Anti-cancer drugs
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To evaluate potential synergistic interactions between topoisomerase I (Topo I) inhibitors, i.e. camptothecin (CPT) and topotecan (TPT), and chemotherapeutic agents known to be active in treatment of brain tumors, in vitro studies were conducted with human glioma and medulloblastoma cell lines. Tumor cells were exposed to CPT or TPT alone or in combination with cisplatin, 4-hydroperoxycyclophosphamide (4-HC), BCNU or etoposide (VP-16). Cytotoxicity was assessed by colony formation assays. ⋯ By contrast, antagonistic interactions were observed after administration of CPT with BCNU or VP-16. Treatment of U251 cells with CPT and cisplatin produced synergistic or antagonistic cytotoxicity depending on the dose combination used. These findings support a role for pharmacokinetic analysis in multiagent phase 11 trials involving Topo I inhibitors and have important implications for clinical trial design strategies.
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UFT is an oral antineoplastic drug combining uracil and tegafur in a 4:1 molar ratio. Tegafur acts as a prodrug of 5-fluorouracil (5-FU), being slowly metabolized by cytochrome P450 to 5-FU. Uracil competitively inhibits the metabolism of 5-FU, resulting in increased plasma and tumor 5-FU concentrations. ⋯ UFT plus leucovorin offers patients an entirely oral cancer treatment, and appears to provide potential advantages over bolus 5-FU regimens with regard to toxicity and convenience of administration. These benefits should be advantageous in the adjuvant setting, as well as in advanced disease settings in which palliation is an important consideration. Ongoing clinical trials will further define the role of this promising oral treatment regimen.
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Randomized Controlled Trial Clinical Trial
Granisetron plus methylprednisolone for the control of high-dose cisplatin-induced emesis.
This double-blind, double-dummy, randomized study compared the 24 h efficacy and safety of granisetron alone (3 mg i.v. over 30 s) or in combination with methylprednisolone (250 mg i.v. twice daily) in preventing nausea and vomiting in 308 patients (254 males) receiving high-dose cisplatin (100 mg/m2 or above) for mainly lung, and head and neck cancers. All patients received oral follow-on therapy comprising oral granisetron and methylprednisolone during the following 6 days. Primary efficacy variables were the proportions of complete responses (CR; no vomiting, no worse than mild nausea, no rescue and no withdrawal), no vomiting and no nausea over the first 24 h following initiation of the cisplatin infusion. ⋯ Significantly fewer patients receiving combination therapy also required rescue therapy with i.v. granisetron (12.2 versus 21.7%, p=0.026). During the follow-on period, complete response rates varied day by day from 50 to 71%. Both treatments were well tolerated, with constipation, abdominal pain and headache as the most frequent adverse events.
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Cytotoxic as well as immunomodulatory effects of mistletoe extracts and their components have been described and seem to depend upon the host tree, the manufacturing process and the composition of the different components present in the extracts. In vitro studies showed that a fermented mistletoe extract derived from Viscum album L. grown on pine trees was less cytotoxic to peripheral blood mononuclear cells (PBMC) than other preparations. This finding could be related to its very low content of mistletoe lectins. ⋯ In the supernatants of stimulated PBMC from healthy individuals, type-1 (interferon-gamma and interleukin-2) and type-2 (interleukin-4 and interleukin-5) associated cytokines were detected in about 20%. In patients with colorectal tumours, however, reduced frequency, suggesting a functional impairment of certain immunocompetent cells in these patients. These studies may help to evaluate properties of the natural and the specific immune system.
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Extracts produced from Viscum album L. (mistletoe) as well as certain isolated components are able to stimulate different functions of the immune system. The natural killer cells have been suggested as one of the candidates for direct tumour cell destruction. These cells are defined by their ability to mediate non-major histocompatibility complex (MHC) restricted cytotoxicity without prior sensitization against a specific antigen. ⋯ In this regard it is interesting that mistletoe extracts are able to stimulate natural killer cell-mediated cytotoxicity in vitro directly as well as indirectly in a cytokine-like manner, with the active components being carbohydrates rather than lectins. Clinical application of mistletoe extracts or isolated lectins is reported to induce augmentation of both number and activity of natural killer cells in peripheral blood in a dose-dependent manner; however, non-responders also have been described. In future work it has to be clarified whether a mistletoe-derived modulation of the natural killer system is of benefit in the tumour defence of cancer patients.