Assuntos
Amifostina/uso terapêutico , Compostos Organotiofosforados/uso terapêutico , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , Amifostina/toxicidade , Animais , Temperatura Corporal/efeitos dos fármacos , Sistema Digestório/efeitos dos fármacos , Sistema Hematopoético/efeitos dos fármacos , Neoplasias Induzidas por Radiação/prevenção & controle , Protetores contra Radiação/toxicidadeRESUMO
We used levamisole, an inhibitor of alkaline phosphatase, to study the role of that enzyme in mediating the metabolic activation, toxicity, and radioprotection of WR-2721 in intact mice. We found the toxicity of WR-2721 was slightly decreased by prior subcutaneous (SQ) injection of 40 mg/kg of levamisole. In studying the effect of levamisole on WR-2721 radioprotection, we found that intraperitoneal (i.p.) injection of levamisole had little or no effect on radioprotection of the gastrointestinal and the hematopoietic systems. Even this small reduction of protection was due in part to the toxicity of levamisole as demonstrated when levamisole was injected following, rather than before, WR-2721-radiation treatment. To determine whether levamisole inhibited the activation (i.e., dephosphorylation) of WR-2721 to WR-1065, we assayed WR-1065 in the jejunum using an HPLC electrochemical assay. SQ injection of 75 mg/kg levamisole 10 min prior to WR-2721 reduced the WR-1065 observed 10 min after WR-2721 administration by 37%. In conclusion, levamisole appears to be too toxic and non-specific to be useful in studying and regulating the metabolism, toxicity and radioprotection of WR-2721.
Assuntos
Fosfatase Alcalina/antagonistas & inibidores , Amifostina/toxicidade , Compostos Organotiofosforados/toxicidade , Protetores contra Radiação/toxicidade , Amifostina/metabolismo , Animais , Biotransformação , Levamisol/farmacologia , Mercaptoetilaminas/metabolismo , Camundongos , Protetores contra Radiação/metabolismoRESUMO
Analogous to certain radiosensitizers which are too hydrophilic to enter tumor cells, certain radioprotectors, because of their hydrophilicity, may also be hindered from entering tumor cells and thus protect only normal tissues. In testing this hypothesis, we utilized thin layer chromatography as convenient means to measure radioprotector hydrophilicity. Dose reduction factors (DRF's) for hematopoietic radioprotection were determined in BALB/c mice given half maximum tolerated doses (MTD/2) of 11 radioprotectors 30 min prior to graded doses of gamma rays. DRF's for tumor protection were determined in MCa-11 tumor-bearing mice using a regrowth delay assay. Differential radioprotection was found to be significantly correlated (r = 0.86) with hydrophilicity. Thus, radioprotector hydrophilicity appears to be a significant factor in the differential radioprotection observed and should be useful in designing or selecting better differential radioprotectors.
Assuntos
Protetores contra Radiação/farmacologia , Animais , Radioisótopos de Césio , Relação Dose-Resposta à Radiação , Raios gama , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos da radiação , Masculino , Neoplasias Mamárias Experimentais/radioterapia , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Irradiação Corporal TotalRESUMO
Although WR-2721, S-2-(3-aminopropylamino)ethylphosphorothioc acid, is the most widely studied and most effective radioprotective drug at present, it is nevertheless clear from animal studies that it has important shortcomings as the ideal radioprotector in clinical radiotherapy. More effective and less toxic radioprotective drugs are needed. For this reason, a chemical radioprotector screening program has been initiated at the Fox Chase Cancer Center under a contract with the National Cancer Institute. Most of the 20 compounds that have now entered the screening program provide good protection of the mouse hematopoietic system as indicated by 30 day survival following the radiation LD100/30. Administration of a radioprotector dose equal to one half of the maximum tolerated dose (MTD/2) gave hematopoietic dose reduction factors (DRF's) as high as 2.3. No radioprotector appeared to be superior to WR-2721, although four others gave DRF's exceeding 1.8.