Value In Cancer Treatment Research Articles

Individualized therapies in colorectal cancer: KRAS as a marker for response to EGFR-targeted therapy

Individualized therapies that are tailored to a patient's genetic composition will be of tremendous value for treatment of cancer. Recently, Kirsten ras (KRAS) status has emerged as a predictor of response to epidermal growth factor receptor (EGFR) targeted therapies. In this article, we will discuss targeted therapies for colorectal cancers (CRC) based on EGFR signaling pathway and review published data about the potential usefulness of KRAS as a biological marker for response to these therapies. Results from relevant studies published since 2005 and unpublished results presented at national meetings were retrieved and summarized. These studies reflected response (or lack of response) to EGFR-targeted therapies in patients with metastatic CRC as a function of KRAS status. It has become clear that patients with colorectal cancer whose tumor has an activating mutation in KRAS do not respond to monoclonal antibody therapies targeting EGFR. It should now become a standard practice that any patients being considered for EGFR targeted therapies have their tumors tested for KRAS status and only those with wild-type KRAS being offered such therapies.

Role of Tyrosine Phosphatase Inhibitors in Cancer Treatment with Emphasis on SH2 Domain-Containing Tyrosine Phosphatases (SHPs)

Protein tyrosine phosphorylation is one of the key mechanisms involved in signal transduction pathways. This modification is regulated by concerted action of protein tyrosine phosphatases and protein tyrosine kinases. Deregulation of either of these key regulators lead to abnormal cellular signaling, which is largely associated with human pathologies including cancer. Although the role of protein tyrosine kinases in cancer is well established, less is known about the involvement of protein tyrosine phosphatases in carcinogenesis and tumor progression. Moreover, several inhibitors targeting protein tyrosine kinases have demonstrated their value in cancer treatment, while interest in protein tyrosine phosphatases as a target for treatment has risen more recently. In this review we describe the progressive efforts and challenges concerning the development of drugs targeting phosphatases as promising novel cancer therapies. We focus on two key regulatory SH2 domain-containing phosphatases, SHP-1 and SHP-2 and one of their substrates, signal regulatory protein alpha. Since SHPs have been linked to many different malignancies, protein tyrosine phosphatases could offer a great spectrum of new, targeted drugs.

Elevated expression of SAG/ROC2/Rbx2/Hrt2 in human colon carcinomas: SAG does not induce neoplastic transformation, but antisense SAG transfection inhibits tumor cell growth

Sensitive-to-apoptosis gene (SAG)/regulator of cullins (ROC)2/Rbx2/Hrt2 is a newly identified component of SCF E3 ubiquitin ligase that controls cell-cycle progression by promoting ubiquitination and degradation of cell-cycle inhibitors. We recently found that SAG protects cells from apoptosis induced by redox agents, promotes S-phase entry and cell growth under serum starvation, and is required for yeast growth. In the present study, we report that the SAG protein level was elevated in six of 10 human colon carcinoma tissues (60%) as compared with adjacent normal tissues from the same patient. SAG overexpression in preneoplastic cells in a JB6 tumor promotion-and-progression model did not induce neoplastic transformation, and SAG overexpression in NIH/3T3 cells did not induce transforming foci formation, suggesting that SAG is not a dominant oncogene. However, when DLD-1 human colon carcinoma cells were transfected with antisense SAG, monolayer growth was significantly inhibited, as shown by a decreased number of stable colonies in the plate after normalization with transfection efficiency. Stable clones that expressed antisense SAG showed a 50% decrease in their ability to form colonies when grown in soft agar versus clones that did not express antisense SAG. We found an inverse correlation in four of 10 tumors between the levels of SAG and p27, a cyclin-dependent kinase inhibitor. We concluded that SAG is not causally related to cellular transformation, but its overexpression may be important for the maintenance of tumor cell phenotype. Therefore, targeting SAG expression may have therapeutic value in cancer treatment. Mol. Carcinog. 30:62-70, 2001.

Oral management of patients following oncology treatment: literature review

Many tumours of the head and neck are treated by clinical oncologists using radiotherapy. This treatment modality is particularly effective in destroying rapidly dividing cells, hence its value in cancer treatment. The tissues of the oral mucosa, the salivary glands and blood vessels can be damaged as the result of radiotherapy treatment. As a result, patients experience unwanted oral effects that have both short and long-term implications. The outlook following treatment for head and neck cancer continues to improve and, as people keep their teeth into later life, dentists will increasingly be expected to address the oral problems that patients experience after radiotherapy. The aim of this article is to review the current literature concerning the implications and management of these oral implications of cancer treatment.

Transforming Growth Factor-β System and Its Regulation by Members of the Steroid-Thyroid Hormone Superfamily

TGF-beta s and their receptors are expressed ubiquitously, and they act as key regulators of many aspects of cell growth, differentiation, and function. Steroid action on target tissues is often associated with increase in TGF-beta isoforms. Regulation of TGF-beta expression and activation is crucial for normal development and growth control. The loss of responsiveness of different tumor cells to the antiproliferative effects of TGF-beta is a common feature in carcinogenesis. Multiple changes are required for the cells to gain complete resistance to TGF-beta growth inhibition (Fynan and Reiss, 1993; Kimchi et al., 1988; Samuel et al., 1992). Although many tumor cells are not growth inhibited by TGF-beta, they respond to TGF-beta treatment by changes in the expression of matrix components and enhanced proteolytic activity (KeskiOja et al., 1988). Agents that induce TGF-beta production in target tissues can have a chemopreventive or chemotherapeutic value for the management of epithelial malignancies. Conversely, data supporting a positive role for TGF-beta in established tumor progression are beginning to emerge (Arteaga et al., 1993a,b; Barrett-Lee et al., 1990; Arrick et al., 1992 ; E. A. Thompson et al., 1991). In later stages of tumor development, cell proliferation is often not inhibited by TGF-beta, and tumor cells secrete large amounts of this growth factor (Fynan and Reiss, 1993). In vivo TGF-beta secreted by tumor or stromal cells can influence host responses such as a natural killer cell function and thus indirctly support tumor cell viability (Arteaga et al., 1993b). TGF-beta may also affect tumor growth indirectly by stromal effects and promotion of angiogenesis. TGF-beta may also be involved in the progression of breast tumors from the steroid-sensitive to steroid-insensitive state (King et al., 1989). Understanding of the net effect of TGF-beta in different stages of tumor development is critical for the evaluation of its therapeutic value in cancer treatment.

Cancer patients who refuse treatment

The value of cancer treatment was assessed using a 'natural experiment' where patients who refused treatment served as no-treatment controls in a situation where withholding treatment to form a control group is unethical. Each cancer patient who refused treatment in Alberta, Canada between 1975 and 1988 was compared with five subjects who accepted treatment, matched on cancer site, age, number of cancers, and time period. Variables associated with treatment-refusal were included in Cox's proportional hazards model of survival, with death from cancer as the endpoint and deaths from other causes as censored observations. Treatment was refused at a rate of 7.5 per 1,000. One-third of patients who refused treatment had lung cancer and most had unstaged disease. Treatment refusal was associated with a difference in median survival of approximately nine months. Site-specific analyses showed a range of effects. Case fatality among the treated patients fell by approximately 10 percent during the 14-year study period. Even in advanced disease, treatment can result in improved survival. However, the results of this study must be interpreted with caution and cannot be generalized to all cancer patients.

Cancer: A reactive mechanism in order to try to save life

Cancer is a process of acquisition of an increased variety of cell functions by originally differentiated cells due to the failure of other organs to maintain their specific functions. Cancer cells take over functions of other organs or even other systems, that are chronically decompensated. The organ specific metabolites play an essential role in this process. Cancer is a reactive mechanism of the body to compensate for functions of decompensated organs (systems), in order to try to save life. Consequently, addition of the body's own or similar cancer extracts may be of great value in cancer treatment. A philosophic view of cancer will be briefly discussed.

DNA repair under stress.

When the excision repair process of eukaryote cells is arrested by inhibitors of repair synthesis including hydroxyurea (HU), 1-beta-D-arabinofuranosylcytosine (araC) or aphidicolin, major cellular changes follow the accumulation of repair-associated DNA breaks. These changes, each of which reflects more or less severe cellular stress, include cycle delay, chromosome behaviour, fall in NAD level, the development of double-stranded DNA breaks, rapid chromosome fragmentation and cell killing. Disruption of the repair process by agents such as araC after therapeutic DNA damage may, therefore, have some potential value in cancer treatment. The extreme cellular problems associated with the artificial arrest of repair may have their subtler counterparts elsewhere, and we discuss several systems where delays in the completion of excision repair in the absence of repair synthesis inhibitors have marked repercussions on cell viability. We also show that the average completion time of an excision repair patch varies according to the state of cell culture, and that completion time is extended after treatment with insulin or following trypsin detachment. Under certain growth conditions ultraviolet irradiation followed by mitogenic stimulation results in double-stranded DNA breakage and additional cell killing, and we discuss these data in the light of protocols that have been used successfully to transform human or rodent cells in vitro. Finally, we consider whether the rejoining of DNA breaks accumulated by repair synthesis inhibitors is a valid model system for studying ligation, and show that this protocol provides an extremely sensitive assay for most incision events and, thereby, a means for discriminating between normal human cells on the one hand, and Cockayne's Syndrome cells and their heterozygotes on the other.