Update on cancer therapeutics最新文献

Cervical cancer is the second commonest causes of cancer death among women worldwide. Uniquely amongst human cancers, it is entirely attributable to infection. Persisting infection of anogenital epithelium with one of a limited subset of human papillomaviruses (HPVs) is necessary for the development of cervical cancer. Several recent large clinical trials have shown that prophylactic vaccines, based on PV virus particles produced using recombinant DNA technology, provide long lasting immunity against infection with the incorporated PV genotypes, and against premalignant conditions caused by these infections. Effective deployment of these vaccines, which have excellent safety and efficacy profiles, could eventually reduce the global burden of cervical cancer by up to 70% through universal immunisation of preadolescent girls. Vaccine use will supplement rather than replace cervical cancer screening programs, where these programs already exist.

Adoptive T-cell therapy is an attractive option for targeting tumors associated with Epstein-Barr virus. In immunogenic Type III latency tumors such as post transplant lymphoproliferative disease, EBV-specific CTL have been used successfully as prophylaxis and treatment. In Type II latency malignancies such as Hodgkin's disease and nasopharyngeal cancer, a more restricted array of EBV antigens are encoded and the clinical response rates after infusion of EBV-specific CTLs have been lower. Current strategies to increase response rates include targeting CTL to subdominant EBV antigens and genetically modifying CTL to increase their potency.

Introduction

Central nervous system (CNS) tumors cause a significant amount of morbidity and mortality. More research is needed to improve the prognosis of patients with CNS tumors, and especially for those with malignant gliomas. The advances over the last several years in the treatment of adult central nervous system tumors are reviewed here.

Materials and methods

Phase II and Phase III trials published in major peer-reviewed journals between 2005 and 2006 were examined. Adult central nervous system tumors including malignant glioma, low-grade glioma, primary central nervous system lymphoma, brain metastases, and neoplastic meningitis, were included.

Results

Phase II treatment trials for patients with gliomas dominated the literature in the time-period examined. Trials primarily addressed radiotherapy as well as chemotherapy in the treatment of gliomas. A number of trials examined targeted agents as single agents and in combination with systemic therapy in glioma patients. A few studies evaluated the role of chemotherapy and radiation in metastatic disease and primary CNS lymphoma.

Conclusions

Temozolomide is now the new standard of care in combination with radiation therapy for newly diagnosed glioblastomas. The optimal dosing and length of adjuvant temozolomide treatment remains unclear, and there remains no current role for neo-adjuvant therapy. Targeted agents that can be used in the salvage or front-line setting, alone or in combination with systemic therapy, will likely be the focus of future research. For metastatic brain tumors, more studies are needed to examine the exact role of radiosurgery, whole brain radiation, and the role of other therapies such as temozolomide or targeted agents. For primary CNS lymphomas, the role of various high-dose methotrexate regimens is being actively investigated.

Preclinical and early clinical trials indicate synthetic oligodeoxynucleotides containing unmethylated CG dinucleotides (CpG ODN) have potent immunostimulatory effects and can enhance the anti-cancer activity of a variety of cancer treatments. Synergy between CpG ODN and monoclonal antibodies has been noted in various preclinical models. Early clinical trials indicate CpG ODN and monoclonal antibodies can be administered safely together. Preclinical models indicate CpG ODN can enhance the anti-tumor activity of both chemotherapy and radiation therapy. Thus, one possible approach to the use of CpG ODN was to use it in combination with cytotoxic chemotherapy with the goal of enhancing presentation of tumor antigen from dying cancer cells. Promising results in a randomized phase II trial in patients with non-small cell lung cancer led to initiation of two large randomized phase III trials comparing CpG ODN plus chemotherapy to chemotherapy alone. Unfortunately, interim analysis of these trials indicated CpG ODN was unlikely to enhance efficacy of chemotherapy, and they were stopped. CpG ODN also holds promise as a component of cancer vaccines including those composed of protein antigen, peptides, whole tumor cells, and antigen-pulsed dendritic cells. Finally, CpG ODN has been combined with a variety of cytokines to enhance NK activation, promote development of an active anti-tumor immune response or induce apoptosis of malignant cells that express the TLR9 receptor. Overall, both preclinical and early clinical trials suggest CpG ODN may be a valuable component of a variety of approaches to cancer therapy. However, clinical development of this recently discovered, novel class of immunostimulatory agents is just beginning, and we still have much to learn about the optimal approach to their use, and their potential.

Although most patients with thyroid cancer do well with traditional therapy, some will go on to develop progressive disease. In the past, few effective treatment options were available for patients with metastatic thyroid carcinoma. However, advances in our understanding of the molecular basis of thyroid cancer initiation and progression have led to many new potential therapies targeted at specific molecular pathways. Many of these novel compounds have been evaluated in cell lines, animal models, and recently, in clinical trials. This review will focus on new potential therapies in the treatment of progressive thyroid cancer, with an emphasis on the activity of these agents in the clinical arena.

Topoisomerase II is an enzyme essential for DNA replication, chromosome condensation and chromosome segregation. Inhibitors of topoisomerase II are important drugs used in the therapy of many neoplasms including breast cancer, lung cancer, testicular cancer, lymphomas and sarcomas. This paper reviews the mechanism of action, toxicities, pharmacology and clinical use of topoisomerase II inhibitors including etoposide, teniposide, doxorubicin, daunorubicin, epirubicin, idarubicin and mitoxantrone. New information regarding these agents and on topoisomerase II inhibitors under development is highlighted.