Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Etoposide phosphate (Etopophos; Bristol-Myers Squibb Company, Princeton, NJ) is a water-soluble derivative of etoposide, a semisynthetic podophyllotoxin that is important in the treatment of a variety of malignancies, including lung cancer, germ cell tumors, non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute leukemia, etc. Because etoposide is poorly water soluble, it must be dissolved in a polysorbate 80-based solvent mixture, which is moderately allergenic and requires a large volume of saline for administration. Etoposide phosphate is water soluble and is rapidly converted in vivo to etoposide by endogenous phosphatases. Because it is water soluble, etoposide phosphate can be administered in volumes much smaller than those required with etoposide therapy, permitting rapid intravenous administration in the outpatient setting. We recently reported the results of a phase I study using etoposide phosphate on a bolus, daily x 5 schedule. Like others, we demonstrated that etoposide phosphate has pharmacokinetic properties virtually identical to those of etoposide. Our dose-finding study indicated that etoposide phosphate can be used in doses up to 100 mg/m2/d x 5 every 3 weeks in patients who have not had extensive prior chemotherapy, and that a dose of 75 mg/m2 would be appropriate for patients who had undergone multiple prior therapies or who had prior radiotherapy. The dose-limiting toxicity was neutropenia. Paclitaxel, a microtubule-stabilizing agent, is active against a variety of solid and hematopoietic malignancies that overlap with those against which etoposide is active. Because the mechanisms of action of these two agents differ, it is logical to suppose that the combination of the two agents might produce some additive effect when used to treat cancers that respond to both individual agents. We therefore undertook a phase I study using paclitaxel as a 3-hour infusion in combination with a 5-minute infusion of etoposide phosphate daily x 3 every 21 days. We used the 3-hour paclitaxel schedule because it has been shown to be less myelotoxic than longer infusions at the same doses. Our goal in this ongoing study is to determine the maximum tolerated doses of the two drugs in combination, to determine the toxicities of the regimen, and to assess its anticancer activity.
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PMID:A phase I study of etoposide phosphate plus paclitaxel. 899 73

About twenty years ago, the leaders of the National Cancer Institute (NCI) decided to start a new branch in the Clinical Oncology Program of the Division of Cancer Treatment. That new entity was named the Clinical Pharmacology Branch (CPB), and its first leader was a brilliant, young, promising investigator named Bruce A. Chabner. Chabner was educated at Yale and Harvard, and appeared to have an extraordinary grasp of novel concepts that were being developed in the emerging area of cancer chemotherapy. What the NCI leaders did not fully appreciate at the time was that they had just given birth to one of the most extraordinary careers in academic medicine. From the early seventies through the early eighties, Bruce Chabner developed a strong laboratory program that was based on scientific discovery and on the development of new talent. The CPB focused on new drug development, elucidation of drug mechanism(s) of action, and the development of new ways to use drugs that were already available. Concurrent with this laboratory effort was active participation in the development of clinical treatment regimens for Hodgkin's disease, non-Hodgkin's lymphoma, and other malignancies. Individuals who trained under Chabner are now cancer center directors, department heads, laboratory chiefs, and hold many other high-profile positions. From 1981 to 1995 Bruce Chabner was Director of the Division of Cancer Treatment (DCT) of the NCI. In that capacity he was Scientific Director of the Intramural Program within DCT, and he had oversight responsibility for the direction of extramural studies that were funded through the NCI, which were focused on the development of new treatments for human malignant disease. The NCI has five divisions for which the NCI Director has ultimate responsibility. While working with one NCI Director from 1981 to 1988, and with another from 1988 to 1995, and during the transition year of 1988, Bruce Chabner provided stability for the DCT while many changes were occurring throughout the five divisions of the NCI. How does one assess the impact of a career on a discipline such as cancer treatment? It's not easy! Each of the articles contributed to this tribute were written by a person who trained directly with Bruce Chabner, or was otherwise directly impacted by Bruce's guidance. As can be seen from the list of contributors to these Proceedings, each individual has made major contributions to the area of cancer treatment in his or her own right. However, Bruce's contribution to cancer treatment goes far beyond the individuals he trained. The many thousands of human lives who have benefited from his efforts cannot be accurately estimated, because his contributions have been so wide-ranging, as indicated below. Being "Scientific Director" is similar in a number of ways to being a football quarterback. One of those ways is that when things go well the quarterback may get a little too much credit, and when things go not-so-well the quarterback may get too much blame. However, it is the quarterback who "calls the plays." With that in mind, a partial list of the accomplishments of the Intramural Program of the DCT while Bruce Chabner was "quarterback" includes the following: * The first human retroviruses, HTLV-1 and HTLV-2, were discovered and shown to be directly linked to the development of specific human malignancies. * Adoptive immunotherapy for human cancer was developed, offering exciting new additions to the anticancer armamentarium. * Paclitaxel (Taxol®) was developed, and shown to be the most important new anticancer agent in the past two decades. * The human genes responsible for the development of several specific malignancies were discovered, such as those for kidney cancer. * Development of blood tests to detect HIV-tainted blood. * Treatment strategies for pediatric AIDS were developed. * The AIDS Drug Development Program within the NIH was established. * New drugs for the treatment of AIDS and AIDS-related conditions were developed. * The only three drugs to date that have been specifically approved for the treatment of AIDS-AZT, DDI, and DDC-were developed under the guidance of the DCT, with Bruce Chabner as Scientific Director. * The first clinical trials conducted with each of these agents-AZT, DDI, and DDC-were performed in the Intramural Program of the DCT. * Concurrently, many of the exciting findings reported by the National Surgical Adjuvant Breast and Bowel Project over the past 10 years (as well as other cooperative groups) were a direct result of the strong support shown by Bruce Chabner during his tenure as Director of the Division of Cancer Treatment. Further, the list above does not include his personal labortory and clinical accomplishments, some of which are: * Development of the principles of use of important antimetabolites, such as methotrexate. * Elucidation of biochemical pathways affected, and the mechanisms of action, of antifols and other antimetabolites. * The conduct of seminal studies in the clinical staging of non-Hodgkin's lymphomas, using laparoscopy as a primary tool. * Important contributions to the development of multiagent regimens in the clinical treatment of lymphomas, and of Hodgkin's disease. * Developed and is editor of the textbook which is considered to be the primary reference source for anticancer chemotherapeutic agents [1]. With all of these accomplishments, his career is long from over. Having just become the Medical Director of the Cancer Center at the Massachusetts General Hospital, Bruce Chabner is uniquely poised to have an even more far-reaching impact on a discipline in which he has played such a strong seminal role. This author was never a postdoctoral fellow in Bruce Chabner's laboratory. However, more than any other single person, he has played a central role in my professional development. I know of many others for whom the same statement would be true. It is a pleasure for me to witness the launching of the second phase of an already tremendous career. From Advances in Cancer Treatment: The Chabner Symposium. Stem Cells 1996;14:64-65.
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PMID:Closing Remarks. 1038 2

Hodgkin/Reed-Sternberg lymphoma (HL) is a clonal B-cell-related malignancy. Although many patients with HL can be cured by the current regimen of high-dose multi-agent chemotherapy, the treatment causes high risks of later pathologies including secondary malignancies. This fact highlights the demand to develop rational treatment for HL. Survival and growth of HL cells are largely dependent on their microenvironment. In this study, using the HL cell lines L1236 and KM-H2 as model systems, we investigated the role of IL-4/IL-13 signaling in regulation of drug sensitivity and resistance in HL. We show that specific blocking of IL-4 and IL-13-mediated STAT6 activation by either an IL-4-binding fusion protein APG598 or an IL-4R antagonist APG201 (R121D/Y124D) renders HL cells more prone to apoptotic killing by chemotherapeutic drugs such as Mitomycin C, 5-Fluorouracil, Etopside, Doxorubicin and Paclitaxel. This effect is due to inhibition of STAT6-mediated elevation of expression of the anti-apoptotic Bcl-2 family protein Bcl-xL. Employing ChIP analysis in combination with APG201 or STAT6-specific siRNA we identified a defined STAT6-binding site in the Bcl-xL promoter region from -1967 to -1957 of the transcription start site. Our data demonstrate that the IL-4/IL-13-STAT6-Bcl-xL axis may be an important target for HL treatment. This study also suggests that combination of classical chemotherapeutic drugs with the IL-4/IL-13 antagonists may enhance efficacy and reduce risks of toxicity from high dose of drugs in HL treatment.
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PMID:Targeting the IL-4/IL-13 signaling pathway sensitizes Hodgkin lymphoma cells to chemotherapeutic drugs. 2355 37