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D Q Brown

Publications and source records attributed to D Q Brown.

25 records · Page 2Linked to original sources
PubMedDate not supplied

Circumvention of the tumor membrane barrier to WR-2721 absorption by reduction of drug hydrophilicity.

In attempting to account for the ability of most solid tumors to restrict the absorption of WR-2721, aminopropyl-aminoethylphosphorothioate, we examined a number of drug characteristics which might allow for this restriction, and observed that drug hydrophilicity was a major contributing factor. When the highly hydrophilic WR-2721 was dephosphorylated, the drug became less hydrophilic and could readily cross tumor cell membranes. In addition, conventional radioprotectants, such as cysteine and mercaptoethylamine, were shown to be less hydrophilic than WR-2721 and also to cross tumor membranes readily. Therefore, drug hydrophilicity would appear to be the factor underlying the ability of WR-2721 to selectively protect normal tissues while most other protectors alter the radiation resistance of normal and tumor tissue alike. A red blood cell model for studying this problem in greater detail is described.

Absorption↗
PubMedDate not supplied

Early results of the screening program for radioprotectors.

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.

Animals↗
PubMedDate not supplied

Metabolic pathways of WR-2721 (ethyol, amifostine) in the BALB/c mouse.

This study investigated the metabolism of the radio- and chemoprotector compound, WR-2721 [amifostine; s-2-(3- aminopropylamino)ethylphosphorothioate], in the Balb/c mouse. The latter was selected for these studies because considerable radiation protection data have been published for this mouse strain using the WR-2721 dose, route of administration, and optimal time for protection following intraperitoneal injection used herein. It is known that protection requires conversion of the parent drug to its free thiol metabolite, WR-1065, in cultured cells. Because it is possible that metabolites of WR-1065 could be involved in protection and because thiols are metabolically very reactive molecules, we investigated the metabolism of WR-2721 using electrochemical detection-HPLC methods. The following are the major findings in this study: 1) WR-2721 drug was rapidly cleared from the bloodstream. Blood concentration of the parent drug decreased 10-fold 30 min after administration from the maximal observed value at 5 min 2) WR-1065 rapidly appeared in the perchloric acid (PCA)-soluble fraction of normal solid tissues. The highest WR-1065 concentrations in liver and kidney were 965 and 2195 mumol/kg, respectively, 10 min after parent drug administration, whereas for heart and small intestine the highest values were 739 and 410 mumol/kg at 30 min. 3) WR-1065 accumulated in the PCA-soluble fraction of two experimental tumors at a lower rate than for the other tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Amifostine↗