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Biomedical subjects

H A Zaren

Publications and source records attributed to H A Zaren.

At least 19 recordsLinked to original sources
PubMed1997

Mechanism of differential efficacy of garlic organosulfides in preventing benzo(a)pyrene-induced cancer in mice.

The mechanism of differential efficacies of diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), dipropyl sulfide (DPS) and dipropyl disulfide (DPDS) in preventing benzo(a)pyrene (BP)-induced cancer in mice has been investigated by determining their effects on the enzymes of BP activation/inactivation pathways. With the exception of DATS, treatment of mice with other organosulfides (OSCs) caused a small but significant increase (37-44%) in hepatic ethoxyresorufin O-deethylase (EROD) activity. However, the forestomach EROD activity did not differ significantly between control and treated groups. Only DAS treatment caused a modest but statistically significant reduction (about 25%) in pulmonary EROD activity. These results suggest that while reduction of EROD activity may, at least in part, contribute to the DAS-mediated inhibition of BP-induced lung cancer, anticarcinogenic effects of OSCs against BP-induced forestomach carcinogenesis seems to be independent of this mechanism. Treatment of mice with DAS, DADS and DATS resulted in a significant increase, as compared with control, in both hepatic (3.0-, 3.2- and 4.4-fold, respectively) and forestomach (1.5-, 2.7- and 2.7-fold, respectively) glutathione transferase (GST) activity toward anti-7beta,8alpha-dihydroxy-9alpha,10alpha-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene (anti-BPDE), which is the ultimate carcinogen of BP. The pulmonary GST activity was not increased by any of the OSCs. Even though epoxide hydrolase (EH) activity was differentially altered by these OSCs, a correlation between chemopreventive efficacy of OSCs and their effects on EH activity was not apparent. The results of the present study suggest that differences in the ability of OSCs to modulate GST activity toward anti-BPDE may, at least in part, account for their differential chemopreventive efficacy against BP-induced cancer in mice.

Allyl Compounds↗
PubMed1997

Mechanism of increased sensitivity to etoposide in a mitomycin C-resistant human bladder cancer cell line.

The mechanism of increased sensitivity to etoposide (VP-16) in a human bladder cancer cell line (J82/MMC-2), which is >9-fold more resistant to mitomycin C (MMC) compared with parental cells (J82/WT), was investigated. Colony formation assays, following 1 hr drug exposure, revealed that about a 2.2-fold higher concentration of VP-16 was required to kill 50% of the J82/WT cell line compared with J82/MMC-2. The MTT assays, following continuous drug exposure, also showed that the J82/MMC-2 cell line was significantly more sensitive to VP-16 compared with J82/WT. Accumulation of VP-16 was significantly higher in the J82/MMC-2 cell line compared with J82/WT at every drug concentration tested. Likewise, intracellular VP-16 retention was significantly higher in the J82/MMC-2 cell line compared with J82/WT when drug uptake was measured as a function of varying incubation time and at a fixed VP-16 concentration. The efflux of VP-16 from the J82/MMC-2 cell line was equivalent to that from J82/WT. In agreement with the results of drug uptake studies, the levels of VP-16-induced protein-DNA complexes were markedly higher in the J82/MMC-2 cell line compared with J82/WT. The catalytic activity of topoisomerase II (topo II) in 0.35 M NaCl nuclear extract of J82/WT cells was equivalent to that of J82/MMC-2. The levels of topo II mRNA were also comparable in these cells. Our results suggest that the mechanism responsible for the collateral sensitivity of the J82/MMC-2 cell line to VP-16 may be attributable to a relatively higher drug accumulation in this cell line compared with parental cells.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Characterization of a BMS-181174-resistant human bladder cancer cell line.

This study was undertaken to elucidate the mechanism of cellular resistance to BMS-181174, a novel analogue of mitomycin C (MMC), in a human bladder cancer cell line. The BMS-181174-resistant variant (J82/BMS) was established by repeated continuous exposures of parental cells (J82) to increasing concentrations of BMS-181174 (9-40 nM) over a period of about 17 months. A 2.6-fold higher concentration of BMS-181174 was required to kill 50% of J82/BMS cell line compared with J82. The J82/BMS cell line exhibited collateral sensitivity to 5-fluorouracil (5-FU), but was significantly more cross-resistant to MMC, melphalan, taxol, doxorubicin and VP-16. NADPH cytochrome P450 reductase and DT-diaphorase activities, which have been implicated in bioreductive activation of MMC, were significantly lower in the J82/BMS cell line than in J82. The cytotoxicity of BMS-181174, however, was not affected in either cell line by pretreatment with dicoumarol, which is an inhibitor of DT-diaphorase activity. These results argue against a role of DT-diaphorase in cellular bioactivation of BMS-181174, a conclusion consistent with that of Rockwell et al (Biochem Pharmacol, 50: 1239-1243, 1995). BMS-181174-induced DNA interstrand cross-link (DNA-ISC) frequency was markedly lower in J82/BMS cell line than in J82 at every drug concentration tested. The results of the present study suggest that cellular resistance to BMS-181174 in J82/BMS cell line may be due to reduced DNA-ISC formation. However, the mechanism of relatively lower BMS-181174 induced DNA-ISC formation in J82/BMS cell line than in parental cells remains to be clarified.

Antineoplastic Agents, Alkylating↗
PubMed1996

Glutathione S-transferases of female A/J mouse liver and forestomach and their differential induction by anti-carcinogenic organosulfides from garlic.

This study characterizes glutathione (GSH) S-transferase (GST) isoenzymes of the liver and forestomach of the female A/J mouse and compares their specificities in catalyzing the conjugation of GSH with 7beta,8alpha-dihydroxy-9alpha,10alpha-oxy-7,8,9, 10-tetrahydrobenzo[a] pyrene (anti-BPDE), the ultimate carcinogenic metabolite of benzo[a]pyrene (BP). The GST activity in female A/J mouse liver was expressed by a minimum of seven isoenzymes which arose from different homo- or heterodimeric combinations of at least two alpha class (designated as alpha1 and alpha4), four micro class (micro1 to micro4), and one pi class GST subunit. The GST isoenzyme composition of A/J mouse forestomach appeared to be different from that of the liver. For example, while GST isoenzymes containing micro3 and micro4 type subunits were selectively expressed in the liver, an alpha class heterodimeric GST isoenzyme (containing alpha2 and alpha3 subunits) was expressed in the forestomach but could not be detected in the liver. The (+)-anti-BPDE appeared to be a better substrate than the (-)-enantiomer for all GSTs, except for isoenzymes containing the alpha4 type GST subunit. The murine pi class GST isoenzyme displayed relativey higher specific activity toward (+)-anti-BPDE compared to other GSTs. The specific activities of mouse GSTs toward (+)-anti-BPDE were in the order of pi > micro > alpha. These results suggest that the pi class GST isoenzyme may play an important role in providing protection against BP-induced cancer. Therefore, it seems logical to postulate that the ability of a chemoprotector to increase the expression of GST pi may be an important determinant of its effectiveness against BP-induced cancer. To test the validity of this contention, we have determined the effects on hepatic and forestomach GST isoenzyme/subunit expression of three naturally occurring organosulfides (OSCs) from garlic, which significantly differ in their effectiveness against BP-induced forestomach cancer. Treatment of mice with diallyl sulfide (DAS) and diallyl trisulfide (DATS), which are potent inhibitors of BP-induced fore- stomach cancer in mice, resulted in a significant increase in hepatic and forestomach GST activity toward anti-BPDE. On the contrary, this activity was not increased in either organ by dipropyl sulfide (DPS), which is ineffective against BP-induced forestomach cancer. The chemopreventive efficacy of these OSCs correlated with their ability to increase the expression of GST pi. For example, DAS treatment resulted in approximate increases of 1.7- and 2.2-fold in hepatic and forestomach GST pi expression, respectively, over the control. Treatment of mice with DATS, which is a relatively more potent inhibitor of BP-induced forestomach cancer than DAS, resulted in about 3.8- and 3.2-fold increases, respectively, in hepatic and forestomach GST pi expression over the control. On the contrary, the expression of hepatic and forestomach GST pi was increased only marginally (10-20%) upon DPS administration. In conclusion, the results of the present study suggest that induction of GST pi can be used as a bioassay for screening potential inhibitors of BP-induced cancer.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1996

Novel anti-carcinogenic activity of an organosulfide from garlic: inhibition of H-RAS oncogene transformed tumor growth in vivo by diallyl disulfide is associated with inhibition of p21H-ras processing.

In this study, we report a novel anticarcinogenic activity of an organosulfur compound from garlic, diallyl disulfide (DADS). DADS treatment significantly inhibited the growth of H-ras oncogene transformed tumors in nude mice. As compared to controls, the appearance of tumors was also delayed markedly by oral administration of DADS. The inhibition of tumor growth by DADS treatment correlated with the inhibition of p21H-ras membrane association in the tumor tissue. The levels of membrane associated p21H-ras were markedly lower in the tumor tissues of DADS treated mice as compared to controls. An opposite trend, however, was evident for cytosolic p21H-ras. Furthermore, DADS treatment resulted in a significant inhibition of hepatic as well as tumoral 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. These results indicate that DADS suppresses the growth of H-ras oncogene transformed tumors in nude mice by inhibiting the membrane association of tumoral p21H-ras.

Allyl Compounds↗
PubMed1996

Lack of a role of glutathione in cellular nonenzymatic activation of BMS-181174, a novel analogue of mitomycin C.

Recent studies, using a cell-free system, have suggested that thiol-dependent nonenzymatic bioactivation may be responsible for the superior antitumor activity of the mitomycin C analogue BMS-181174 [N-7-[2-(4-nitrophenyldithio)ethyl]mitomycin C] when compared to the parent compound. If operational in tumor cells, this pathway could have enormous clinical implications since tumor cell resistance to a variety of anticancer agents is often associated with increased glutathione (GSH) levels and BMS-181174 may be used to reverse this mechanism of resistance. The present study was undertaken to determine the role of GSH in cellular activation of BMS-181174 using a pair of well-characterized human bladder cancer cells (J82 and SCaBER) as a model. A 20-h pretreatment of J82 and SCaBER cells with a nontoxic concentration of D,L-buthionine-S,R-sulfoximine (BSO) caused about 80-88% reduction in cellular GSH levels. Surprisingly, the sensitivity of both cells to BMS-181174 was increased, not reduced, by BSO-induced GSH depletion. On the other hand, the cytotoxicity of BMS-181174 was significantly reduced in both cells by a 4-h pretreatment with 1 mM GSH. Like BSO, a 4-h pretreatment with another thiol compound (cysteine) resulted in a statistically significant sensitization of both cells to BMS-181174. Cellular GSH levels were not affected in either of the cell lines by pretreatment with GSH or cysteine. In conclusion, the results or the present study argue against a role of GSH in cellular nonenzymatic activation of BMS-181174 in J82 and SCaBER cells.

Antineoplastic Agents, Alkylating↗
PubMed1996

Biochemical characterization of a mitomycin C-resistant human bladder cancer cell line.

This study describes characteristics of a mitomycin C (MMC)-resistant human bladder cancer cell line, J82/MMC-2, which was established by repeated in vitro exposures of a 6-fold MMC-resistant variant (J82/MMC) to 18 nM MMC. A 9.6-fold higher concentration of MMC was required to kill 50% of the J82/MMC-2 sub-line compared with parental cells (J82/WT). NADPH cytochrome P450 reductase and DT-diaphorase activities were significantly lower in J82/MMC-2 cells compared with J82/WT, suggesting that reduced sensitivity of J82/MMC-2 cells to MMC resulted from impaired drug activation. Consistent with this hypothesis, the formation of MMC-alkylating metabolites was significantly lower in J82/MMC-2 cells compared with J82/WT. Furthermore, DT-diaphorase activity in J82/MMC-2 cells was significantly lower compared with the 6-fold MMC-resistant variant. Glutathione (GSH) levels were comparable in all 3 cell lines. Although GSH transferase (GST) activity was significantly higher in the J82/MMC-2 cells compared with J82/WT, this enzyme activity did not differ between 6- and 9.6-fold MMC-resistant variants. Whereas DNA polymerase alpha mRNA expression was comparable in these cell lines, levels of DNA ligase I mRNA were slightly lower in both MMC-resistant variants relative to J82/WT. However, the DNA polymerase beta mRNA level was markedly higher in the J82/MMC-2 cell line compared with either J82/WT or J82/MMC. Thus, emergence of a higher level of resistance to MMC in J82/MMC-2 cells compared with J82/MMC may be attributed to (i) impaired drug activation through further reduction in DT-diaphorase activity and (ii) enhanced DNA repair through over-expression of DNA polymerase beta.

Antibiotics, Antineoplastic↗
PubMed1996

Technique of laparoscopic ultrasound examination of the liver and pancreas.

Since the introduction of a recent laparoscopic ultrasound (LU), the value of this modality in examining the liver and pancreas has been reported. However, a precise scanning technique of LU has not previously been described. Based on our experience with intraoperative ultrasound during laparotomy, we have developed a technique for complete examination of the entire organs using a rigid LU probe. A 7.5-MHz rigid probe, 10 mm in diameter, was employed. The scanning was performed through three trocar ports: right subcostal, subxiphoid, and umbilical. For the liver, the subcostal scanning provided fundamental transverse views. The subxiphoid and umbilical scanning delineated the areas unable to be imaged by the subcostal scanning. For the pancreas, the subcostal and umbilical scanning demonstrated longitudinal and transverse views, respectively. The subxiphoid scanning enhanced examination of the pancreatic head. Three basic probe maneuvers (advancement-withdrawal, lateral movement, and rotation) and various scanning techniques (contact, probe-standoff, and compression scanning) should be utilized appropriately. With a rigid probe, complete LU examination of the liver and pancreas is possible using these techniques. We believe the present scanning method will help more surgeons learn LU.

Humans↗
PubMed1995

Modulation of cisplatin sensitivity and accumulation by interferon alpha-2A in human squamous carcinoma cell lines.

This study was undertaken to elucidate the mechanism(s) of potentiation of cisplatin (CDDP) cytotoxicity by interferon alpha-2a (IFN alpha-2a) in human squamous carcinoma cell lines SCC-25 and SCC-4. IFN alpha-2a treatment significantly increased the cytotoxicity of CDDP in both cell lines in a dose-dependent manner. In SCC-25 cells, the cytotoxicity of CDDP was increased by about 2- and 4-fold, respectively, by treating the cells with 400 and 800 IU/ml IFN alpha-2a. Sensitivity of SCC-4 cells to CDDP was increased by about 3- and 7-fold, respectively, by 400 and 800 IU/ml IFN alpha-2a treatment. Drug uptake experiments revealed approximately 1.4- to 5-fold higher platinum accumulation in IFN alpha-2a-treated cells as compared to respective controls. Cellular levels of glutathione (GSH) and GSH transferase, which have been suggested to be important determinants of tumor cell sensitivity to CDDP, were not altered by IFN alpha-2a treatment in either of the cell lines. Northern blot analysis showed a moderate increase (about 30-40%) in the level of MT-IIA mRNA by IFN alpha-2a treatment in these cells. Our results suggest that IFN alpha-2a-mediated sensitization of SCC-25 and SCC-4 cell lines to CDDP in vitro may be due to an increase in intracellular platinum accumulation.

Antineoplastic Agents↗
PubMed1995

Characterization of a human bladder cancer cell line selected for resistance to BMY 25067, a novel analogue of mitomycin C.

This study describes characteristics of a human bladder cancer cell line, SCaBER/R, selected for resistance to a mitomycin C (MMC) analogue BMY 25067. The SCaBER/R cell line was isolated by repeated 24 h exposures of the parental cells to 0.09 microM BMY 25067 (IC90, 24 h drug exposure) over a period of about 180 days. Approximately 2.2-fold higher concentration of BMY 25067 was required to kill 50% of the SCaBER/R cell line compared with parental cells (p < 0.001). The IC20 and IC90 values for BMY 25067 were also significantly higher in the SCaBER/R cell line than in SCaBER. Unlike most MMC resistant cell lines, the SCaBER/R cell line displayed a marked cross-resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and lacked cross-resistance to cisplatin, doxorubicin or VP-16. The SCaBER/R cell line also displayed a marked cross-resistance to the parent drug (MMC) and BMY 25282, another analogue of MMC. NADPH cytochrome P450 reductase activity, an enzyme implicated in bio-reductive activation of MMC, did not differ significantly in these cells. DT-diaphorase activity, another MMC activation enzyme, was significantly lower in the SCaBER/R cell line when compared to the SCaBER cells. These results suggest that relatively lower sensitivity of SCaBER/R cell line to MMC and BMY 25067 may result from impaired drug activation. Cellular levels of glutathione (GSH) and GSH-transferase (GST), which have been suggested to affect the cytotoxicity of MMC, were comparable in SCaBER and SCaBER/R cell lines. BMY 25067 induced DNA interstrand cross-links (DNA-ISC) could not be detected in either of the cell lines even at drug concentrations which produced a significant cell kill. These findings suggest that (a) cellular resistance to BMY 25067 in the SCaBER/R cell line may be due to impaired drug activation, and (b) the nature of the cytotoxic produced by BMY 25067 may be different from that of MMC.

Antineoplastic Agents↗
PubMed1994

Accuracy of viscera slide detection of abdominal wall adhesions by ultrasound.

Viscera slide is the normal, longitudinal movement of the intraabdominal viscera caused by respiratory excursions of the diaphragm. By detecting areas of restricted viscera slide, ultrasonic imaging was used to identify anterior abdominal wall adhesions prior to laparotomy or laparoscopy. Transcutaneous ultrasound examination was performed on 110 patients. A prediction of adhesions was made for each patient and then compared to the findings during subsequent laparotomy or laparoscopy. Only patients with previous abdominal surgery or history of peritonitis demonstrated adhesions. Sensitivity and specificity of viscera slide ultrasound in predicting adhesions were 90% and 92%. Nine out of 10 false results involved misinterpretation of ultrasound images of the lower one-third of the abdomen. Ultrasonic imaging of viscera slide is highly accurate in detecting abdominal wall adhesions. This technique is most useful in guiding the insertion of trocar in laparoscopic surgery, and as a noninvasive method in studying the formation of adhesions.

Abdominal Muscles↗
PubMed1993

Differentiation of breast tumors by ultrasonic tissue characterization.

The ability of ultrasonic tissue characterization to differentiate and classify benign and malignant breast tissues in vivo in patients with palpable breast masses and in vitro in excised breast tissue was evaluated. One-hundred and twenty-four in vivo and 89 in vitro studies were performed using a technique of UTC based on parameters from the power spectrum of backscattered echoes. Sensitivities and specificities for diagnosing carcinoma were 86 and 84% for in vivo studies and 94 and 92% for in vitro studies. These UTC parameters provided threshold values for color-coding breast lesion images. The results of this preliminary investigation suggest that UTC provides a basis for assessing more accurately lesions suspected of being malignant prior to biopsy and possibly for evaluating breast lesions noninvasively.

Breast Neoplasms↗
PubMed1993

Operative color Doppler imaging for general surgery.

Operative CDI was performed during 125 general surgical operations (53 hepatic, 25 biliary, 24 pancreatic, 7 esophagogastric, 10 pulmonary, 3 kidney transplant, and 3 soft tissue operations). Operative CDI provided beneficial information in 108 of 125 operations (86.4%). On the basis of operative CDI findings, surgical management was altered in 34 of 125 operations (27.2%), most frequently hepatic and pancreatic operations. Operative CDI demonstrated advantages over B-mode imaging in (1) detection and localization of small blood vessels that are impossible or difficult to identify by B-mode imaging, (2) rapid and definitive distinction of blood vessels from other hypoechoic areas, such as tissue spaces and ducts, (3) determination of the relation of tumors to vascular structures such as vascular invasion of carcinoma, (4) confirmation of blood flow to organs after surgical procedures, and (5) clearer needle localization for guidance of needle placement by color motion marking.

Blood Flow Velocity↗
PubMed1991

Technique of ultrasonic detection and mapping of abdominal wall adhesions.

A technique for noninvasive ultrasound examination to detect and map abdominal wall adhesions is described. The examination is based on the demonstration of movement of abdominal viscera during real-time imaging. This movement is called viscera slide and either occurs spontaneously as a result of respiratory movement or may be induced by manual compression. Abdominal wall adhesions produce a restriction of viscera slide. Ultrasonic demonstration of restricted viscera slide has been used for the precise localization and mapping of abdominal wall adhesions prior to abdominal surgery. The technique may be particularly useful in providing safe initial access in patients undergoing laparoscopy who are at increased risk for trocar injury of viscera due to abdominal wall adhesions resulting from previous surgery or peritonitis.

Abdominal Muscles↗
PubMed1991

Surgical treatment of peptic ulcer disease.

Elective surgery for peptic ulcer disease has diminished significantly over the past 15 years. However, emergency surgery has not shown a decline. Some series have even reported an increase in hospitalizations and operations for hemorrhage. The appropriate surgical procedure for peptic ulcer disease must be tailored to the specific needs of the individual patient. During emergency operations for hemorrhage from duodenal ulcer, we recommend suture ligature of the bleeding vessel and vagotomy-pyloroplasty for high-risk patients, or vagotomy-antrectomy for the lower-risk patient. Bleeding gastric ulcers should be resected, if possible. For massive hemorrhage from stress ulceration requiring surgery, near-total or total gastrectomy should be performed. Perforated duodenal ulcers are best managed by closure and a definitive ulcer operation, such as vagotomy-pyloroplasty. Perforated gastric ulcers are best excised but may be simply closed if conditions do not favor resection. In these situations, biopsy should be performed. We recommend truncal vagotomy-antrectomy for patients presenting with obstruction. Vagotomy (truncal or proximal gastric) with drainage is an acceptable alternative in this situation. For patients with intractable ulcer disease or for those who are noncompliant, proximal gastric vagotomy is the preferred operation. However, other operations may need to be considered, depending on the specific situation. Recurrent ulceration needs appropriate work-up to determine the possible cause. Although patients with ulcer recurrence initially may be placed on medical treatment, about 50% will require reoperation. The most effective procedure for peptic ulcer disease is truncal vagotomy-antrectomy, which has a recurrence rate of less than 1%. The procedure with the least morbidity and the fewest undesirable side effects is proximal gastric vagotomy. Ulcer recurrence after proximal gastric vagotomy or truncal vagotomy-pyloroplasty is in the range of 10% to 15%.

Gastrectomy↗
PubMed1991

Detection of preoperatively unrecognized multiple pancreatic pseudocysts by intraoperative ultrasonography. Report of two cases.

During two pancreatic operations, intraoperative ultrasonography detected multiple pancreatic pseudocysts that were unrecognized preoperatively. In each operation, a single pseudocyst was detected by preoperative ultrasonography, computed tomography, and intraoperative surgical exploration. In addition, high-resolution ultrasonography used during the operations also identified and precisely localized additional smaller pseudocysts. Also, the use of color Doppler imaging during the operations enabled the delineation of small blood vessels around the pseudocysts. The accurate diagnosis of multiple pseudocysts and the precise anatomic information provided by intraoperative ultrasonography permitted appropriate surgical treatment of the pancreatic pseudocysts which, in turn, might help prevent recurrence of the disease.

Adult↗