Seminars in oncology
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Seminars in oncology · Oct 2000
Biological rationale for HER2/neu (c-erbB2) as a target for monoclonal antibody therapy.
The physical characteristics of tumor antigens that would make the most ideal targets for antibody therapeutics include cell surface expression; high, stable expression levels in tumor cells; low or absent expression in normal tissues; lack of a soluble form of the antigenic target; and lack of internalization of the antigen/antibody complex. HER2/neu is a 185-kd surface membrane protein that is overexpressed in approximately 25% of human breast cancers due to amplification of the HER2 gene. Overexpression of the gene results in ligand-independent activation of HER2 kinase, causing mitogenic signal transduction and increased cell proliferation. ⋯ We propose that the efficacy of trastuzumab may be explained on the basis of its effects on signal transduction, which is independent from its immune mechanism(s) of action. Furthermore, trastuzumab is synergistic with some chemotherapeutic drugs, resulting in improved therapeutic efficacy. Thus, in the case of trastuzumab, a clear distinction may be drawn between the use of monoclonal antibodies as immuneactive agents and their use to achieve a desired cellular/biochemical activity.
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Seminars in oncology · Jun 2000
ReviewTemozolomide in early stages of newly diagnosed malignant glioma and neoplastic meningitis.
Temozolomide is a novel, oral, second-generation alkylating agent. Preclinical and phase I/II studies have demonstrated its efficacy against newly diagnosed high-grade glioma and anaplastic astrocytoma. Its antineoplastic effect is accompanied by quality of life benefits in patients with these debilitating tumors. ⋯ Patients treated with temozolomide benefit from both its systemic and intracranial activity. Recently, intrathecal temozolomide has been shown to increase median survival in athymic rats bearing subarachnoid human malignant glioma xenografts. Its efficacy, convenient dosing, and predictable safety profile make it an ideal agent for future study of these difficult-to-treat central nervous system malignancies.
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Seminars in oncology · Jun 2000
ReviewChemotherapy for advanced ovarian cancer: overview of randomized trials.
Until the mid-1970s, standard therapy for ovarian carcinoma was a single alkylating agent. Subsequently, combination chemotherapy was shown to be superior to such therapy. During the 1980s, cisplatin-based combination chemotherapy became the standard chemotherapy regimen for advanced ovarian cancer; however, other classes of agents with documented activity against ovarian tumors appeared to be cross-resistant with platinum. ⋯ During the 1990s, the combination of platinum (cisplatin or carboplatin) plus paclitaxel rapidly evolved into front-line chemotherapy for advanced ovarian cancer. The series of randomized phase III studies that have compared the activity of platinum/paclitaxel with alternative regimens, including the previous standard combination of cisplatin/cyclophosphamide, support the combination of platinum/paclitaxel as the current standard chemotherapy for advanced ovarian cancer. Outstanding issues that stem from this phase III experience include the impact of nonprotocol salvage regimens on survival and the potential benefits of sequential single-agent regimens.
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Glioblastoma multiforme and anaplastic astrocytoma are the most common primary central nervous system malignancies and are the major cause of morbidity/ mortality despite combined modality approaches. Temozolomide (TMZ), a novel, oral, second-generation alkylating agent, has demonstrated antitumor activity against a broad range of solid tumors and highly resistant malignancies, including high-grade glioma Temozolomide does not require hepatic metabolism for activation, rapidly penetrates the cerebrospinal fluid, and consistently demonstrates reproducible linear pharmacokinetics with approximately 100% oral bioavailability. In preliminary clinical studies, TMZ has demonstrated meaningful efficacy and an acceptable safety profile in the treatment of patients with malignant glioma. ⋯ These studies represent the largest evaluation of a single agent in patients with recurrent malignant gliomas and were rigorously controlled with strict, prospectively defined criteria for assessment of tumor response, central review of histology, and validated instruments to assess health-related quality of life. Temozolomide was effective in delaying disease progression and maintaining health-related quality of life. Temozolomide represents a promising new agent in the treatment of malignant glioma.