all exposed cells, but the response may require a quorum of cells in order to be expressed. The major response involving low LET (x- or gamma-ray) radiation exposure discussed in the existing literature is a death response. This has many characteristics of apoptosis but may be detected in cell lines without p53 expression, although the death response is suppressed in many tumor cell lines. While a death response in unirradiated normal cells around a tumor might appear to be adverse, it can in fact be protective and remove damaged cells from the population. If harnessed correctly, it could lead to the development of new drugs aimed not at tissue destruction but at enabling homeostatic mechanisms to control tumor expansion. In this scenario, the level of harmful or beneficial response will be related to the background damage, carried by the cell population, and the genetic programme determining response to damage. This focus may be important when attempting to predict the consequences of mixed therapies involving radiation and other cytotoxic agents. In this review, our current knowledge of the mechanisms underlying the induction of bystander effects by ionizing radiation is reviewed, and the question of how bystander effects may be harnessed to produce a new generation of anti-cancer drugs aimed at stabilization of tissue homeostasis rather than tissue destruction is considered.