Biomedical subjects

M R Boyd

Publications and source records attributed to M R Boyd.

At least 217 records · Page 12Linked to original sources

PubMed1987

Hepatotoxicity of precocene I in rats. Role of metabolic activation in vivo.

The mechanism of the hepatotoxicity of precocene I has been investigated in male, Sprague-Dawley rats. Administration of a single dose of precocene I caused a large depletion of liver glutathione (GSH) levels that was both time and dose dependent. Concomitant with the decrease of liver GSH, there was an increase in serum glutamic pyruvic transaminase (GPT) levels which was also time and dose dependent. Administration of a single dose of [4-3H]precocene I resulted in extensive covalent binding of the radiolabel to liver proteins and DNA in the liver; the extent of binding increased with increasing dose. Treatment of the rats with the mixed-function oxidase inhibitor piperonyl butoxide, before administration of precocene I, significantly decreased the proportion of the radiolabel bound covalently to proteins and DNA, although the total radioactivity (bound and unbound) in the liver remained the same. Piperonyl butoxide pretreatment limited both the liver GSH depletion and the hepatic necrosis normally caused by precocene I. These results are consistent with the view that the hepatotoxicity of precocene I is due to reactive metabolites formed through cytochrome P-450 mediated metabolism of precocene I.

Alanine Transaminase↗

PubMed1987

Synthesis and antiviral activity of 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purines.

Alkylation of 2-amino-6-chloropurine with 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxane (5) provided 2-amino-6-chloro-9-[2,(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (6) in high yield. This aminochloropurine 6 was readily converted to the antiviral acyclonucleoside 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine (1) and to its 6-chloro (10), 6-thio (11), 6-alkoxy (12-17), 6-amino (20), and 6-deoxy (21) purine analogues. The guanine derivative 1 was converted to its xanthine analogue 9. Similarly, alkylation of 6-chloropurine with 5 provided a route to 8, the hypoxanthine analogue of 1. Of these 9-substituted purines, the guanine derivative 1 showed the highest activity against herpes simplex virus types 1 and 2 in cell cultures, and in some tests it was more active than acyclovir, with no evidence of toxicity for the cells. A series of monoesters (30-33) and diesters (24-27, 29) of 1 were prepared, and some of these also showed antiherpes virus activity in cell cultures, the most active ester being the dihexanoate 27.

Animals↗

PubMed1987

Antiherpesvirus activity of 9-(4-hydroxy-3-hydroxy-methylbut-1-yl)guanine (BRL 39123) in cell culture.

The activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL 39123) against several herpesviruses was compared with that of acyclovir (ACV). In plaque reduction tests with clinical isolates of herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella-zoster virus, mean 50% inhibitory concentrations (IC50S) (n = number tested) for BRL 39123 were 0.4 (n = 17), 1.5 (n = 13), and 3.1 (n = 5) micrograms/ml, respectively. Corresponding IC50S for ACV were 0.2, 0.6, and 3.8 micrograms/ml. Cytomegalovirus was relatively resistant to BRL 39123 (IC50, 51 micrograms/ml), but equid herpesvirus 1, bovid herpesvirus 2, and felid herpesvirus 1 were susceptible (IC50S, 1.6, 1.2, and 0.9 micrograms/ml, respectively). BRL 39123 was inactive against an HSV-1 strain which does not express thymidine kinase activity, but a DNA polymerase mutant selected for resistance to ACV was sensitive to BRL 39123 (IC50, 1.5 micrograms/ml). In contrast to the results from plaque reduction tests, BRL 39123 was more active than ACV against HSV-1 and of equal activity against HSV-2 in virus yield reduction assays in MRC-5 cells. After treatment of HSV-infected cultures for short periods, BRL 39123 was considerably more effective than ACV at reducing virus replication, and furthermore, after removal of extracellular BRL 39123, virus replication remained depressed for long periods, whereas such persistent activity was not observed with ACV. Neither compound significantly affected MRC-5 cell replication at 100 micrograms/ml, but at 300 micrograms/ml BRL 39123 was more inhibitory than ACV.

Acyclovir↗

PubMed1987

Metastasis models for human tumors in athymic mice: useful models for drug development.

Although human tumor xenografts have been extensively used for preclinical evaluation of antitumor agents, most of this work has utilized subcutaneous or subrenal capsule assays based on change in tumor size. To obtain experimental models more reflective of the human clinical situations, we have developed several metastatic models that are based on and complement a panel of cell strains used in large-scale in vitro drug screening. One melanoma and four lung tumors produced metastatic lesions in the lung within 60 days following subcutaneous, intraperitoneal, or intrasplenic inoculation of BALB/C athymic nude mice. Several tumors also produced liver lesions, and one lung tumor strain showed metastasis to the brain. The metastatic lesions histologically resembled the tumors that grew at the inoculation site. In vitro and in vivo cell strains were rederived from the metastatic lesions. These systems may provide practical models for experimental drug and immunotherapeutic trials.

Animals↗

PubMed1987

Preclinical toxicology studies of 4-ipomeanol: a novel candidate for clinical evaluation in lung cancer.

4-Ipomeanol (ipomeanol) is being developed as a potential antitumor agent to treat lung cancer. Ipomeanol produced a dose-related toxicity in CD2F1 mice, Fischer 344 rats, and beagle dogs. The LD50 in mice after a single iv dose of ipomeanol was 35 mg/kg in males and 26 mg/kg in females. Minimal cumulative toxicity occurred in mice after seven doses; LD50 was 30 mg/kg/day in males and 21 mg/kg/day in females. In rats, iv doses greater than or equal to 15 mg/kg were lethal. Labored respiration, terminal bronchiolar epithelial necrosis, interstitial inflammation, and alveolar edema were present in rats dosed with ipomeanol at greater than or equal to 9 mg/kg. In addition to pulmonary lesions, splenic and thymic lymphocyte depletion and/or necrosis was present. Ipomeanol had little cumulative toxicity in rats given seven daily doses. In dogs, iv doses greater than 12 mg/kg were lethal. Dogs treated with lethal doses of ipomeanol showed rapid, shallow respiration and pulmonary edema prior to death; diffuse pulmonary congestion or hemorrhage and diffuse renal congestion were present at necropsy. Pulmonary microscopic changes caused by nonlethal doses of ipomeanol included subacute interstitial inflammation and necrosis of respiratory bronchiolar and alveolar duct epithelium. In contrast to rodents, seven daily doses of ipomeanol were cumulatively toxic in dogs. The nonlethal pulmonary effects of ipomeanol were reversible in all three species. Tolerance to lethal doses of ipomeanol occurred in animals of all three species pretreated with multiple nontoxic doses of the drug. The LD50 of ipomeanol in male and female mice increased 2.4- and 4.5-fold, respectively, in tolerant mice. In rats and dogs, previously lethal doses of 48 and 24 mg/kg were nonlethal after tolerance was induced by pretreatment with seven daily doses of ipomeanol.

Animals↗

PubMed1986

In vivo studies on the relationship between hepatic metabolism and the renal toxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU).

Administration of a single sc dose of the nephrotoxic anticancer agent 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) to rats led to a time-dependent decrease in renal function (i.e., renal slice anion accumulation, renal concentrating ability, and urinary output) which was correlated with the accumulation of carbamylating and alkylating intermediates of 14C-labeled MeCCNU that bound irreversibly to kidney protein. MeCCNU also produced a dose-dependent decrease in glutathione (GSH) preferentially in liver, but not in kidney. Pretreatment with piperonyl butoxide (PIP) decreased the renal toxicity and covalent binding of MeCCNU, and ameliorated the MeCCNU-dependent decrease in liver and kidney GSH. Radioactivity detected in the urine from the PIP-pretreated group was markedly lower than that in the MeCCNU-only group. In contrast, PIP pretreatment increased the accumulation of parent MeCCNU into fatty tissue. Pretreatment with phenobarbital (PB) increased the renal toxicity of MeCCNU. Moreover, PB pretreatment resulted in the increased alkylation of both liver and kidney macromolecules and to an increase in the urinary clearance of ethylene-labeled MeCCNU. In all experiments, modifiers of hepatic biotransformation produced changes in the level of covalent binding by ethylene-labeled MeCCNU (alkylation) which correlated with the degree of toxicity of MeCCNU in the kidney. Additional evidence supporting a role for hepatic biotransformation in the toxicity of MeCCNU was provided by an in vivo/in vitro colony-forming assay which demonstrated the presence of a cytotoxic metabolite in the bile of a MeCCNU-administered rat. These studies suggest that hepatic metabolism contributes significantly to the alkylating activity of MeCCNU in the liver and the kidney, and indicate that a liver-derived metabolite may be responsible for the renal toxicity of MeCCNU.

Animals↗

PubMed1986

Comparative nephrotoxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) and chlorozotocin: functional-structural correlations in the Fischer 344 rat.

1-(2-Chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) and chlorozotocin (CZ; 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose) are structurally related anticancer agents which differ by virtue of the increased water solubility, and comparatively low carbamylating activity, of CZ relative to MeCCNU. In the present study, a single sc injection of either of these chloroethylnitrosoureas was nephrotoxic to male Fischer 344 rats. However, at equimolar doses, CZ was shown to be a much more potent nephrotoxicant. A lethal 40-mg/kg dose of CZ (127 microM) initially resulted in acute tubular necrosis of the proximal tubules of the cortex, followed later by a necrosis of papillary collecting ducts. In contrast, lethal doses of MeCCNU (100-180 mg/kg; 400-730 microM) produced only minimal proximal tubule injury. A 250-mg/kg (1 mM) dose of MeCCNU resulted in massive papillary necrosis within 7 days, with only limited necrosis to the proximal tubules. Sublethal doses of either drug, resulted in a similar, chronic, progressive nephropathy which was delayed in onset and was characterized by polyuria, enzymuria, a decrease in urine concentrating ability, and in renal slice organic ion accumulation. Alterations in less sensitive indicators of renal toxicity (i.e., proteinuria, glucosuria, and elevated blood urea nitrogen) were observed no earlier than 3 to 7 days after administration of only the highest tested doses of CZ (40 mg/kg) or MeCCNU (250 mg/kg). At sublethal doses, administration of either drug resulted in karyomegaly to the collecting ducts in the renal medulla within 2 to 4 weeks. These studies demonstrate that carbamylation-mediated reactions may not be necessary for nephrotoxicity to develop following administration of this class of antitumor agent.

Animals↗

PubMed1986

Reductive metabolism of nitrofurantoin by rat lung and liver in vitro.

In the present study, the metabolism of NF has been examined in detail in both rat lung and liver 9000 g supernatants using a specific radiometric HPLC assay. Over 92% of the total radioactivity chromatographed with authentic NF after incubations from either organ were carried out under oxygen for 60 min. Under anaerobic conditions, only 19% and 5% of the total unbound radioactivity corresponded to unchanged NF in lung and liver respectively. At least 4 metabolites were evident from the HPLC trace (M1, M2, M3, M4 according to increasing retention times). In the absence of oxygen, liver 9000 g supernatants generated 65% more M1 and 260% more M3 than did lung 9000 g supernatants, but the lung produced significantly more M4. Covalent binding to tissue macromolecules was similar in both tissues under oxygen but was 7 times greater in lung than in liver in the absence of oxygen (compared per unit protein). Neither piperonyl butoxide nor indomethacin affected NF metabolism. However, allopurinol almost completely inhibited the anaerobic and aerobic (superoxide generation measured by the rate of acetylated cytochrome c reduction) metabolism in the lung with little or no effect in the liver. The data indicate a quantitative difference in NF metabolism between the two tissues that may be related to the organ-selective toxicity of the drug.

Allopurinol↗

PubMed1986

2-Methylfuran toxicity in rats--role of metabolic activation in vivo.

Administration of a single ip dose of 2-methylfuran (2-MF) to male Sprague-Dawley rats at a dose of 100 mg/kg produced centrilobular necrosis of the liver and bronchial injury of the lung, the severity of the lesions increasing with increasing doses up to 400 mg/kg. Kidneys, however, showed no visible evidence of tissue damage even at the highest dose. Liver injury was also evidenced by an increase in serum glutamic pyruvic transaminase (SGPT) levels. Tissue distribution and covalent binding studies conducted over a dose of 50-200 mg/kg of [14C]2-MF indicated that the total radioactivity present per gram of wet tissue was in the order of liver greater than kidney greater than lung greater than blood. Covalent binding of the label to protein was greatest in the liver followed by kidney and the lung. Radioactivity bound covalently per milligram of DNA was also highest in the liver followed by kidney. Tissue distribution and covalent binding studies were conducted over a period of 0.5 to 24 hr after an ip dose of 100 mg/kg of [14C]2-MF. Maximal covalent binding was observed in the liver at 4 hr. At all time points binding of the label was greatest in liver, followed by kidney. Liver glutathione levels were depressed following 2-MF administration. Pretreatment of rats with phenobarbital markedly increased the covalent binding to protein and DNA and caused a twofold increase in SGPT compared to rats treated with 2-MF alone. Pretreatment with 3-methylcholanthrene had no effect on either parameter. Administration of N-octylimidazole, an inhibitor of cytochrome P-450, prior to administration of the radiolabeled 2-MF decreased the covalent binding of the label to protein and DNA. Moreover, the SGPT levels remained the same in the pretreated rats compared to the rats treated with vehicle alone. Thus, pretreatment with phenobarbital, an inducer of cytochrome P-450, enhanced both covalent binding and toxicity while prior treatment with N-octylimidazole, an inhibitor of cytochrome P-450 decreased covalent binding and prevented hepatotoxicity of 2-MF. These results support the view that at least some of the toxic effects of 2-MF are mediated by reactive metabolite(s) formed in vivo.

Alanine Transaminase↗

PubMed1986

Profiling of prostaglandin biosynthesis in biopsy fragments of human lung carcinomas and normal human lung by capillary gas chromatography-negative ion chemical ionization mass spectrometry.

Methods for the profiling of prostaglandin F2 alpha (PGF2 alpha), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6KPGF1 alpha) biosynthesis in tissue samples of clinical origin by capillary gas chromatography-negative ion chemical ionization mass spectrometry (CGC-NICIMS) are detailed. Aliquots (25 microliter 1) of incubates (1 ml volume) of human lung carcinoma and normal human lung tissue fragments (total protein content = 0.2 to 2.0 mg) were derivatized for vapor phase analysis in the presence of 0.75 to 1.60 ng of tetradeuterated analogs of PGE2, PGF2 alpha and 6KPGF1 alpha without prior extraction and/or chromatography. The derivatized analytes and internal standards were detected by simultaneous monitoring of ions at six different masses characteristic for each of the derivatized prostanoids. The inter-sample and intra-sample coefficients of variation for the assay method were typically less than 12%. The analysis of biological samples was completed with less than 2.5% of each derivatized sample per injection. The samples were of adequate purity for the identification and quantitation of each of the eicosanoids. The methods described in this report are highly selective and highly sensitive with detection limits of 0.1 to 0.2 picograms per injection. The analytical procedures provide the basis for comparisons of the qualitative and quantitative profiles of prostaglandin biosynthesis and should be adaptable for use in a variety of biological and clinical studies.

Biopsy↗

PubMed1986

Improvement of the bioavailability of the anti-herpes virus agent BVDU by use of 5'-O-alkoxycarbonyl derivatives with increased metabolic stability.

(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was found by HPLC analysis to be rapidly metabolized in mice and in liver homogenates from mouse and man to the antivirally inactive (E)-5-(2-bromovinyl) uracil (BVU) but was comparatively stable in blood from both species. Of a series of 5'-O-alkoxycarbonyl derivatives of BVDU, the 5'-O-tert.-butoxycarbonyl derivative (BRL 37000) was the most stable in mouse and human blood and liver homogenates, neither its ester bond nor its N-glycosidic linkage being readily cleaved enzymically. Oral administration of BRL 37000 and the 5'-O-ethoxycarbonyl derivative (BRL 36101) to mice gave prolonged serum concentrations of BVDU and delayed the appearance of BVU compared with the BVDU control. BRL 36101 was more active than BVDU when administered orally to mice infected cutaneously with herpes simplex virus type 1.

Animals↗

PubMed1986

Metabolic activation and cytotoxicity of 4-ipomeanol in human non-small cell lung cancer lines.

In the normal lungs of many animal species, 4-ipomeanol is transformed to a highly reactive metabolite preferentially in pulmonary bronchiolar Clara cells and to a lesser extent in alveolar type II cells, potentially leading to damage or destruction of these cell types. Since Clara cells and type II cells are suspected sites of origin of certain "non-small cell" lung cancers, the metabolic activation of 4-ipomeanol (measured by the metabolism-dependent covalent binding of 4-ipomeanol to cellular macromolecules) was compared in two human non-small cell carcinoma derived cell lines (NCI-H322 and NCI-H358) and two human small cell carcinoma derived cell lines (NCI-H128 and NCI-H69). Metabolic activation of 4-ipomeanol was evident in the non-small cell lines; the production of covalently bound metabolite was somewhat greater in NCI-H322 (morphology related to Clara cells) compared to NCI-H358 (morphology related to alveolar type II cells), but was entirely undetectable in the small cell lines. The activation pathway was concentration (4-ipomeanol) and time dependent and followed Michaelis-Menten kinetics. Metabolism to the reactive intermediate required oxygen and was strongly inhibited by carbon monoxide. Covalent binding was enhanced in the non-small cell lines by prior incubation with beta-naphthoflavone and by supplementation of the incubate with exogenous reduced nicotinamide adenine dinucleotide phosphate. 4-Ipomeanol was more cytotoxic to the non-small cell lines than to the small cell lines under the in vitro growth conditions used. These studies indicate that certain human non-small cell lung cancers have metabolic characteristics of normal bronchiolar Clara cells and alveolar type II cells; these results would therefore be consistent with an origin of these tumors from Clara cells or type II cells, respectively. The present studies indicate that the further preclinical testing and development of 4-ipomeanol is warranted, with a view toward possible clinical evaluation against human lung cancers.

Biotransformation↗

PubMed1985

Differential distribution and covalent binding of two labeled forms of methyl-CCNU in the Fischer 344 rat.

The present study compares the organ distribution and covalent binding of MeCCNU labeled either within the carbamylating [( cyclohexyl-1-14C]MeCCNU; Chx-14C-MeCCNU) or alkylating [( 2-chloroethyl-1,2-14C]MeCCNU; Cle-14C-MeCCNU) region of the compound in an animal model shown to be suitable for studying the nephrotoxicity of the nitrosoureas. Extraction of tissue homogenates with organic solvents of increasing polarity, and subsequent analysis of these extracts by HPLC showed fat to accumulate the highest concentration of parent compound. Kidney accumulated the highest levels of the more polar ether- and methanol-extractable metabolites and/or degradation products of either cyclohexyl-derived or chloroethyl-derived 14C-MeCCNU. Striking differences were apparent in the accumulation, degradation and/or metabolism, and tissue distribution of covalently bound radioactivity for the chloroethyl and cyclohexyl moieties. For example, approximately twice as much cyclohexyl-derived 14C was bound covalently to protein of kidney than to protein of liver or lung. In contrast, approximately twice as much chloroethyl-derived 14C was bound to lung protein than to liver of kidney protein. No radioactivity was bound covalently to tissue DNA following Chx-14C-MeCCNU administration. On the other hand, at 4 h, chloroethyl-derived 14C was irreversibly bound to DNA in the relative amounts of kidney (5.0 nmol/mg), liver (2.7 nmol/mg), and lung (1.25 nmol/mg). These results demonstrate that MeCCNU metabolites and/or degradation products are preferentially accumulated in kidney, a primary target organ for MeCCNU toxicity. Moreover, kidney protein and DNA were subject to extensive carbamylation and alkylation reactions as measured by irreversibly bound cyclohexyl-derived and chloroethyl-derived 14C, respectively. These data suggest that the extent of irreversibly bound drug to tissue macromolecules may be a valid predictor of MeCCNU toxicity. However, the relative toxicological significance of either protein carbamylation or DNA alkylation in mediating MeCCNU-induced nephropathy is not yet understood.

Adipose Tissue↗

PubMed1985

Metabolic activation of 2-methylfuran by rat microsomal systems.

2-Methylfuran (2-MF), a constituent of cigarette smoke and coffee, causes necrosis of liver, lungs, and kidneys in rodents. 2-MF is metabolically activated by mixed-function oxidases to acetylacrolein, a reactive metabolite that binds covalently to microsomal protein. The hepatic microsomal metabolism of 2-MF to reactive metabolite required the presence of NADPH and oxygen and was dependent on incubation time and substrate concentration. The microsomal metabolism of 2-MF was inducible by pretreatment of rats with phenobarbital and was inhibited by piperonyl butoxide and N-octyl imidazole, which indicates that the metabolism of 2-MF may be mediated by cytochrome P-450. Acetylacrolein was a potent inhibitor of mixed-function oxidase and completely inhibited the microsomal metabolism of 2-MF, indicating that 2-MF is a suicide substrate for the enzyme. The sulfhydryl nucleophile cysteine was a better trapping agent of the reactive metabolite of 2-MF than N-acetylcysteine or glutathione. Lysine decreased the covalent binding of 2-MF metabolites, presumably by reacting with the aldehyde group of acetylacrolein. In addition, in the presence of NADPH, 2-MF was bioactivated by both pulmonary and renal cortical microsomes to reactive metabolites that were covalently bound to microsomal proteins.

Acrolein↗

PubMed1985

Long-term effects of repeated exposure to 3-methylfuran in hamsters and mice.

Male and female Syrian golden hamsters were exposed for 2 h once a week for 10 consecutive weeks to 344 mumol/l of 3-methylfuran (3MF), an agent known to produce acute Clara-cell necrosis. Ten months later their respiratory function was evaluated. No functional differences were found between control and treated animals, and histopathologic evaluation of the lungs did not reveal any major treatment-related alterations. Male and female BALB/c mice were exposed for 1 h to 26.8 mumol/l of 3MF once weekly for 10 wk. After 2 yr the tumor incidence in exposed animals was not increased when compared to controls. It is concluded that the acute Clara-cell necrosis produced by 3MF at the doses used is of little long-term consequence.

Air Pollutants↗

PubMed1985

Sequential pathological changes induced in rats with the anti-cancer drug I, 3-bis (2-chloroethyl)-I-nitrosourea (BCNU).

The pathology of pulmonary toxicity induced by the anticancer drug 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) was studied in F344 rats. The compound was administered in a multiple-dose regimen comparable to the dose schedule commonly given patients. Morphological aspects were investigated by light and electron microscopy in a serial sacrifice experiment. All animals developed pulmonary fibrosis accompanied by formation of peribronchial and peribronchiolar foci of granulomatous tissue. The first morphologically detectable changes were identified in alveolar type II cells and were suggestive of disturbed surfactant synthesis. Endothelial damage accompanied by pronounced plasma cell infiltration developed subsequently and was followed by the development of diffuse interstitial fibrosis.

Animals↗

PubMed1985

Pulmonary endothelial and bronchiolar epithelial lesions induced by 4-ipomeanol in mice.

The morphogenesis of pulmonary edema and bronchiolar injury induced by the toxic furan, 4-ipomeanol, was studied by combined light and transmission electron microscopy. Weanling male CD-1 mice received 47 mg 4-ipomeanol/kg body weight by intraperitoneal injection and were studied at intervals from 2 to 360 hours after treatment. Interstitial edema associated with damaged endothelial cells was observed as early as 2 hours after treatment. The most severe endothelial damage was observed from 12 to 24 hours after treatment and occurred in association with alveolar edema. Capillary endothelial cell damage was characterized by marked dilation of endoplasmic reticulum and perinuclear envelopes, marked swelling of mitochondria, separation of cytoplasmic processes from other endothelial cells and their basal laminae, and occasional disruptions in the plasmalemma. Endothelial cell lesions in small caliber veins were similar but less pronounced as compared with the alterations observed in capillary endothelium. Minimal changes were present in alveolar epithelial cells. Damage to nonciliated bronchiolar epithelial cells was first observed at 4 hours after injection. The most severe changes in nonciliated cells occurred from 36 to 48 hours after treatment and included swelling of endoplasmic reticulum, necrosis, and sloughing. There was also necrosis and sloughing of ciliated bronchiolar epithelial cells. Endothelial and bronchiolar epithelial repair and resolution of the alveolar edema were complete by 240 hours after treatment. It is concluded that the endothelium lining capillaries and small veins, in addition to the nonciliated bronchiolar epithelial cell, are early targets in the development of 4-ipomeanol toxicity in the mouse and that the endothelial cell injury plays a major role in the development of pulmonary edema in this species. The results further suggest the possibility that pulmonary endothelial cells have the capability of metabolizing xenobiotic compounds such as 4-ipomeanol to form ultimate toxins.

Animals↗

PubMed1985

Activity of mitozolomide (NSC 353451), a new imidazotetrazine, against xenografts from human melanomas, sarcomas, and lung and colon carcinomas.

The chemosensitivity of human tumor xenografts to mitozolomide, 8-carbamoyl-3-(2-chloroethyl)imidazo[5-1-d]-1,2,3,5-tetrazin-4(3H) -one, was studied in 3 different assay systems. In concentrations of 1 to 500 micrograms/ml, mitozolomide completely inhibited the colony-forming ability in soft agar of cell suspensions from sarcomas, melanomas, lung and colon cancers, and a mammary carcinoma. When a panel of tumors of the different histological types was tested for its sensitivity to mitozolomide in vitro, in the 6-day subrenal capsule assay in conventional mice, and, in some cases, as s.c. growing tumors in nude mice, good agreement between the different assay systems was seen. In most cases, a very pronounced antitumor effect was observed. The efficacy of mitozolomide was as good or better than that of the drugs clinically used against the tumor types tested. Tumor size measurements and histological examinations indicated that nude mice carrying a melanoma, a small cell lung cancer, and an osteosarcoma were cured of their tumors. The approach here used for evaluating the effect of a new drug on human cancers may be useful for selecting the tumor types which primarily should be studied in clinical trials. The results indicate that clinical responses to mitozolomide may be anticipated in sarcoma, melanoma, small cell lung cancer, and possibly in colon cancer.

Animals↗