Anti-cancer drugs
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Randomized Controlled Trial Comparative Study Clinical Trial
A double-blind randomized study comparing intramuscular (i.m.) granisetron with i.m. granisetron plus dexamethasone in the prevention of delayed emesis induced by cisplatin. The Italian Multicenter Study Group.
Granisetron has been shown to exert a beneficial therapeutic effect in the prophylaxis and treatment of acute nausea and vomiting due to chemotherapy. However, limited data regarding its efficacy in the prevention and treatment of delayed emesis are available. A total of 532 patients entered this multicenter double-blind study, aimed at comparing the efficacy and safety of intramuscular (i.m.) granisetron with that of i.m. granisetron plus dexamethasone. ⋯ Similarly, over the same period total control was 44.7% with granisetron alone and 65.3% with granisetron plus dexamethasone (p<0.01). Local and systemic tolerability of the i.m. therapy with granisetron were satisfactory. In conclusion, granisetron plus dexamethasone showed good protection against delayed emesis due to emetogenic chemotherapy.
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Tricyclic pyrones (TPs) may represent a novel synthetic class of microtubule (MT) de-stabilizing anticancer drugs previously shown by us to inhibit macromolecule synthesis, tubulin polymerization, and the proliferation of leukemic and mammary tumor cells in vitro. A linear skeleton with a N-containing aromatic ring attached at C3 of the top A-ring, a central pyran B-ring and a six-membered bottom C-ring with no alkylation at C7 are required for the antitumor activities of the lead compounds, a 3-pyridyl benzopyran (code name H10) and its somewhat weaker 2-pyridyl regioisomer (code name H19). Increasing concentrations of H10 do not alter the binding of [3H]vinblastine and [3H]GTP to tubulin but mimic the ability of unlabeled colchicine (CLC) to reduce the amount of [3H]CLC bound to tubulin, suggesting that TPs may interact with the CLC binding site to inhibit tubulin polymerization. ⋯ The anticancer potential of TPs in vivo is demonstrated by the fact that i.p. injections of the water-soluble H10-HCl decrease the growth of solid tumors in mice inoculated s.c. with Lewis lung carcinoma. A critical finding is that the antimitotic H10 is a bifunctional anticancer drug, which also blocks the cellular transport of nucleosides (IC50: 6 microM) to inhibit DNA synthesis. Since few CLC site-binding antimitotic agents are active in solid tumor models in vivo, the ability of these new MT destabilizing TPs to totally block nucleoside transport might be valuable in polychemotherapy to arrest tumor cells at several phases of their cycle, potentiate the action of antimetabolites and sensitize multidrug-resistant tumor cells.
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Gallium chloride (GaCl3), an antitumor agent with antagonistic action on iron, magnesium and calcium, was tested for its ability to alter the polymerization of purified tubulin (2.2 mg/ml) in a cell-free system in vitro. GaCl3 (250 microM) does not mimic the effect of 10 microM paclitaxel and, therefore, is not a microtubule (MT)-stabilizing agent that can promote tubulin polymerization in the absence of glycerol and block MT disassembly. In contrast, GaCl3 mimics the effect of 1 microM vincristine (VCR) and inhibits glycerol-induced tubulin polymerization in a concentration-dependent manner (IC50: 125 microM), indicating that GaCl3 is a MT de-stabilizing agent that prevents MT assembly. ⋯ After a 24 h delay, the viability of GaCl3-treated L1210 leukemic cells is reduced in a concentration-dependent manner at days 2 (IC50: 175 microM), 3 (IC50: 35 microM) and 4 (IC50: 16 microM). Since GaCl3 (100-625 microM) increases the percentage of mitotic cells at 2-4 days, it might arrest tumor cell progression in M phase, but its antimitotic activity is much weaker than that of 0.25 microM VCR. Because the concentrations of GaCl3 that inhibit tubulin polymerization also increase the mitotic index and decrease the viability of L1210 cells in vitro, the antitubulin and antimitotic effects of GaCl3 might contribute, at least in part, to its antitumor activity.
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Preclinical and clinical data have suggested antitumor efficacy in squamous cell carcinoma (SCC) of interferon (IFN)-alpha and 13-cis-retinoic acid (13-c-RA) as single agent with greater activity in combination. Cisplatin was added to potentiate activity. Twenty-three patients with pretreated advanced or metastatic head and neck squamous cell carcinoma were given a combination of IFN-alpha (6 x 10(6) U/day, 84 days s.c.), 13-c-RA (1 mg/kg/day, 84 days) and cisplatin (40 mg/kg/day, day 1, 28 and 56). ⋯ Median duration of response was 6 months with a 9 month median survival. Association of IFN-alpha, 13-c-RA and cisplatin induces modest but definite antitumor activity with moderate and manageable toxicity. Further studies of different combination modality therapy with chemotherapy and differentiating agents need to be performed in less pretreated patients.
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Comparative Study
Comparative activity of the cyclopropylpyrroloindole compounds adozelesin, bizelesin and carzelesin in a human tumor colony-forming assay.
Adozelesin, bizelesin and carzelesin are synthetic cyclopropylpyrroloindole (CPI) analogs, a class of potent antineoplastic agents modeled on the antitumor antibiotic CC-1065, that specifically bind to the minor groove of DNA and preferentially alkylate AT-rich regions. These compounds were evaluated against fresh human tumors in a human tumor colony-forming assay (HTCFA) to assess and to compare their relative antitumor spectra, concentration-response relationships and schedule-dependence. Human tumor colony-forming units were treated with adozelesin and bizelesin at concentrations of 0.02, 0.1 and 0.5 ng/ml as a continuous exposure for 14 days, and to 0.2, 1.0 and 5.0 ng/ml as a 1 h exposure. ⋯ At the highest concentration, the overall response rate was significantly higher (p < 0.01) with carzelesin on the continuous schedule (71%) compared to the 1 h schedule (46%). However, overall response rates for adozelesin and bizelesin were similar on both schedules (1 h/continuous: adozelesin, 67/58%; bizelesin, 49/44%), indicating that adozelesin and bizelesin are less schedule dependent than carzelesin in the HTCFA. These results demonstrate that the CPIs have broad-spectrum activity against human tumor colony-forming units in the HTCFA at very low concentrations, as well as differences with regard to schedule dependence which may help guide the optimal clinical development of these agents.