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PubMed1979

Physiological and genetic effects of puromycin aminonucleoside on ultraviolet-irradiated Escherichia coli strains.

Puromycin aminonucleoside (PAN) increased significantly the mutation rate of Escherichia coli B/r strains when used in conjunction with certain ultraviolet dosages. PAN (2.5 mM) when added to the post-irradiation medium of hcr+ cells slowed down RNA synthesis to 65%, protein to 76% and DNA to 48% of the control rate. Purine ribosides such as adenosine decreased the inhibitory action of PAN on DNA, RNA and protein synthesis. Quantitatively quite different results were obtained with the hcr- strains. PAN did not increase killing of UV, but decreased the frequency of UV-induced mutations. Antimutagenic purine ribosides decreased the synergistic mutagenic activity of PAN. Increases in DNA synthesis in the presence of antimutagens correspond to reductions in the rate of mutation to streptomycin resistance. The excision of UV-induced pyrimidine dimers was investigated in the presence and absence of PAN. The pattern of repair-inhibition reversion of pre-mutagenic lesions by adenosine suggests that PAN behaves as a feedback inhibitor of purine biosynthesis in UV-irradiated cells. It is probable that this inhibition results in an impairment of repair which produces the increase in mutant numbers.

Bacterial Proteins↗
PubMed1976

Drug effects on the fine structure of Trypanosoma rhodesiense: puromycin and its aminonucleoside, Cordycepin and Nucleocidin.

The effects of four trypanocidal adenine nucleosides on the fine structure of a monomorphic strain of Trypanosoma rhodesiense have been examined. All four drugs, Puromycin and its aminonucleoside, Cordycepin and Nucleocidin, induced electron-lucent cytoplasmic clefts in the cytoplasm, which were generally acicular or spindle-shaped, with long axes lying in any direction. The clefts had an intimate relationship with the rough endoplasmic reticulum. The drugs also produced excessive lysosomal vacuolation, and two, Cordycepin and Nucleocidin, caused nucleolar fragmentation and probable segregation, indicative of interference with RNA synthesis. The significance of the lesions is discussed in relation to known properties of adenine nucleoside drugs.

Adenosine↗
PubMed1988

Evidence suggesting a role for hydroxyl radical in puromycin aminonucleoside-induced proteinuria.

A single intravenous injection of puromycin aminonucleoside (PAN) results in marked proteinuria and glomerular morphological changes that are similar to minimal change disease in humans. We examined the effect of hydroxyl radical scavengers and an iron chelator on PAN-induced proteinuria. PAN in a dose of 5 mg/100 g body wt significantly increased urinary protein by day 5 (saline: 15 +/- 2, N = 24: PAN: 63 +/- 17, N = 23, P less than 0.001); the proteinuria rapidly increased thereafter, reaching 216 +/- 34, N = 23 by day 7. Concurrent administration of hydroxyl radical scavengers dimethylthiourea, (DMTU 500 mg/kg followed by 125 mg/kg i.p. twice a day) and sodium benzoate (BENZ, 150 mg/kg followed by 125 mg/kg i.p. twice a day) starting the evening before PAN injection markedly reduced proteinuria throughout the course of the study (urinary protein, mg/24 hours on day 7, mean +/- SEM: PAN: 229 +/- 45, N = 15; PAN + DMTU: 30 +/- 5, N = 18; PAN + BENZ: 80 +/- 18, N = 16. Because of the participation of iron in biological systems to generate hydroxyl radical, we also examined the effect of deferoxamine (DFO, 30 mg/day), an iron chelator, on the PAN-induced proteinuria. Concurrent administration of DFO was also protective. In a second series of experiments, DMTU and DFO (administered as described above and then for two additional days after the PAN) provided marked protection even when they were stopped prior to the onset of proteinuria. The protective effects of two hydroxyl radical scavengers and iron chelator implicate an important role for hydroxyl radical in PAN-induced nephrotic syndrome.

Animals↗
PubMed1980

Induction of differentiation of murine erythroleukemia cells by aminonucleoside of puromycin and inhibition of this induction by purines and purine derivatives.

The effect of the aminonucleoside of puromycin (AMS) on Friend erythroleukemia cells in culture was investigated, because purines and purine analogues are known to act as inducers of differentiation. After treatment with 20-30 micro M AMS for 4 days, the cultures contained between 80 and 90% benzidine-positive cells. Stimulation of hemoglobin synthesis was dose and time dependent. Inosine had no stimulatory activity; however, when it was added to the medium together with AMS, erythroid differentiation was almost completely inhibited. The inhibitory effect of inosine on this potent inducer was also dose and time dependent. No cytotoxicity was observed with either compound, alone or in combination. Inhibition of AMS stimulation of erythroid differentiation was also observed in the presence of inosine monophosphate and poly(inosinic acid). Hypoxanthine had a dual effect. At high concentrations (500 microgram/ml) it acted as an inducer, but when added at low concentrations (20 microgram/ml) together with AMS it inhibited differentiation. These findings suggest there is a link between purine biosynthesis and the event(s) required to trigger differentiation. Agonist-antagonist activity of closely related biological compounds has thus been revealed in the erythroleukemia cells.

Animals↗
PubMed1989

Effects of cyclosporine on puromycin aminonucleoside-induced nephrotic rats.

The effects of cyclosporine (CY) were determined to see whether CY has the potency of reducing urinary protein excretions due to puromycin aminonucleoside (PAN) in nephrotic rats which are the model of minimal change nephrotic syndrome (MCNS). CY had a marked reduction of urine protein excretion during treatment with this drug, but it was observed that an increment in urinary protein excretion was introduced within a few days after the withdrawal of CY. Immunological and histological studies were performed to know the mechanisms of reducing urinary protein excretion in PAN rats. Firstly, the lymphocyte subsets of peripheral blood were evaluated using monoclonal antibodies of W3/25 and MRCOX/8. We found that the W3/25/MRCOX-8 ratio increased to 3.2 +/- 0.3 in the PAN rats but significantly decreased to 2.8 +/- 0.3 with CY treatment. From these data it was impossible to decide whether the effect with CY had direct activity or not, because the interleukin-2 (IL-2) activity was not measured in rats. Secondly, polyethyleneimine (PEI) staining was performed to detect the sites of anion charge on glomerular basement membrane (GBM), and anionic dots on GBM in the CY-treated rats were clearly defined as nearly normal. Although there persist questions as to why nephrotic rats relapsed after the withdrawal of CY treatment, our results indicate that CY might reduce urinary protein excretion through immunological and non-immunological mechanisms.

Animals↗
PubMed1988

Effect of puromycin aminonucleoside on HSPG core protein content of glomerular epithelial cells.

It has been suggested that the glomerular basement membrane heparan sulfate proteoglycan (HSPG) is an important determinant of the glomerular permselectivity barrier. Derangements in the content of basement membrane heparan sulfate have been implicated in alterations in glomerular permselectivity seen in many glomerular diseases such as aminonucleoside nephrosis. The cellular origin and metabolism of the glomerular basement membrane HSPG have not been studied in detail. We have detected the expression of the proteoglycan by cloned glomerular visceral epithelial cells of the rat by employing a specific antibody against the core protein of HSPG isolated from the rat glomerular basement membrane. These findings suggest that in the rat in vivo glomerular visceral epithelial cells are one source of heparan sulfate present in the glomerular basement membrane. The effect of puromycin aminonucleoside (PAN) on the HSPG core protein content of the cloned glomerular epithelial cells was studied. By a quantitative immunoperoxidase method, the aminonucleoside caused a 28% reduction in the core protein content of the epithelial cells (P less than 0.01) following 72 h of incubation. However, the content of Heymann nephritis-related antigen, Fx1A was unchanged. Studies employing [3H]leucine incorporation showed that PAN was a weak inhibitor of de novo protein synthesis at 24 h of incubation, with complete recovery at 48 and 72 h. These data suggest that PAN effect on heparan sulfate core protein cannot be attributed to generalized inhibition of protein synthesis. The precise mechanism underlying the aminonucleoside effect on heparan sulfate core protein remains to be elucidated.

Aggrecans↗
PubMed1989

Severe proteinuria without impairment of sodium and volume excretion after puromycin aminonucleoside administration in rats.

The effects of a single intravenous injection of 100 mg/kg puromycin aminonucleoside (PAN) on renal protein, electrolyte, and fluid excretion as well as inulin and lithium clearances in rats were investigated under basal conditions, after iso-oncotic blood volume expansion with bovine serum albumin (BSA) and during infusion of atrial natriuretic peptide (ANP). All treated rats developed severe proteinuria 7-28 days after injection. On day 17, the protein excretion of the PAN group was 1,050 +/- (SE) 118 micrograms/(min x kg body weight) compared with 42.3 +/- 3.9 micrograms/(min x kg body weight) in the control group. Hypoproteinemia, edema or ascites were not observed. The renal protein excretion increased dramatically after BSA infusion and even more during ANP infusion in the PAN group. The PAN-treated animals lost about 62% of the infused BSA during the time of the experiment. No significant changes in protein excretion were observed in the controls. Both groups had similar basal excretions of urine volume, sodium, chloride, and potassium and responded to the BSA and PAN infusions with comparable increases in these parameters. The glomerular filtration rate was slightly, but not significantly higher in the PAN group during the control periods. Increases after BSA and ANP occurred in both groups, reaching significance only in the control group. Proximal tubular function was slightly impaired in PAN-treated rats as judged from a lower increase of the fractional excretion of lithium after BSA. Mean arterial blood pressure was higher in the PAN group (136.2 +/- 2.4 vs. 127.0 +/- 2.2 mm Hg) and fell in both groups to a comparable degree after BSA infusion. A further fall in blood pressure occurred after ANP infusion. Plasma ANP immunoreactivity was not different between the groups and increased after BSA infusion. Our data demonstrate that severe glomerular lesion as indicated by proteinuria can be observed after PAN administration without impairment of distal tubular function as judged from sodium and fluid excretion, and therefore support the view that the sodium retention observed in nephrotic syndrome is due to a separate intrarenal defect rather than a consequence of protein loss.

Animals↗
PubMed1977

Mechanisms of the puromycin-induced defects in the transglomerular passage of water and macromolecules.

To investigate the mechanism(s) of increased filtration of serum proteins after glomerular injury, polydisperse samples of uncharged [(3)H]dextran (D) or anionic [(3)H]dextran sulfate (DS) were infused into 14 control and 16 puromycin aminonucleoside- (PAN) treated Munich-Wistar rats. Fractional clearances of D or DS ranging in radius from 18 to 42A were determined in these rats, together with direct measurements of the forces governing the glomerular filtration rate of water. Whole kidney and single nephron glomerular filtration rates were approximately 40% lower in PAN-treated rats, relative to controls, due mainly to a marked reduction in the glomerular capillary ultrafiltration coefficient and, to a lesser extent, to a small reduction in glomerular plasma flow rate as well. In PAN-treated rats, as in normal controls, inulin was found to permeate the glomerular capillary wall without measurable restriction, and both D and DS were shown to be neither secreted nor reabsorbed. Fractional clearances of uncharged D were reduced after PAN administration, falling significantly for effective D radii from 22 to 38A. Utilizing a theory based on macromolecular transport through pores, these results indicate that in PAN-treated rats, effective pore radius is the same as in controls, approximately 44A. In PAN nephrosis, however, the ratio of total pore surface area/pore length, a measure of pore density, is reduced to approximately one-third that of control, due very likely to a reduction in filtration surface area. In contrast to the results with uncharged D, fractional clearances of DS were found to increase after PAN administration for all DS radii studied. These results with D and DS suggest that proteinuria in PAN nephrosis is due, not to an increase in effective pore radius or number of pores, but rather to a diminution of the electrostatic barrier function of the glomerular capillary wall, thereby allowing increased passage of polyanions such as DS and albumin.

Animals↗
PubMed1983

Renin-sodium profile in experimental nephrosis induced by puromycin aminonucleoside.

The roles of the renin-angiotensin system (RAS) and aldosterone in the pathogenesis of nephrotic syndrome were investigated with rats following subcutaneous injections of puromycin aminonucleoside (PAN) for 7 d. Prominent reduction in plasma renin activity (PRA) was observed at day-15 after the initial treatment with PAN preceded by the onset of the nephrosis and there was no significant difference in plasma aldosterone concentration (PAC) between the nephrosis and normal control groups despite the higher levels obtained in the nephrosis animals. Although we could not elucidate the precise mechanism of reduction in PRA, it was suggested that neither the RAS nor aldosterone secretion played a primary role in the pathogenesis of the nephrosis. PAN-induced nephrosis is interesting in studying the pathophysiological mechanism of the lowered activity of plasma renin in some patients with nephrotic syndrome.

Animals↗
PubMed1987

Urinalysis for detection of chemically induced renal damage (2)--Changes in urinary excretions of enzymes and various components caused by p-aminophenol, puromycin aminonucleoside and hexadimethrine.

In order to establish sensitive methods of detecting minor renal damage, changes of enzymes, protein, tubular cell counts, and creatinine in the urine were investigated in rats to which nephrotoxic chemicals had been administered. Daily administration of p-aminophenol (PAP) dose-dependently increased urinary excretions of lactate dehydrogenase (LDH) and its isoenzymes (LDH5 = LDH4 greater than LDH3 greater than LDH2 = LDH1), aspartate aminotransferase (GOT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (gamma-GTP), leucine aminopeptidase (LAP), lysozyme (LZM), N-acetyl-beta-D-glucosaminidase (NAG) and acid protease together with increased counts of tubular cells in the urine. Tubular cell counts, LDH and GOT were more sensitive indicators in the PAP tubulonephritis. Single i.v. injection of puromycin aminonucleoside (PM) dose-dependently increased urinary excretions of LDH and its isoenzymes (LDH1 = LDH5 greater than LDH2 = LDH4 greater than LDH3), GOT, NAG, acid protease and protein but degree of the increases in these enzymes was lower than those in the rats treated with PAP. PM increased excretions of high molecular weight proteins but did not increase ALP, gamma-GTP, LAP, LZM and tubular cells excretions. Single i.v. injection of hexadimethrine increased urinary excretion of LDH and its isoenzymes (LDH1 = LDH5 greater than LDH2 greater than LDH3 = LDH4), GOT, LZM, NAG and acid protease together with increased counts of tubular cells in the urine but did not increase ALP, gamma-GTP and LAP excretions. It is concluded that tubular cell counts, LDH isoenzymes and battery of these enzymes in urine are useful markers for detecting the severity and the site of renal damage in addition that urinary protein is a useful marker for detecting glomerular damage.

Aminophenols↗
PubMed1975

Effects of various protein-modifying agents and the aminonucleoside of puromycin on dithioerythritol-reducible disulfide in glomerular basement membrane.

Comparative study of dithioerythritol-reducible (DTE) disulfide bonds in glomerular basement membranes (GBM) isolated from normal rats and from similar groups of rats treated with the nephrosis-producing aminonucleoside of puromycin emphasize not only the importance of such linkages in the interaction and structural organization of the macromolecular GBM collagen-glycoprotein matrix but also suggest a modality by which GBM semi-permeability might be engendered. Although DTE-reducible disulfide is significantly reduced in GBM of rats as early as the fourth day after administration of a nephrosis-producing dose of the aminonucleoside it has not been possible to demonstrate an unequivocal in vitro or direct effect of the drug on DTE-reducible disulfide in normal GBM. Several-fold increases in DTE-reducible disulfide in GBM subjected to the denaturing action of guanidine-HCl or the proteolytic action of pronase indicates that most of the disulfide lies buried in the GBM. Location of disulfide crosslinks in the innermost regions or core of the GBM might be expected to not only stabilize the membrane but also to protect the GBM from a considerable array of disulfide cleaving (reductases) within the kidney cortex.

Animals↗
PubMed1987

Changes in glomerular heparan sulfate in puromycin aminonucleoside nephrosis.

Changes in glomerular anionic sites in puromycin aminonucleoside nephrosis (PAN) in the rat are controversial. The authors examined glomerular anionic sites in PAN by in vivo staining with polyethyleneimine (PEI). They also quantitated and characterized glomerular heparan sulfate (HS), which is known to be a major glomerular polyanion in PAN, using in vivo incorporation of 35S-sulfate. PAN rats had a mean protein excretion of 96 +/- 23 mg per 24 hours. Staining of anionic sites with PEI showed 15.3 +/- 2.8 sites per 1000-nm length of glomerular basement membrane in controls, 13.7 +/- 1.9 sites in PAN rats (P greater than 0.05), and 50% of rats with early PAN had absent staining. Total 35S-sulfate incorporation was similar in both the controls and established PAN rats (2900 +/- 150 dpm/mg dry wt of glomeruli versus 3005 +/- 260, P greater than 0.05) but decreased in early PAN rats (2025 +/- 148). The percentage of 35S-sulfate incorporated into chondroitin sulfate was similar in all three groups of animals. HS uronic acid was also similar (1.8 +/- 0.2 g/mg dry wt of glomeruli versus 1.7 +/- 0.3, P greater than 0.05) but decreased in early PAN (1.1 +/- 0.2). The distribution of 35S-sulfate activity within the HS subfractions was examined by ion-exchange chromatography and showed a shift in percent present from 1.0 M to 1.25 M fraction in established and early PAN animals (control 1.0 M 37% +/- 3.2% versus PAN 19% +/- 3.4%, P less than 0.01, and 1.25 M 36% +/- 2.9% versus 53% +/- 2.9%, P less than 0.01). These results demonstrate that glomerular heparan sulfate is unchanged in established PAN but decreased in early PAN. SO4 incorporation is unchanged in established PAN and diminished in early PAN. Thus, early in PAN HS synthesis is impaired, but in established PAN the HS is normal, and changes in glomerular HS cannot explain the increased permeability.

Animals↗
PubMedDate not supplied

Glomerular basement membrane heparan sulfate glycosaminoglycan in aminonucleoside of puromycin nephrosis.

Proteinuria in aminonucleoside of puromycin (PAN) nephrosis is due to an alteration of the glomerular charge- and size-selective barrier. Heparan sulfate seems to play a role in glomerular charge permeability to plasma proteins. We report a quantitative analysis and metabolism of glomerular basement membrane (GBM) heparan sulfate in PAN nephrosis. Studies were performed 5 and 10 days post-PAN administration (15 mg/100 g) to Sprague-Dawley rats. GBM heparan sulfate glycosaminoglycan was measured using the dimethylmethylene blue test after chromatographic separation of the digested GBM. Sulfate-35 uptake by GBM and catabolism of GBM-sulfated compounds were studied using glomerular cultures. The heparan sulfate glycosaminoglycans concentration on day 5 (1.42 micrograms/mg GBM protein) was within the normal range (1.17 +/- 0.25), but the concentration on day 10 was below the limit of detection (0.57 micrograms/mg). The sulfate-35 incorporated in the GBM glycosaminoglycan on day 5 (158 cpm/micrograms glycosaminoglycan) was lower than the uptake of control GBM (270 cpm/micrograms glycosaminoglycan), and markedly lower than the uptake on day 10 (1,590 cpm/micrograms glycosaminoglycan). The catabolism of the GBM sulfated compounds on day 5 and 10 was not different than the one seen in controls. These data suggest that PAN administration is associated with a decrease in synthesis of GBM-sulfated compounds on day 5 and a decrease in GBM heparan sulfate glycosaminoglycan on day 10. However, on day 10, an increased compensatory synthesis is observed. This may subsequently normalize the GBM heparan sulfate concentration and explain the resolution of the proteinuria.

Animals↗
PubMed1986

Effect of captopril on chronic puromycin aminonucleoside nephrosis in rats.

The effect of captopril, an angiotensin converting enzyme inhibitor, on the progression of chronic puromycin aminonucleoside (PAN) nephrosis was examined. Rats were injected with 15 mg/100 gm body weight PAN and 5 mg/100 gm body weight, on weeks - 1 and 5, respectively. A third group was injected with an equivalent volume of 0.9% saline, intraperitoneally (Group III) on week - 1 and 5. Beginning week 0, group I received 50 mg/kg captopril daily in the drinking water for 12 weeks. Group II received no treatment. Captopril failed to attenuate the peak level of proteinuria induced by the first injection of PAN or to alter the rate of decline of proteinuria when begun 1 week after the PAN injection. However, captopril did blunt the increase in urinary protein excretion following the second injection of PAN (p less than 0.05). Group II became hypertensive compared to Group I on week 8 and 12 and Group III on week 12 (p less than 0.05). Group I and II could not be distinguished on the basis of renal histologic rank (p = 0.80). We conclude that captopril affords some protection against the development of PAN-induced proteinuria, but it does not accelerate the recovery phase when glomerular permselectivity is being regained.

Animals↗
PubMed1979

Determinants of glomerular localization of subepithelial immune deposits: effects of altered antigen to antibody ratio, steroids, vasoactive amine antagonists, and aminonucleoside of puromycin on passive Heymann nephritis in rats.

The role of circulating immune complex deposition versus in situ complex formation in membranous nephropathy is controversial. Passive Heymann nephritis in rats resembles membranous nephropathy in man and was induced by injection of sheep antibody to rat proximal tubular epithelial cell brush border antigen (anti-Fx1A). Minutes after injection of 1 ml. of anti-Fx1A, subepithelial immune deposits were seen by immunofluorescence and electron microscopy, and proteinuria appeared within 5 days. The effects of alterations in the dose of administered antibody, corticosteroid therapy, and vasoactive amine blockade on the development of subepithelial deposits and consequent proteinura were studied. Variation of the dose of anti-Fx1A from 0.25 ml. to 1 ml. resulted in a progressive increase in the size and number of glomerular capillary wall deposits, but no alterations in their distribution. Only those rats which received 1 ml. became proteinuric within 5 days. Corticosteroid therapy and vasoactive amine blockade, begun 24 hours prior to the induction of passive Heymann nephritis and continued until termination of the study 5 days later, had no effect on the amount or site of immune complex formation, nor on the extent of proteinuria as compared to untreated controls. In contrast, in rats with unilateral proteinuria produced by the selective perfusion of one kidney with aminonucleoside of puromycin 7 days prior to the induction of passive Heymann nephritis, there was a marked reduction of subepithelial deposits in the perfused kidney as compared to the nonperfused contralateral kidney. In this model of membranous nephropathy, systemic factors play little role in the development of subepithelial deposits, whereas local factors are critical. These findings are consistent with the hypothesis that subepithelial immune deposits form locally.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Incorporation of 35sulfate into the glomerular basement membrane in puromycin aminonucleoside nephrosis.

The in vitro incorporation of 35sulfate into the glomerular basement membrane (GBM) of rats with puromycin aminonucleoside was compared with that of normal rats. 35Sulfate incorporation into the GBM of glomeruli from nephrotic rats did not differ significantly from that observed in normal rats. These data suggest that 35sulfate anionic charges in the GBM play no important role in the pathogenesis of the proteinuria in this experimental model.

Animals↗
PubMed1980

Nascent RNA chain termination and ultrastructural changes in nucleoli isolated from SV40-transformed fibroblasts treated with aminonucleoside of puromycin.

The mechanism for the selective inhibition of preribosomal RNA synthesis by puromycin aminonucleoside (AMS) was investigated in cultured AG 2804 cells, which are human embryonic lung fibroblasts transformed by SV40 virus. Sequential high voltage electrophoresis and paper chromatography of the RNA of fractionated nuclei isolated from fibroblasts exposed to tritiated AMS (340 microM, 5 microCi. per ml., for 18 hours) demonstrated that the inhibitor is demethylated to 3'-amino-3'-deoxyadenosine and incorporated into terminal positions in both nucleolar and nonnucleolar nuclear RNA chains in the same relative amounts. 3'-Amino-3'-deoxyadenosine was not detected in the RNA obtained from the cytoplasm of AMS-treated fibroblasts. Electron microscopic observation of isolated nucleoli showed that neighboring intranucleolar fibrils have a tendency to coalesce after AMS treatment. It is suggested that, when the modified AMS molecule has reached the growing ends of nascent polyribonucleotide chains elongation stops, the chain remains attached to its template, and the strong positive charge of the aminosugar portion of AMS interacts with negatively charged components (e.g., phosphate groups) of adjacent nascent RNA chains. The high density of the components of the nucleolus produces frequent interactions of this type and leads to secondary interference with nucleolar RNA synthesis, thus accounting for the selective effect of AMS on preribosomal RNA synthesis.

Cell Nucleolus↗
PubMed1981

Delayed growth inhibition of human leukaemic cells in culture following treatment with aminonucleoside of puromycin.

The effects of the aminonucleoside analogue of puromycin (AMS) on the growth of the CCRF-CEM human leukaemic lymphoblast cell line have been studied. CEM lymphoblasts are capable of growth in the presence of AMS for a limited period of time, in a manner similar to other transformed cell lines in culture. However, a delayed effect of AMS was found to take place at the time of the third cell division after application of the drug. This phenomenon of delayed growth inhibition has not yet been described for any other type of cell. The delayed inhibition of CEM cells caused by AMS manifests regardless of the subsequent presence or absence of the drug. The magnitude of the delayed inhibition is linearly dependent on the concentration of AMS during the initial incubation period. Cell proliferation during drug application is not necessary for establishing the inhibition. Following the inhibition period, the cells resume a normal rate of growth.

Cell Division↗