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PubMed1996

Modulation of antitumor immunity of tumor-bearing mice with low-dose cyclophosphamide.

As a tumor progressively grows, the tumor-bearing host usually is under a tumor-mediated immune suppression status. Although surgical resection of the tumor may immediately eliminate most tumor-induced detrimental influences, perioperatively the antitumor immunity of the host remains temporarily suppressed. The major purpose of this study is to investigate the modulation effect of low-dose cyclophosphamide (CY) on the antitumor immunity of tumor-bearing mice (TBM). Using the C3H/He-MBT-2 murine bladder tumor model, we demonstrate that low-dose CY (100 mg/kg) intraperitoneal injection 2 days before tumor resection can significantly enhance the specific antitumor immunity of the TBM. It consequently suppresses the outgrowth of perioperative rechallenged tumor cells and improves the survival of the animals. Phenotypic analysis of cellular subset of spleen by flow cytometry revealed that low-dose CY, when given to both naive and tumor-bearing mice, causes significant reduction of both absolute number and percentage of cells with CD4-CD8- subset in the spleens of TBM. As a result of a parallel increase in the percentage of both CD4+CD8- and CD4-CD8+ subsets, the CD4+/CD8+ ratio remains unchanged. However, after short-term in vitro culture with IL-2 the percentage of the CD4-CD8- subset and CD4+/CD8+ ratio markedly decreased because of the relatively predominant proliferation of the CD4-CD8+ subset. Evidence from in vitro cytotoxicity assays on panel tumor cells and phenotypic analysis revealed that this enhancement of host antitumor immunity, following low-dose CY pretreatment, may be due to augmenting the activity of NK, LAK, and CD11b+ myeloid/macrophages in addition to cytotoxic T lymphocytes.

Animals↗
PubMed1997

Sepsis impairs anastomotic collagen gene expression and synthesis: a possible role for nitric oxide.

Although intra-abdominal sepsis is known to impair colon healing by inhibiting anastomotic collagen synthesis, the effect of systemic sepsis on this process is unknown. Endotoxins and cytokines associated with sepsis induce nitric oxide synthesis both systemically and locally within colonic tissue. We hypothesized that systemic sepsis impairs colonic healing and examined a possible correlation with nitric oxide expression. Male Sprague-Dawley rats received intraperitoneal injections of either saline (sham group) or Escherichia coli endotoxin (lipopolysaccharide 1 mg/100 g body weight) at Times -24 and -12 hr (LPS group). All animals underwent laparotomy and left colonic anastomosis at Time 0. At 24 and 96 hr postlaparotomy rats were sacrificed, the anastomoses excised, and [3H]-proline incorporation into protein measured as an index of total new protein synthesis (TNP). Digestion with purified collagenase yielded incorporation into the collagen fraction (CDP). Additional sham and LPS-treated rats were sacrificed at 24, 72, and 120 hr, the anastomoses excised, and nitric oxide synthase activity in the tissue measured by the conversion of [3H]-arginine to [3H]citrulline in an ex vivo culture system. Finally, sham and LPS rats were sacrificed at 120 hr for measurement of colon anastomotic bursting pressure. Systemic sepsis significantly impaired new collagen synthesis in anastomotic tissue at 24 hr compared to control samples (P < 0.02). No difference was noted at 96 hr. TNP synthesis was similar in both groups at 24 or 96 hr. Northern blot analysis confirmed a significant decrease in Type I and Type III collagen mRNA expression at 24 hr in septic rats. Anastomotic bursting pressure was also decreased in the septic group (P < 0.003). Sepsis elevated nitric oxide synthase activity in anastomotic tissue 24 hr postanastomosis, when compared to sham tissue (P < 0.0001). These data suggest that systemic endotoxin induces nitric oxide synthesis at the anastomotic site. The simultaneous dysregulation of collagen gene expression and synthesis with decreased anastomotic strength suggests a possible regulatory role for nitric oxide in gastrointestinal healing.

Anastomosis, Surgical↗
PubMed2002

Human interleukin 10 gene therapy decreases the severity and mortality of lethal pancreatitis in rats.

BACKGROUND: Studies have proven the validity of interleukin-10 (IL-10) in the treatment of experimental pancreatitis. Prophylactic human IL-10 (hIL-10) gene treatment attenuated the severity in cerulein models. Our research aims to study whether the therapeutic hIL-10 gene could decrease both severity and mortality in a lethal pancreatic model. METHODS: Severe acute pancreatitis (SAP) was induced by sodium taurocholate. A plasmid-hIL-10 construct (pcDNA3-hIL-10) complexed with cationic liposomes was administered to SAP rats by a single intraperitoneal injection. Levels of hIL-10 in the pancreas, liver, and lungs were determined by ELISA kits. The severity of pancreatitis was assessed in terms of serum amylase, histology, and tissue tumor necrosis factor alpha (TNF-alpha). Mortality, observed for 7 days, was evaluated for gene therapy or control groups. RESULTS: After hIL-10 gene therapy, hIL-10 levels in the pancreas, liver, and lungs increased significantly and the serum amylase, tissue TNF-alpha, and histological changes in pancreas, liver, and lungs decreased markedly. Therefore, mortality was significantly reduced in the hIL-10 gene therapy group, in which 70% of rats survived in the 7-day observation, while only 10% survived in untreated groups (P < 0.05). CONCLUSION: We found that liposome/hIL-10 gene therapy decreased severity and mortality in SAP, even carried out after SAP establishment, predicting a more convenient shift to clinical applications.

Acute Disease↗
PubMed1993

Covalent cross-linking of erythrocyte spectrin by carbon disulfide in vivo.

Covalent cross-linking of proteins by CS2 has been demonstrated in vitro and represents a potential mechanism for the toxicity of this compound. In the present investigation the ability of CS2 to cross-link proteins covalently in vivo is demonstrated using denaturing polyacrylamide gel electrophoresis. Intraperitoneal injection of CS2 in rats at 2 or 5 mmol/kg for 21 or 42 days produced several high-molecular-weight (approximately 410 kDa) proteins eluted from erythrocyte membranes which were not present in control animals. Limited proteolysis of the high-molecular-weight protein bands, monomeric alpha spectrin, and monomeric beta spectrin using endoproteinase glu-C, followed by peptide mapping on denaturing polyacrylamide gels, showed the high-molecular-weight proteins to be alpha,beta heterodimers. The production of multiple heterodimers exhibiting different distances of migration was consistent with the existence of several preferred sites for cross-linking. Evidence for the presence of dithiocarbamate ester and thiourea cross-linking structures in spectrin dimers was obtained using selective base hydrolysis. No spectrin dimer was detected in control animals, and dimer formation demonstrated a cumulative dose response in CS2-treated rats. The longevity of red blood cells, the cumulative dose response, and the stability of the cross-linking structures endows spectrin cross-linking with the potential to serve as a biomarker of chronic low-level exposures to CS2 and may provide a means to correlate pathological changes with existing methods of CS2 exposure monitoring. The ability of CS2 to covalently cross-link erythrocyte spectrin suggests that CS2 may also cross-link other proteins in vivo and supports covalent cross-linking of proteins as a possible molecular mechanism through which CS2 manifests toxicity. If so, then spectrin cross-linking may parallel cross-linking reactions in the axon and provide a sensitive, preneurotoxic biomarker of this molecular event.

Animals↗
PubMed1994

The correlation of serum luteinizing hormone levels with the induction of Leydig cell tumors in rats by oxolinic acid.

Studies were performed to examine the mechanism by which testicular Leydig cell tumors are induced in rats by administration of the antimicrobial agent oxolinic acid (1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-3-quinolinecarboxylic acid). In these studies, the effects of oxolinic acid on serum levels of luteinizing hormone (LH), testosterone, and prolactin and the binding of testosterone to prostatic androgen receptors were examined. In a long-term hormonal study, male Wistar rats were fed a diet containing oxolinic acid at 0, 100, 1000, or 3000 ppm for 104 weeks. A statistically significant increase in serum LH levels was observed at 1000 and 3000 ppm, but no dose of oxolinic acid had a significant effect on serum testosterone levels. Serum LH levels were no longer elevated above control levels within 2 weeks of cessation of the administration of oxolinic acid. Oxolinic acid was found to have no effect on the rate of clearance of exogenous LH from the circulation. Serum prolactin levels were decreased by the administration of oxolinic acid. The increase in serum LH induced by oxolinic acid was completely blocked by the intraperitoneal injection of the dopamine antagonist haloperidol (2 mg/kg). In addition, no significant affinity of oxolinic acid for androgen receptors was found in an in vitro study. These findings suggest that: (1) oxolinic acid induces Leydig cell tumors in rats by chronically stimulating the release of LH from the pituitary, (2) the mechanism of stimulating the release of LH involves facilitation of the dopaminergic systems in the hypothalamus-pituitary axis, and (3) oxolinic acid has no effect on androgen-mediated feedback inhibition.

Administration, Oral↗
PubMed1996

Disulfiram and diethyldithiocarbamate intoxication affects the storage and release of striatal dopamine.

Acute intoxication and chronic therapy with the alcohol consumption deterrent dithiocarbamate disulfiram have been associated with several neurological complications perhaps involving the impairment of neurotransmitter pathways. In this study we have tested the hypothesis that dopaminergic malfunction is a critical component in disulfiram-evoked neurotoxicity. Disulfiram antagonized the in vitro striatal binding of [3H]tyramine, a putative marker of the vesicular transporter for dopamine, and the uptake of [3H]dopamine into striatal synaptic vesicles, with inhibitory constants (Ki) in the range of reported blood dithiocarbamate levels in treated alcoholics. Furthermore, disulfiram provoked a loss of radioactivity from [3H]dopamine-preloaded striatal vesicles, when added directly to the incubation mixture. Several metal-containing fungicide analogs were also potent displacers of specifically bound [3H]tyramine. Diethyldithiocarbamate (DDC), the major metabolite of disulfiram, had none of these effects. The intraperitoneal injection of a high dose of disulfiram and DDC into rats, mimicking acute intoxication, induced in vivo overflow of striatal dopamine from both a reserpine-sensitive (vesicular) and an alpha-methyl-p-tyrosine-sensitive (cytoplasmic) pool. The vesicular component of in vivo dopamine release resulted mainly from a direct activity of disulfiram, on the organelles (interaction with the carrier for dopamine plus membrane permeabilization) and indirectly through the mediation of serotonergic 5-HT3 receptors. DDC acted poorly at the vesicle membrane, and the in vivo releasing effect of dopamine was only partially prevented by the inhibition of 5-HT3 receptors, thus suggesting the role of additional mechanisms. It is concluded that disulfiram intoxication may acutely disrupt dopamine balance, an effect probably underlying some of the central neurotoxic, extrapyramidal symptoms associated with dithiocarbamate overdose.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Cinnamyl anthranilate causes coinduction of hepatic microsomal and peroxisomal enzymes in mouse but not rat.

Cinnamyl anthranilate is a synthetic food flavoring and fragrance agent, formerly used at low levels. Although it is not genotoxic, very high doses have been shown to cause liver tumors in mice but not rats. In this report we characterize hepatic changes brought about by cinnamyl anthranilate in rats and mice. Groups of male CD1 mice and Fischer 344 rats received 0, 100, or 1000 mg/kg cinnamyl anthranilate by intraperitoneal injection daily for 3 days. After euthanization on the 4th day, plasma lipids and relative liver weight, tissue DNA, the peroxisome marker CN(-)-insensitive palmitoyl-CoA oxidation, cytochrome P450, microsomal lauric acid hydroxylation, aminopyrine N-demethylase and ethoxyresorufin O-deethylase, bilirubin UDP-glucuronosyltransferase, microsomal and cytosolic epoxide hydrolase, and the peroxisome/mitochondria ratio in liver sections were monitored. In mice a pattern of change pointing to peroxisomal proliferation was seen at both doses of cinnamyl anthranilate, but in rats fewer and smaller changes were seen with little or no evidence of peroxisomal proliferation at the doses used. Groups of male CD1 mice were given 0-200 mg/kg cinnamyl anthranilate daily for 3 days. At doses of 20 mg/kg and above, there were dose-dependent increases in relative liver weight, total cytochrome P450, and CN(-)-insensitive palmitoyl-CoA oxidation. The hepatic effects of cinnamyl anthranilate are apparently due to the intact ester, since neither its expected metabolites alone nor an equimolar mixture of the hydrolysis products, cinnamyl alcohol and anthranilic acid, had any significant effect on the weight or marker enzyme content of mouse liver. The data are discussed in relation to the species specificity of the hepatocarcinogenicity of cinnamyl anthranilate and to metabolic studies in rats and mice. It is suggested that in mice, peroxisomal proliferation occurs only at doses high enough to prevent complete metabolic hydrolysis.

Animals↗
PubMed1998

Pulmonary cytokine and chemokine mRNA levels after inhalation of lipopolysaccharide in C57BL/6 mice.

Inhaled endotoxin (lipopolysaccharide, LPS) can induce acute lung injury and at high doses may lead to respiratory distress syndrome. Using a mouse model of acute lung inflammation induced by inhalation of low doses of LPS we examined the kinetics of chemokine, proinflammatory cytokine, and metallothionein. Eight-week-old C57BL/6 mice were dosed for 10 min with LPS, resulting in an estimated alveolar dose of < 10 ng LPS/mouse, and euthanized 2,6, or 24 h postexposure. Analysis of bronchoalveolar lavage fluid demonstrated increased polymorphonuclear neutrophils (PMNs) of 6.94, 32.7, and 38.8% after 2, 6, and 24 h, respectively. Examination of proinflammatory cytokine, chemokine, and Mt mRNA in the lung revealed increases for messages encoding IL-1 alpha, IL-1 beta, IL-6, IFN-gamma, TNF alpha, Eotaxin, MIP-1 alpha, MIP-1 beta, MIP-2, Mt, and IP-10, while messages encoding IL-12, IL-10, IFN-beta, Ltn, MCP-1, TGF beta 1 + 2, and RANTES were unchanged from those of sham-exposed mice 2 h postexposure. By 6 h most messages had returned to near control levels. Comparison to 5 mg/kg body weight intraperitoneal injection and 5 micrograms/mouse intratracheal instillation 2 h postexposure demonstrated similar message responses. Our results demonstrate that low levels of LPS exposure by inhalation induce a strong PMN response and a selective cytokine response in the lung, supporting the hypothesis that PMNs may regulate inflammatory processes via cytokine and chemokine response.

Administration, Inhalation↗
PubMed2005

The antioxidant effect of N-acethylcysteine on experimental contusion in rats.

N-acethylcysteine (NAC) is known to have direct and indirect antioxidant abilities. We investigated the potential protective effect of NAC on ICP, brain edema and contusion volume after Controlled Cortical Impact (CCI) injury. A moderate CCI injury was induced on the left hemisphere in 48 Sprague Dawley rats. The animals were treated with intraperitoneal injection of NAC (163 mg/kg/KG) or physiological saline. Measurements of intracranial pressure (ICP) were performed and brains were removed at 24 hours. Gravimetric analysis of post-traumatic edema and morphometric measurements (TTC staining) of contusion volume were carried out in 24 animals, respectively. ICP measurements increased significantly over time with no significant differences between both groups. The relative difference in water content in NAC treated animals (1.45 +/- 0.1%) did not differ significantly versus placebo (1.47 +/- 0.2%). The contusion volume was diminished by 19% in the NAC group (53.52 +/- 5.3 mm3) versus placebo (66.28 +/- 4.7 mm3) without showing statistical significance. The antioxidant properties of NAC did not affect intracranial pressure or posttraumatic brain edema formation, although the moderate reduction of contusion volume might reveal beneficial effects on focal contusion.

Acetylcysteine↗
PubMed1977

Lung tumor response in mice to metals and metal salts.

Two studies tested the ability of metals and their salts to produce lung tumors in strain A mice. Of 13 compounds examined, lead subacetate, manganous sulfate, molybdenum trioxide, and nickelous acetate elicited a weakly carcinogenic response following intraperitoneal injection. Nine metallic compounds were negative. There was no evidence of cocarcinogenic effect between metals and the chemical carcinogen, 3-methylcholanthrene. On the basis of these and other data, recommendation is made for further investigations in metal carcinogenesis.

Animals↗
PubMed1994

Localization of experimental brain tumors in MRI by gadolinium porphyrin.

The contrast between edema and F98 glioma in rat brain was distinctly enhanced in T2-weighted MRI (TE 130 ms, TR 3 s) by intraperitoneal injection of the synthetic gadolinium-porphyrin complex, GdTPPS. The T1 relaxation time of the gliomas was selectively shortened by about 50% from 1339 +/- 109 ms to 628 +/- 106 ms, and the T2 relaxation time was shortened by about 35% from 86 +/- 6 ms to 57 +/- 5 ms. The relaxation times of normal tissues under investigation (cortex, corpus callosum, temporal muscle, ventricles) were unaltered. Therefore, GdTPPS-application causes F98 gliomas to appear hyperintense in T1-weighted MRI and hypointense in T2-weighted MRI.

Animals↗
PubMed1991

Effect of propionyl-L-carnitine on mechanical function of isolated rabbit heart.

We studied the acute and chronic effects of propionyl-L-carnitine (PLC) on mechanical function of isolated rabbit heart. Propionyl-L-carnitine was either directly delivered in the perfusate (10(-9) to 10(-3) M) or intraperitoneally injected (250 mg/kg) for 10 days to the animals. When added acutely, propionyl-L-carnitine had no effect on inotropism, heart rate, or coronary perfusion pressure. When added chronically, propionyl-L-carnitine induced a positive inotropic effect, with no changes in heart rate or in coronary perfusion pressure, and it ameliorated the pressure-volume relationship. This effect of propionyl-L-carnitine was independent of the calcium concentration of the perfusion medium, but it was correlated with an increase in the myocardial content of propionyl-L-carnitine. The effect was not apparent after 5 days of treatment, although the tissue content of propionyl-L-carnitine remained unchanged. These data suggest that propionyl-L-carnitine, when given chronically, exerts a positive inotropic effect.

Acetylcarnitine↗
PubMed1994

Cyclophosphamide induced early biochemical changes in lung lavage fluid and alterations in lavage cell function.

The present investigation evaluated the changes in bronchoalveolar lavage fluid (BALF) biochemical constituents and indices of bronchoalveolar lavage cell functions to detect early lung injury in rats following intraperitoneal administration of cyclophosphamide (CP). Rats were exposed to a single intraperitoneal injection of CP (200 or 300 mg/kg body weight). Experimental and control rats were sacrificed at various time intervals (2, 3, 5, 7, 11, 21, and 42 days after cessation of exposure), and lung lavage was performed to examine several markers of lung injury. Biochemical analyses revealed dose-related increases in BALF angiotensin converting enzyme activity, total protein, lactate, lactate dehydrogenase, and N-acetyl-beta-D-glucosaminidase (NAG) levels on days 2, 3, 5, 7, and dose-related increases in albumin, alkaline phosphatase, acid phosphatase, and lipid peroxidation on days 2, 3, 5, 7, and 11 after CP treatment. In contrast, reduced levels of ascorbic acid and glutathione (GSH) content were observed in lung lavage fluid. We also examined bronchoalveolar lavage cells for acid hydrolases (acid phosphatase, beta-glucuronidase, NAG) and GSH content. Activity of acid hydrolases was slightly elevated on day 2 and peaked on days 3, 5, and 7. However, lavage cell GSH content was decreased. Thus, measurements of pulmonary changes by analyzing lavage fluid and lavage cell functions seems to be a useful marker for assessing the early onset and development of CP-induced lung injury.

Animals↗
PubMed1988

Environment-dependent tolerance to ethanol produced by intracerebroventricular injections in mice.

In comparison to other routes of drug administration, an intracerebroventricular (ICV) injection requires the use of a very small amount of ethanol in mice to produce a brief but substantial hypothermic response. By avoiding the longer duration of drug action, use of ICV injections may facilitate the demonstration of the contribution of certain aspects of learning in the expression of tolerance. Therefore, tolerance to ethanol was developed in mice in a Pavlovian conditioning paradigm with eight ICV injections of ethanol delivered at 2-h intervals so that the animals received four injections per day for 2 days. The effect of ethanol in a different environment was tested on the following day. Environment-dependent tolerance to the hypothermic effect of ethanol and a robust conditioned compensatory response were demonstrated when the mice were trained and tested with ICV injections of 2.0 mg ethanol. The environment-dependent tolerance was also evident when the mice were trained with ICV injections and tested with intraperitoneal injections of ethanol. These results demonstrate that ICV injections are a beneficial means of clarifying the role of learning phenomena in the development of tolerance.

Animals↗
PubMed1996

Increase in number of Weibel-Palade bodies and endothelin-1 release from endothelial cells in the cadmium-treated rat thoracic aorta.

Male rats received daily intraperitoneal injections of cadmium sulphate (2.0 mg/kg) for 3 (Cd-3 group), 6 (Cd-6 group) and 8 days (Cd-8 group). The blood samples were prepared for endothelin (ET)-1 assay, and the thoracic aorta was investigated by both electron microscopy and immunoelectron microscopy using anti ET-1 sera. The plasma ET-1 concentrations of both Cd-6 and Cd-8 groups increased significantly in a cumulative dose-dependent manner. The cadmium-treated rat aorta showed an increase in the number of Weibel-Palade (WP) bodies in endothelial cells, and degranulation and exocytosis of WP bodies occurred exclusively in the Cd-8 group. Immunoreaction for ET-1 was localized preferentially in WP bodies of both cadmium-treated and control groups, and in the rough endoplasmic reticulum of the cadmium-treated groups only. Reactivity was also found on the WP bodies undergoing exocytosis in the Cd-8 group. Cadmium intoxication induces an increase in number of ET-1-storing WP bodies in the rat aorta endothelium. The enhancement of extracellular release of their contents by exocytosis results in elevation of the plasma ET-1 concentration.

Animals↗
PubMed1995

Immunotoxicity in channel catfish, Ictalurus punctatus, following acute exposure to tributyltin.

Tributyltin (TBT) is a trialkylated organotin formulated for use primarily as a biocide for aquatic and agricultural industries. Although macrophages isolated from toadfish (Opsanus tau) are sensitive to exposure, very little is known about the effects of TBT on fish humoral immunity and non-specific cytotoxic cell (NCC) functions. To evaluate the effects of TBT on these parameters, channel catfish (Ictalurus punctatus) were given a single intraperitoneal injection of corn oil with 0 (vehicle control) or with 0.01, 0.1, and 1.0 mgTBT/kg as TBTCl. Three and seven days later, NCC activity and phagocyte oxidative burst were evaluated and related to allometric indices and hematology. The humoral immune response to Edwardsiella ictaluri was evaluated fourteen days after treatment. Peripheral blood neutrophilia and specific antibody secreting cell (SASC) numbers were the most sensitive parameters and were affected in all three TBT treatment groups. Allometric indices, peripheral blood lymphocyte and monocyte percentages, NCC activity, and phagocyte oxidative burst were less sensitive and were affected only at the highest dose of TBT.

Animals↗
PubMed1995

Macrophage depletion in the rat after intraperitoneal administration of liposome-encapsulated clodronate: depletion kinetics and accelerated repopulation of peritoneal and omental macrophages by administration of Freund's adjuvant.

The purpose of this study was to develop a method for the depletion of macrophages from the peritoneal cavity and the omentum of the rat. Rats received two intraperitoneal injections (at days 0 and 3) with liposome-encapsulated clodronate (dichloromethylene bisphosphonate: Cl2MBP-liposomes). This treatment resulted in complete elimination of mature tissue macrophages (ED2-positive macrophages) from the peritoneal cavity and the omentum within 2 days. The elimination included the strongly ED2-positive spindle-shaped cells of the omental membrane. Repopulation of the omental ED2-positive macrophages was not seen within the next 23 days. Whereas ED2-positive macrophages were completely depleted, few ED1-positive cells remained and repopulation of ED1-positive cells was faster. The treatment further depleted macrophages from the spleen, especially from the red pulp, parathymic lymph nodes and liver. Freund's incomplete adjuvant administered one day after the last injection of Cl2MBP-liposomes considerably accelerated repopulation in the omentum. The protocol described might be used to investigate the contribution of mature tissue macrophages to the induction of immune responses, drug metabolism and the elimination of intestinal tumours.

Animals↗
PubMed1977

[Partial synchronization of tumor cells in vivo with hydroxyurea (author's transl)].

For the partial synchronization of tumor cells, Yoshida ascitic sarcoma bearing rats were treated with Hydroxyurea using two methods, one in the form of a single intraperitoneal injection (0.5 mg/g body weight) and the other by continuous intraascitic infusion over a period of 12h (1.428 mg/g body weight total dose). The synchronization obtained by continuous infusion of Hydroxyurea is superior to that by a one time injection with respect to cell accumulation in one phase of the cell cycle and in the duration of synchronous proliferation. The degree of cell loss caused by infusion depends on the concentration of Hydroxyurea. Concentrations of slightly more than the minimal inhibitory concentration of DNA synthesis cause the least damage to the tumor cells.

Animals↗