A variety of cytogenetic assays have been used successfully for monitoring populations exposed to... more A variety of cytogenetic assays have been used successfully for monitoring populations exposed to environmental mutagens. The traditional chromosome aberration (CA) assay is one of the most useful, and it also predicts cancer outcome on a population basis. However, the sensitivity of this assay requires improvement, and researchers need to understand other factors that influence the expression of CA and health outcome, especially on an individual basis. The sensitivity and specificity of the CA assay are improved with the use of the fluorescence in situ hybridization (FISH) procedure, which employs a variety of chromosome-specific and chromosome region-specific fluorescence probes to elucidate CA. Factors that influence the expression of CA in a population study include inadequate study design, genetic variations in metabolism of chemicals (genetic susceptibility), and lifestyle differences in response to exposure to environmental mutagens (acquired susceptibility). The latter may i...
The progression of malignant melanoma is characterized by overex- pression of a number of matrix ... more The progression of malignant melanoma is characterized by overex- pression of a number of matrix metalloproteinases (MMPs), especially MMP-2, which play a critical role in the degradation of basement mem- branes and the extracellular matrix. Consequently, we assessed a drug targeting strategy in which the protease activity of MMP-2 is exploited to release an anticancer agent from a macromolecular carrier,
... Original Paper. Effect of L-Histidinol on Cisplatin Nephrotoxicity in the Rat Osama A. Badary... more ... Original Paper. Effect of L-Histidinol on Cisplatin Nephrotoxicity in the Rat Osama A. Badary, Mahmoud N. Nagi, Hussein A. Al-Sawaf, Mohammed Al-Harbi, Abdullah M. Al-Bekairi Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. ...
This study aimed to investigate the long-term toxicity of a preventive regimen of tamoxifen (TAM)... more This study aimed to investigate the long-term toxicity of a preventive regimen of tamoxifen (TAM) and recombinant human interferon alpha 2b (rHuIFN alpha 2b) on the uterine responsiveness of tumour-bearing rats. The experimental tumour was induced by dimethylbenz(a)anthracene (DMBA) in virgin female albino rats and the therapy was started two months after carcinogen administration. The acute effect of DMBA on the uterine sensitivity was also assessed 24 h post-carcinogen. The uterotonic potentials of oxytocin and prostaglandin F2 alpha (PGF2 alpha) were markedly reduced in the control tumour-bearing group as compared to the normal one. Similarly, acute DMBA administration showed reduced uterine sensitivity to both agents. Treatment with either TAM or combined TAM/rHuIFN alpha 2b did not affect the uterine response to either oxytocin or PGF2 alpha, while rHuIFN alpha 2b increased the uterine sensitivity to oxytocin but not to PGF2 alpha. These data indicate that the carcinogenic agent per se and the presence of tumour reduce the contractile response in the rat uterus to oxytocic agents. Moreover, combined TAM/rHuIFN alpha 2b does not markedly affect the uterine sensitivity in DMBA-induced mammary carcinoma-bearing rats.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2000
Cremophor EL (CR), the paclitaxel vehicle, has previously been reported to alter the pharmacokine... more Cremophor EL (CR), the paclitaxel vehicle, has previously been reported to alter the pharmacokinetics and/or pharmacodynamics of some anticancer drugs including paclitaxel. Several experimental and clinical studies suggested that cisplatin (CDDP) in combination with paclitaxel results in less hematological toxicity than anticipated. To reveal the role of CR in this important pharmacological interaction, we evaluated the interaction of CR with CDDP in vitro and in vivo using experimental Ehrlich ascites carcinoma (EAC) tumor. CR (1 microg/ml) significantly enhanced the in vitro cytotoxicity of CDDP in cultured EAC cells. This enhancement was not associated with a parallel increase in CDDP cellular uptake. In tumor-bearing mice, CR (2.5 ml/kg, i.v.) given in combination with CDDP (7 mg/kg, i.v.) did not significantly change CDDP pharmacokinetics, antitumor activity or nephrotoxicity. On the other hand, CDDP-induced hematological toxicity was significantly reduced by CR. This protective effect was related to CR-induced inhibition of cellular CDDP accumulation in bone marrow. This study presents evidence that CR may play an important role in the pharmacological interaction between CDDP and paclitaxel. The present data may suggest formulation of CDDP with CR for systemic treatment. Further studies are yet necessary to establish the clinical value of CR as a modifier for CDDP therapeutic index.
Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2008
Aneuploidy of germ cells contributes to reduced fertility, foetal wastage and genetic defects. Th... more Aneuploidy of germ cells contributes to reduced fertility, foetal wastage and genetic defects. The possible risk of aneuploidy induction by the cancer chemotherapeutic drugs amsacrine (AMSA) and nocodazole (NOC) was investigated in male mice. Two molecular cytogenetic approaches were used: (1) the BrdU-incorporation assay to test the altered duration of meiotic divisions and (2) the sperm-FISH assay to determine aneuploidy induction during meiosis by observing hyperhaploid and diploid sperm. Sperm were sampled from the Caudae epididymes of treated and solvent control males. Single intraperitoneal injections with NOC (35 mg/kg) and AMSA (15 mg/kg) caused a meiotic delay of 24h. The timing of sperm sampling for the sperm-FISH assay was adjusted accordingly, i.e. 23 days after treatment. Mice were treated with 18, 35 and 50 mg/kg of NOC, or 5, 10, 15 and 20 mg/kg of AMSA. Significant dose-dependent increases above the concurrent controls in the frequencies of hyperhaploid sperm were found with both agents. Significant increases in the frequencies of diploid sperm were found only with AMSA. These results provide a basis for genetic counselling of patients under AMSA or NOC chemotherapy. During a period of 3-4 months after the end of chemotherapy, they may stand a higher risk of siring chromosomally abnormal offspring.
The modulating effect of thymoquinone (TQ) on benzo(a)pyrene (BP)-induced forestomach tumours was... more The modulating effect of thymoquinone (TQ) on benzo(a)pyrene (BP)-induced forestomach tumours was investigated in female Swiss albino mice, receiving oral administration of BP at a dose of 1 mg twice weekly for 4 weeks. Administration of 0.01% of TQ in drinking water 1 week before, during and after BP treatment until the end of the experiment resulted in significant suppression of BP-induced tumourigenesis when compared with the group receiving BP alone. TQ inhibited both BP-induced forestomach tumour incidence and multiplicity by 70% and 67%, respectively. Lipid peroxide accumulation and decreased glutathione (GSH) content and glutathione-S-transferase (GST) and DT diaphorase activities were observed in the liver of BP-treated tumour-bearing mice. TQ alone showed a significant induction in the enzyme activities of hepatic GST and DT diaphorase. Mice treated with TQ along with BP showed almost normal hepatic lipid peroxides and GSH levels, and normal enzyme activities compared to the control group. The present data may indicate the potential of TQ, the main constituent of the volatile oil of Nigella sativa seed, as a powerful chemopreventive agent against BP-induced forestomach tumours in mice. The possible modes of action of TQ may be through its antioxidant and anti-inflammatory activities, coupled with enhancement of detoxification processes.
The topoisomerase II (topo II) inhibitors etoposide (VP-16) and merbarone (MER) were investigated... more The topoisomerase II (topo II) inhibitors etoposide (VP-16) and merbarone (MER) were investigated with the in vivo micronucleus test (MN test) combined with fluorescence in situ hybridization (FISH) using the mouse minor satellite DNA probe to discriminate MN of clastogenic and aneugenic origin. All experiments were performed with male (102/ElxC3H/El) F1 mice bred in the mouse colony of the GSF Research Center. The sample size per experimental group was five animals and 2,000 polychromatic erythrocytes (PCE) were scored per animal from coded slides in the conventional MN test. A separate set of coded slides was used for the FISH analysis. All treatments consisted of single intraperitoneal injections. Colchicine (COL, 3 mg/kg) and mitomycin (MMC, 1 mg/kg) were used as a positive control aneugen and clastogen, respectively, and these compounds produced the expected responses. A dose of 1 mg/kg VP-16 induced 3.44% MNPCE (compared to the concurrent solvent control of 0.37%, P < 0.001) and of these 39.9% (1.4% MNPCE) showed one or more fluorescent signals. MER (7.5-60 mg/kg) increased the MNPCE frequencies in a dose-dependent manner, with 15 mg/kg being the lowest positive dose. At the highest dose of 60 mg/kg of MER, a total of 4.26% MNPCE were found (compared to 0.31% in the concurrent solvent control, P < 0.001) and of these 46.2% (2.0% MNPCE) contained one or more fluorescent signals. The data demonstrate that VP-16 and MER induced both clastogenic and aneugenic events despite their different modes of topo II inhibition.
Atherosclerosis (AR) is the leading cause of morbidity and mortality in the US and cigarette smok... more Atherosclerosis (AR) is the leading cause of morbidity and mortality in the US and cigarette smoking is a major contributing factor to the disease. Like cigarette smoking in lung cancer, genetic susceptibility may be an important factor in determining who is more likely to develop AR. However, the current emphasis has been on susceptibility based on altered cardiovascular homeostasis. In this investigation, we studied 120 AR patients and 90 matched controls to elucidate the association between polymorphisms in some metabolizing genes (GSTM1, GSTT1, CYP2E1, mEH, PON1, and MPO) and susceptibility to AR. We found that the GSTT1 null allele and the fast allele of mEH(*) (exon 4) are associated with risk for AR. Furthermore, the combined genotypes GSTM1 null/ CYP2E1(*)5B, GSTM1 null/mEH YY, and GSTT1 null/mEH YY are significantly associated with susceptibility to AR (OR = 15.42, 95% CI = 1.33-77.93, P = 0.021; OR = 3.48, 95% CI = 1.63-8.04, P = 0.0008; OR = 3.4; 95% CI = 0.99-17.38, P = 0.05; respectively). We have also conducted cytogenetic analysis to elucidate if induction of chromosome aberrations (CAs) is a biomarker of AR susceptibility. We found that among cigarette smokers (AR patients and smoker controls), individuals having the GSTM1 null allele had a significantly higher frequency of CAs compared to those with the normal allele (P < 0.05). This association was not found among nonsmokers. In addition, individuals who had inherited the CYP2E1(*)5B allele exhibited a significantly higher CA frequency (8.0 +/- 0.82) compared to those with the CYP2E1 wild-type genotype (4.31 +/- 0.35). Since the analysis of genetic susceptibility factors is still in its infancy, our study may stimulate additional investigations to understand the roles of genetic susceptibility and cigarette smoking in AR.
... Acute and subchronic toxicity of thymoquinone in mice. Osama A. Badary,; Othman A. Al-Shabana... more ... Acute and subchronic toxicity of thymoquinone in mice. Osama A. Badary,; Othman A. Al-Shabanah,; Mahmoud N. Nagi,; Abdullah M. Al-Bekairi,; Mohamed MA Elmazar. ... Department of Pharmacology, College of Pharmacy, King Saud University Riyadh, Saudi Arabia. ...
A variety of cytogenetic assays have been used successfully for monitoring populations exposed to... more A variety of cytogenetic assays have been used successfully for monitoring populations exposed to environmental mutagens. The traditional chromosome aberration (CA) assay is one of the most useful, and it also predicts cancer outcome on a population basis. However, the sensitivity of this assay requires improvement, and researchers need to understand other factors that influence the expression of CA and health outcome, especially on an individual basis. The sensitivity and specificity of the CA assay are improved with the use of the fluorescence in situ hybridization (FISH) procedure, which employs a variety of chromosome-specific and chromosome region-specific fluorescence probes to elucidate CA. Factors that influence the expression of CA in a population study include inadequate study design, genetic variations in metabolism of chemicals (genetic susceptibility), and lifestyle differences in response to exposure to environmental mutagens (acquired susceptibility). The latter may i...
The progression of malignant melanoma is characterized by overex- pression of a number of matrix ... more The progression of malignant melanoma is characterized by overex- pression of a number of matrix metalloproteinases (MMPs), especially MMP-2, which play a critical role in the degradation of basement mem- branes and the extracellular matrix. Consequently, we assessed a drug targeting strategy in which the protease activity of MMP-2 is exploited to release an anticancer agent from a macromolecular carrier,
... Original Paper. Effect of L-Histidinol on Cisplatin Nephrotoxicity in the Rat Osama A. Badary... more ... Original Paper. Effect of L-Histidinol on Cisplatin Nephrotoxicity in the Rat Osama A. Badary, Mahmoud N. Nagi, Hussein A. Al-Sawaf, Mohammed Al-Harbi, Abdullah M. Al-Bekairi Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. ...
This study aimed to investigate the long-term toxicity of a preventive regimen of tamoxifen (TAM)... more This study aimed to investigate the long-term toxicity of a preventive regimen of tamoxifen (TAM) and recombinant human interferon alpha 2b (rHuIFN alpha 2b) on the uterine responsiveness of tumour-bearing rats. The experimental tumour was induced by dimethylbenz(a)anthracene (DMBA) in virgin female albino rats and the therapy was started two months after carcinogen administration. The acute effect of DMBA on the uterine sensitivity was also assessed 24 h post-carcinogen. The uterotonic potentials of oxytocin and prostaglandin F2 alpha (PGF2 alpha) were markedly reduced in the control tumour-bearing group as compared to the normal one. Similarly, acute DMBA administration showed reduced uterine sensitivity to both agents. Treatment with either TAM or combined TAM/rHuIFN alpha 2b did not affect the uterine response to either oxytocin or PGF2 alpha, while rHuIFN alpha 2b increased the uterine sensitivity to oxytocin but not to PGF2 alpha. These data indicate that the carcinogenic agent per se and the presence of tumour reduce the contractile response in the rat uterus to oxytocic agents. Moreover, combined TAM/rHuIFN alpha 2b does not markedly affect the uterine sensitivity in DMBA-induced mammary carcinoma-bearing rats.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2000
Cremophor EL (CR), the paclitaxel vehicle, has previously been reported to alter the pharmacokine... more Cremophor EL (CR), the paclitaxel vehicle, has previously been reported to alter the pharmacokinetics and/or pharmacodynamics of some anticancer drugs including paclitaxel. Several experimental and clinical studies suggested that cisplatin (CDDP) in combination with paclitaxel results in less hematological toxicity than anticipated. To reveal the role of CR in this important pharmacological interaction, we evaluated the interaction of CR with CDDP in vitro and in vivo using experimental Ehrlich ascites carcinoma (EAC) tumor. CR (1 microg/ml) significantly enhanced the in vitro cytotoxicity of CDDP in cultured EAC cells. This enhancement was not associated with a parallel increase in CDDP cellular uptake. In tumor-bearing mice, CR (2.5 ml/kg, i.v.) given in combination with CDDP (7 mg/kg, i.v.) did not significantly change CDDP pharmacokinetics, antitumor activity or nephrotoxicity. On the other hand, CDDP-induced hematological toxicity was significantly reduced by CR. This protective effect was related to CR-induced inhibition of cellular CDDP accumulation in bone marrow. This study presents evidence that CR may play an important role in the pharmacological interaction between CDDP and paclitaxel. The present data may suggest formulation of CDDP with CR for systemic treatment. Further studies are yet necessary to establish the clinical value of CR as a modifier for CDDP therapeutic index.
Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2008
Aneuploidy of germ cells contributes to reduced fertility, foetal wastage and genetic defects. Th... more Aneuploidy of germ cells contributes to reduced fertility, foetal wastage and genetic defects. The possible risk of aneuploidy induction by the cancer chemotherapeutic drugs amsacrine (AMSA) and nocodazole (NOC) was investigated in male mice. Two molecular cytogenetic approaches were used: (1) the BrdU-incorporation assay to test the altered duration of meiotic divisions and (2) the sperm-FISH assay to determine aneuploidy induction during meiosis by observing hyperhaploid and diploid sperm. Sperm were sampled from the Caudae epididymes of treated and solvent control males. Single intraperitoneal injections with NOC (35 mg/kg) and AMSA (15 mg/kg) caused a meiotic delay of 24h. The timing of sperm sampling for the sperm-FISH assay was adjusted accordingly, i.e. 23 days after treatment. Mice were treated with 18, 35 and 50 mg/kg of NOC, or 5, 10, 15 and 20 mg/kg of AMSA. Significant dose-dependent increases above the concurrent controls in the frequencies of hyperhaploid sperm were found with both agents. Significant increases in the frequencies of diploid sperm were found only with AMSA. These results provide a basis for genetic counselling of patients under AMSA or NOC chemotherapy. During a period of 3-4 months after the end of chemotherapy, they may stand a higher risk of siring chromosomally abnormal offspring.
The modulating effect of thymoquinone (TQ) on benzo(a)pyrene (BP)-induced forestomach tumours was... more The modulating effect of thymoquinone (TQ) on benzo(a)pyrene (BP)-induced forestomach tumours was investigated in female Swiss albino mice, receiving oral administration of BP at a dose of 1 mg twice weekly for 4 weeks. Administration of 0.01% of TQ in drinking water 1 week before, during and after BP treatment until the end of the experiment resulted in significant suppression of BP-induced tumourigenesis when compared with the group receiving BP alone. TQ inhibited both BP-induced forestomach tumour incidence and multiplicity by 70% and 67%, respectively. Lipid peroxide accumulation and decreased glutathione (GSH) content and glutathione-S-transferase (GST) and DT diaphorase activities were observed in the liver of BP-treated tumour-bearing mice. TQ alone showed a significant induction in the enzyme activities of hepatic GST and DT diaphorase. Mice treated with TQ along with BP showed almost normal hepatic lipid peroxides and GSH levels, and normal enzyme activities compared to the control group. The present data may indicate the potential of TQ, the main constituent of the volatile oil of Nigella sativa seed, as a powerful chemopreventive agent against BP-induced forestomach tumours in mice. The possible modes of action of TQ may be through its antioxidant and anti-inflammatory activities, coupled with enhancement of detoxification processes.
The topoisomerase II (topo II) inhibitors etoposide (VP-16) and merbarone (MER) were investigated... more The topoisomerase II (topo II) inhibitors etoposide (VP-16) and merbarone (MER) were investigated with the in vivo micronucleus test (MN test) combined with fluorescence in situ hybridization (FISH) using the mouse minor satellite DNA probe to discriminate MN of clastogenic and aneugenic origin. All experiments were performed with male (102/ElxC3H/El) F1 mice bred in the mouse colony of the GSF Research Center. The sample size per experimental group was five animals and 2,000 polychromatic erythrocytes (PCE) were scored per animal from coded slides in the conventional MN test. A separate set of coded slides was used for the FISH analysis. All treatments consisted of single intraperitoneal injections. Colchicine (COL, 3 mg/kg) and mitomycin (MMC, 1 mg/kg) were used as a positive control aneugen and clastogen, respectively, and these compounds produced the expected responses. A dose of 1 mg/kg VP-16 induced 3.44% MNPCE (compared to the concurrent solvent control of 0.37%, P < 0.001) and of these 39.9% (1.4% MNPCE) showed one or more fluorescent signals. MER (7.5-60 mg/kg) increased the MNPCE frequencies in a dose-dependent manner, with 15 mg/kg being the lowest positive dose. At the highest dose of 60 mg/kg of MER, a total of 4.26% MNPCE were found (compared to 0.31% in the concurrent solvent control, P < 0.001) and of these 46.2% (2.0% MNPCE) contained one or more fluorescent signals. The data demonstrate that VP-16 and MER induced both clastogenic and aneugenic events despite their different modes of topo II inhibition.
Atherosclerosis (AR) is the leading cause of morbidity and mortality in the US and cigarette smok... more Atherosclerosis (AR) is the leading cause of morbidity and mortality in the US and cigarette smoking is a major contributing factor to the disease. Like cigarette smoking in lung cancer, genetic susceptibility may be an important factor in determining who is more likely to develop AR. However, the current emphasis has been on susceptibility based on altered cardiovascular homeostasis. In this investigation, we studied 120 AR patients and 90 matched controls to elucidate the association between polymorphisms in some metabolizing genes (GSTM1, GSTT1, CYP2E1, mEH, PON1, and MPO) and susceptibility to AR. We found that the GSTT1 null allele and the fast allele of mEH(*) (exon 4) are associated with risk for AR. Furthermore, the combined genotypes GSTM1 null/ CYP2E1(*)5B, GSTM1 null/mEH YY, and GSTT1 null/mEH YY are significantly associated with susceptibility to AR (OR = 15.42, 95% CI = 1.33-77.93, P = 0.021; OR = 3.48, 95% CI = 1.63-8.04, P = 0.0008; OR = 3.4; 95% CI = 0.99-17.38, P = 0.05; respectively). We have also conducted cytogenetic analysis to elucidate if induction of chromosome aberrations (CAs) is a biomarker of AR susceptibility. We found that among cigarette smokers (AR patients and smoker controls), individuals having the GSTM1 null allele had a significantly higher frequency of CAs compared to those with the normal allele (P < 0.05). This association was not found among nonsmokers. In addition, individuals who had inherited the CYP2E1(*)5B allele exhibited a significantly higher CA frequency (8.0 +/- 0.82) compared to those with the CYP2E1 wild-type genotype (4.31 +/- 0.35). Since the analysis of genetic susceptibility factors is still in its infancy, our study may stimulate additional investigations to understand the roles of genetic susceptibility and cigarette smoking in AR.
... Acute and subchronic toxicity of thymoquinone in mice. Osama A. Badary,; Othman A. Al-Shabana... more ... Acute and subchronic toxicity of thymoquinone in mice. Osama A. Badary,; Othman A. Al-Shabanah,; Mahmoud N. Nagi,; Abdullah M. Al-Bekairi,; Mohamed MA Elmazar. ... Department of Pharmacology, College of Pharmacy, King Saud University Riyadh, Saudi Arabia. ...
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