Anti-cancer agents in medicinal chemistry
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Anticancer Agents Med Chem · Jul 2010
ReviewExploiting cyclooxygenase-(in)dependent properties of COX-2 inhibitors for malignant glioma therapy.
Cyclooxygenase 2 (COX-2) is frequently found up-regulated during pathological conditions and in cancer, where it is thought to support carcinogenesis and tumor angiogenesis. The development of newer-generation non-steroidal anti-inflammatory drugs (NSAIDs) able to more selectively inhibit cyclooxygenase 2 (COX-2) raised expectations that these agents might be beneficial for cancer prevention and therapy. However, while chemopreventive effects of some selective COX-2 inhibitors have been established, it has remained unpersuasive whether these new NSAIDs, such as celecoxib, rofecoxib or etoricoxib, are able to exert cancer therapeutic effects, i.e., whether they would be beneficial for the treatment of advanced cancers that are already grown and established. ⋯ In fact, newly synthesized close structural analogs of the celecoxib molecule revealed that it was possible to separate COX-2 inhibitory function from the ability to trigger apoptosis; for example, the analog 2,5-dimethyl-celecoxib (DMC) has lost COX-2 inhibitory function, yet exerts increased cytotoxic potency. This review will summarize pertinent results from the exploratory therapeutic use of NSAIDs, in particular celecoxib, in preclinical and clinical studies of malignant glioma. Several COX-2 independent targets will be presented, and it will be discussed how DMC has helped to delineate their relevance for the surmised COX-2 independent tumoricidal effects of celecoxib.
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Anticancer Agents Med Chem · Jun 2009
ReviewCan the status of the breast and ovarian cancer susceptibility gene 1 product (BRCA1) predict response to taxane-based cancer therapy?
Taxanes (paclitaxel and docetaxel) are currently used to treat ovarian, breast, lung, and head and neck cancers. Despite its clinical success taxane-based treatment could be significantly improved by identifying those patients whose tumors are more likely to present a clinical response. ⋯ We argue that levels of BRCA1 in tumors may provide a predictive marker for the response to treatment with taxanes. In addition, the study of the role of BRCA1 in the mechanism of action of taxanes might reveal alternative approaches to avoid resistance.
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Anticancer Agents Med Chem · Feb 2009
ReviewRole 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. ⋯ 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.
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Anticancer Agents Med Chem · Jun 2008
ReviewInhibition of receptor tyrosine kinases in combination with chemotherapy for the treatment of breast cancer.
Although significant advances have been made in the treatment of breast cancer using chemotherapy, less than half of the patients treated for localized breast cancer benefit from adjuvant chemotherapy and most patients with metastatic cancer eventually develop disease that is chemotherapy resistant. Targeted agents, such as inhibitors of tyrosine kinases, offer the opportunity to reverse chemotherapy resistance and enhance response in patients with localized and advanced breast cancer. Such combined approaches have been established for the treatment of advanced breast cancer and are now demonstrating benefit in the adjuvant arena. This review summarizes the results of several trials involving the use of tyrosine kinase inhibition in combination with chemotherapy for the treatment of breast cancer and discusses future directions for breast cancer biotherapy.
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Anticancer Agents Med Chem · May 2008
ReviewTargeting poly (ADP) ribose polymerase I (PARP-1) and PARP-1 interacting proteins for cancer treatment.
Cancer is a disease of uncontrolled cellular proliferation. Chemotherapy and radiation therapy are the two main modalities for cancer treatment. However, some cancer types have been found to be refractory to these treatments. ⋯ Since the resistance of cancer cells to DNA damaging agents stems from the modulation of DNA repair pathways, pharmacological inhibition of these pathways has been emerging as an effective tool for cancer treatment. Inhibition of key proteins involved in the molecular cascade of DNA damage detection and repair such as poly (ADP) ribose polymerase I (PARP-1) and its interacting proteins [DNA dependent protein kinase (DNA-PK) and Cockayne syndrome group B (CSB)] has recently proven to be successful for the treatment of various types of cancer cells and tumor xenografts in vitro. This review summarizes some of the recent findings and the potential application of DNA repair inhibitors in cancer treatment.