Acidic and neutralized metoclopramide formulations sensitize ionizing radiation induced cytotoxicity in a human lung adenocarcinoma xenografted to scid mice

Hua, Jianyi; Olsson, Åsa; Sheng, Yuchen; Pero, Ronald W.

doi:10.1097/00001813-199506000-00014

Cited by 10 publications

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“…Our normal procedure has been to use initial tumor volumes of 60-200 mm3 (4) but recently we have observed the fact that our results have become more consistent with initial tumor volumes of 50-75 mm3 (2). As a consequence our laboratory has investigated this point in a more direct fashion and our data have indicated that nMCA was much more effective when the experiments were started with smaller tumor volumes (Table 5).…”

Section: Resultsmentioning

confidence: 62%

“…transplanted into scid mice (2). In an attempt to improve the sensitized cytotoxic effect of combined treatment of radiation with nMCA (2 mg/kg; Ih pre-exposure), the radiation dose was increased to single doses of 6 and 10 Gy and combined with nMCA.…”

Section: Resultsmentioning

confidence: 99%

“…However, in the last five years the interest in MCA has been focused on its sensitizing properties of radio-and chemotherapy both in animals (2)(3)(4)(5)(6) and in the clinic (7,8). Three potential modes of action for MCA have been identified: a) MCA can induce DNA damage and inhibit DNA repair (9, 10); b) MCA can in the presence of radiation react with cellular reducing components such as glutathione and may thereby increase radiation induced DNA damage (8) and c) MCA induces apoptosis in hiiman leukemic HL-60 cells (1 1 ).…”

mentioning

confidence: 99%

“…Cell death by apoptosis involves metabolic changes and aitered gene expression which results in cell shrinkage, membrane blebbing, nuclear condensation and increased activity of endonucleases causing DNA degradation (20,21). Hence, because MCA has been shown to sensitize radiation at relatively low radiation doses (2) and induces apoptosis in vitro in HL-60 cells (1 1 ), apoptosis may be another possible mechanism to explain the radiosensitizing properities of MCA as an enhancer of cytotoxicity in vivo.…”

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confidence: 99%

“…A new formulation of MCA (Neu-SensamideTM, Oxigene Inc.), conformationally altered by neutralization of pH and with a reduced side effect profile (8, ll), potentiates cytotoxicity induced by ionizing radiation at relatively low doses in the human lung adenocarcinoma (H298 1) transplanted into scid mice (2). Here we further characterize the anti-tumor properties of neutralized metoclopramide (nMCA) using two different tumor models, by varying the doses of nMCA and ionizing radiation, or by modifying the dose schedules of nMCA and radiation given alone or in combination.…”

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confidence: 99%

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Neutral Metoclopramide Induces Tumor Cytotoxicity and Sensitizes Ionizing Radiation of a Human Lung Adenocarcinoma and Virus Induced Sarcoma in Mice

et al. 1997

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Section: Resultsmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Neutral Metoclopramide Induces Tumor Cytotoxicity and Sensitizes Ionizing Radiation of a Human Lung Adenocarcinoma and Virus Induced Sarcoma in Mice

et al. 1997

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Neutral metoclopramide sensitizes cytotoxicity induced by ionizing radiation in SCID mice xenografted with a human brain astrocytoma

1997

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A formulation of metoclopramide (MCA) conformationally altered by neutralization of pH (nMCA, Neu‐Sensamide) has been shown to have the same efficacy of enhancing the cytotoxicity of a single dose of 1 Gy radiation as acidic formulations (e.g., Primperan, Sensamide) in a human lung adenocarcinoma (H2981) xenografted into SCID mice. In the present study, 2 × 1 Gy radiation was combined with 2 × 2 mg nMCA/kg body weight injected 2 hr before radiation treatment for evaluation of radiosensitization in SCID mice xenografted with a human brain astrocytoma (T24). Given in this treatment schedule, nMCA alone at 2 mg/kg showed no cytotoxic effect on tumor growth in vivo. When combined with 2 × 1 Gy of radiation, however, the cytotoxicity was significantly increased as measured by tumor growth delay over the radiation‐only‐treated group. Furthermore, nMCA was absorbed into brains of mice and rats as efficiently as acidic MCA (aMCA) when analyzed 45 min after i.m. injection by high‐performance liquid chromatography. Int. J. Cancer 73:871–874, 1997. © 1997 Wiley‐Liss, Inc.

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Comparative Central Nervous System Effects and Pharmacokinetics of Neu‐metoclopramide and Metoclopramide in Healthy Volunteers

Rotmensch

Mould

Sutton

et al. 1997

The Journal of Clinical Pharma

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Metoclopramide, a drug used for the relief of nausea and emesis, is currently under development as a radio- and chemosensitizing agent. Its usefulness in high doses, however, is limited by its central nervous system side effects. Neu-metoclopramide (Neu-Sensamide), a novel, concentrated, phosphate-buffered, pH-adjusted (pH = 6.5-7.0) formulation of metoclopramide, has been shown to have an improved side-effect profile in animal studies. The present double-blind, four-way crossover study compared the central nervous system effects and pharmacokinetics of neu-metoclopramide (intravenously and intramuscularly at 1.8 mg/kg) with intravenous metoclopramide and intramuscular placebo in 19 healthy male volunteers. Eight participants withdrew from the study, one because of noncompliance and seven because of adverse events. A total of 28 central nervous system events were observed with intravenous metoclopramide administration, whereas 16, 15, and 6 such events were attributed to intravenous neu-metoclopramide, intramuscular neu-metoclopramide, and placebo, respectively. Extra-pyramidal effects occurred on 10 occasions: 7 after intravenous metoclopramide, 2 after intravenous neu-metoclopramide, and 1 after intramuscular neu-metoclopramide. No significant differences were observed in the pharmacokinetic profiles of the three formulations of metoclopramide. It may be speculated, therefore, that the molecular conformational changes inherent to neu-metoclopramide result in a reduced side-effect profile compared with conventional metoclopramide formulations.

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Acidic and neutralized metoclopramide formulations sensitize ionizing radiation induced cytotoxicity in a human lung adenocarcinoma xenografted to scid mice

Cited by 10 publications

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Neutral Metoclopramide Induces Tumor Cytotoxicity and Sensitizes Ionizing Radiation of a Human Lung Adenocarcinoma and Virus Induced Sarcoma in Mice

Neutral Metoclopramide Induces Tumor Cytotoxicity and Sensitizes Ionizing Radiation of a Human Lung Adenocarcinoma and Virus Induced Sarcoma in Mice

Neutral metoclopramide sensitizes cytotoxicity induced by ionizing radiation in SCID mice xenografted with a human brain astrocytoma

Comparative Central Nervous System Effects and Pharmacokinetics of Neu‐metoclopramide and Metoclopramide in Healthy Volunteers

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