Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation. (41/620)

PURPOSE: In the setting of target-based anticancer drug development, it is critical to establish that the observed preclinical activity can be attributed to modulation of the intended target in early phase trials in human subjects. This paradigm of target modulation allows us to determine a Phase II or III dose (optimal biochemical/biological modulatory dose) that may not necessarily be the maximum tolerated dose. A major obstacle to target-based (often cytostatic) drug development has been obtaining relevant tumor tissue during clinical trials of these novel agents for laboratory analysis of the putative marker of drug effect. EXPERIMENTAL DESIGN: From 1989 to present, we have completed seven clinical trials in which the end point was a biochemical or biological modulatory dose in human tumor tissues (not surrogate tissue). Eligibility enrollment required that patients have a biopsiable lesion either with computerized tomography (CT) guidance or direct visualization and consent to sequential (pre and posttreatment) biopsies. RESULTS: A total of 192 biopsies were performed in 107 patients. All but 8 patients had sequential pre and posttreatment biopsies. Seventy-eight (73%) of the 107 patients had liver lesion biopsies. In eight patients, either one or both biopsies contained insufficient viable tumor tissue or no tumor tissue at all for analysis. Of a total of 99 patients in whom we attempted to obtain paired biopsies, a total of 87 (88%) were successful. Reasons for failure included patient refusal for a second biopsy (n = 2), vasovagal reaction with first biopsy precluding a second biopsy (n = 1), subcapsular hepatic bleeding (n = 1), and most commonly obtaining necrotic tumor, fibrous, or normal tissue in one of the two sequential biopsies (n = 8). CONCLUSIONS: This is the first and largest reported series demonstrating that with adequate precautions and experience, sequential tumor biopsies are feasible and safe during early phase clinical trials.  (+info)

The proteasome: a new target for novel drug therapies. (42/620)

The proteasome is an enzyme present in all cells, from yeast to human, and has a central role in the proteolytic degradation of the vast majority of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in controlling inflammatory processes, cell cycle regulation, and gene expression. As such, agents that inhibit the proteasome have been shown to be active in numerous animal models of inflammation and cancer Two proteasome inhibitors are under clinical evaluation. PS-519 is being studied for the treatment of reperfusion injury that occurs following cerebral ischemia and myocardial infarction. The other, PS-341, has recently entered multiple phase 2 clinical trials for the treatment of multiple myeloma, chronic lymphocytic leukemia, and a variety of solid tumors. The proteasome may have an important role in the evolution of HIV-related disorders including AIDS and inflammatory disorders. Therapeutic strategies using proteasome inhibitors for the treatment of these conditions have now entered preclinical development.  (+info)

The development of camptothecin analogs in childhood cancers. (43/620)

Camptothecin analogs, agents that target the intranuclear enzyme topoisomerase I, represent a promising new class of anticancer drugs for the treatment of childhood cancer. In preclinical studies, camptothecins, such as topotecan and irinotecan, are highly active against a variety of pediatric malignancies including neuroblastomas, rhabdomyosarcomas, gliomas, and medulloblastomas. In this paper, we review the status of completed and ongoing clinical trials and pharmacokinetic studies of camptothecin analogs in children. These and future planned studies of this novel class of cytotoxic agents are critical to defining the ultimate role of topoisomerase I poisons in the treatment of childhood cancer.  (+info)

Induction of cytostasis in mammary carcinoma cells treated with the anticancer agent perillyl alcohol. (44/620)

The monoterpene perillyl alcohol (POH) has preventive and therapeutic effects in a wide variety of pre-clinical tumor models, including those for breast cancers, and is currently being tested in human phase I clinical trials. POH causes both cytostasis and apoptosis in rat mammary carcinomas. In vitro, POH inhibits cellular proliferation in a variety of mammalian cell lines. Here we investigated the mechanisms underlying cytostasis by studying the effects of POH on the cell cycle in vitro using the murine mammary transformed cell line TM6. In TM6 cells, POH causes an early G(1) cell-cycle block and slows the G(2)-M transition. An increase in pRB in its hypophosphorylated state is associated with the early G(1) block caused by POH. POH treatment inhibits two important targets in the cells during the G(1)-S transition: cyclin D1- and cyclin E-associated kinase. POH treatment leads to a reduction in cyclin D1 RNA and protein levels and prevents the formation of active cyclin D1-associated kinase complexes in synchronous cells during the exit of G(0) and entry into the cell cycle. In addition, POH treatment induces an increased association of p21(WAF1) with cyclin E-Cdk2 complexes, and inhibits the activating phosphorylation of Cdk2. All these effects of POH may contribute to the inhibition of the transition out of the G(1) phase of the cell cycle.  (+info)

Gene therapy for liver diseases: recent strategies for treatment of viral hepatitis and liver malignancies. (45/620)

Gene therapy has emerged as a powerful and very plastic tool to regulate biological functions in diseased tissues with application in virtually all medical fields. An increasing number of experimental and clinical studies underline the importance of genes as curative agents in the future. However, intense research is needed to evaluate the potential of gene therapy to improve efficacy and minimise the toxicity of the procedure.  (+info)

The status of high-dose chemotherapy with hematopoietic stem cell transplantation in germ cell tumor patients. (46/620)

BACKGROUND AND OBJECTIVES: Germ cell tumors (GCTs) are very chemosensitive cancers, in which high-dose chemotherapy (HDCT) has been investigated as salvage therapy or as first-line treatment in poor prognosis patients. This paper presents an update of available information in order to define the status of HDCT in GCT patients. INFORMATION SOURCES: The authors have been working in this field, contributing to international clinical trials and to peer-reviewed journals with original papers. The material examined in this review includes articles published in journals covered by MedLine, reviews from journals with high impact factor, and unpublished data from the European Group for Blood and Marrow Transplantation (EBMT) registry. STATE OF THE ART AND PERSPECTIVES: The delineation of prognostic factors associated with a poor probability of survival after HDCT contributed to the selection of patients who are likely to get an advantage from HDCT and those who should be spared from dose-intensive treatment. HDCT as first-line therapy for poor prognosis GCT (IGCCCG classification), and in a salvage setting in good risk GCT (prognostic index from Beyer et al.77), has been associated with a very high rate of complete remissions and long-term disease-free survivors. However, it is important to wait for the results of ongoing randomized trials for the validation of these findings. Other strategies are required for patients with refractory GCTs. Several new treatment options are currently emerging for this subset of patients.  (+info)

Angiogenic gene therapy: pre-clinical studies and phase I clinical data. (47/620)

Over the last three decades, significant progress has been made in the management of patients with atherosclerotic coronary and peripheral vascular diseases using medical, surgical, and percutaneous therapies. Despite these advances, there remains a significant population of patients who are not optimal candidates for surgical or percutaneous revascularization. These patients continue to suffer from the debilitating symptoms of their disease and remain at risk for myocardial infarction, limb loss, or death. It was this clinical need, coupled with the advances in the understanding of angiogenesis, that has led to efforts to develop angiogenic therapies for patients with peripheral and myocardial ischemia. In general, these conditions are characterized by local hypovascularity, and the approach to treatment is therefore focused on stimulating neovascularization.  (+info)

Telomerase as a universal tumor-associated antigen for cancer immunotherapy. (48/620)

Although the search for pharmacologic inhibitors of telomerase activity represents a promising approach for telomerase-based anti-cancer therapy, the immunological properties of the telomerase reverse transcriptase hTERT suggest that the enzyme is also an attractive target for novel immunotherapies against cancer. Data from both human and murine systems demonstrate that cytotoxic T-lymphocytes (CTL) can recognize peptides derived from TERT and kill TERT-positive tumor cells of multiple histologies. Given the vast overexpression of hTERT in human tumors and its low-level expression in rare normal tissues, clinical trials have begun that test the credentials of hTERT as a broadly applicable target for immunotherapy of cancer.  (+info)