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A M Shamsuddin

Publications and source records attributed to A M Shamsuddin.

At least 19 recordsLinked to original sources
PubMed1996

Gal-GalNAc: a biomarker of colon carcinogenesis.

The disaccharide tumor marker Gal-GalNAc visualized by galactose oxidase-Schiff sequence is commonly present in cancer cells and in rectal mucous of patients with colon cancer. The expression of this marker on tissue sections taken during experimental colon carcinogenesis shows excellent correlation with human precancerous lesions and even higher percentage of colon cancers express this marker, whereas, no expression is seen in the normal human large intestine. Multifocal expression of the marker is seen throughout the entire colon of patients with precancer and cancer; these include dysplasia, dilated and distorted crypts, regenerative dysplasia and hyperplastic crypts, as well as the morphologically normal crypts remote from cancer. Nearly identical pattern of Gal-GalNAc expression throughout the entire colon also appear during rat colon carcinogenesis induced by azoxymethane including non-expression by the normal and regenerative epithelia during wound healing following mechanical injury. Thus, Gal-GalNAc detected by the simple technique of galactose oxidase-Schiff sequence, is a biomarker that appears during the very early stages of progression of carcinogenesis. The expression pattern supports the field effect theory of carcinogenesis and also explains the basis for mass screening for cancer and precancerous conditions. Chemoprevention strategy using Gal-GalNAc as an intermediate marker detected by accurate and cost-effective rectal mucus test may have great potential.

Adenoma↗
PubMed1995

Common expression of the tumor marker D-galactose-beta-[1-->3]-N-acetyl-D-galactosamine by different adenocarcinomas: evidence of field effect phenomenon.

The simple carbohydrate tumor marker D-galactose-beta-[1-->3]-N-acetyl-D-galactosamine (Gal-GalNAc) can be easily identified by a sequential galactose oxidase (GO)-Schiff reaction either on tissues or on rectal mucus samples from patients with colorectal cancer. To check the usefulness of this marker and technology in identifying cancers and precancers of other organs, we have assessed the differential expression of Gal-GalNAc in various adenocarcinomas and their corresponding normal tissues. The expression of Gal-GalNAc determined by GO-Schiff sequence was examined in a total of 133 tissue samples from 81 cases of the adenocarcinomas of the breast, ovary, pancreas, stomach, and endometrium and 52 cases of respective normal controls. None of the 52 cases of normal tissues (except 15 cases of stomach) showed expression of Gal-GalNAc. In contrast, 100% of adenocarcinomas from the breast (19 of 19), ovary (15 of 15), and pancreas (6 of 6), 94.1% of stomach (16 of 17) cancers, and 91.7% (11 of 12) of uterine adenocarcinomas expressed Gal-GalNAc. The expression of Gal-GalNAc in cancerous tissues was mostly strong and widespread and was distributed in both secreted mucin and cytoplasmic mucin droplets. The normal epithelia and their secretions in the vicinity of the carcinoma (within the "field") in the breast, bronchus, endometrium, and pancreatic duct also expressed Gal-GalNAc in contrast to normal tissues obtained from noncancerous individuals, which were totally nonreactive. It is concluded that the tumor marker Gal-GalNAc recognized by GO-Schiff sequence was highly expressed not only by a variety of adenocarcinomas but also by the apparently normal-appearing epithelia and their secretions in the vicinity of carcinomas, strongly suggesting a field effect phenomenon of carcinogenic agent(s). Identification of the marker in these secretions may have great potential in our strategies for mass screening for those cancers.

Adenocarcinoma↗
PubMed1995

Inositol hexaphosphate and inositol inhibit DMBA-induced rat mammary cancer.

Because inositol hexaphosphate (InsP6) and inositol (Ins), contained in plants and most mammalian cells, have been demonstrated to have anti-cancer and anti-cell proliferative action in several experimental models of carcinogenesis we have examined the effect of InsP6 +/- Ins on DMBA-induced rat mammary tumor model. Starting two weeks prior to induction with DMBA, the drinking water of female Sprague-Dawley rats was supplemented with either: 15 mM InsP6, 15 mM Ins, or 15 mM InsP6 + 15 mM Ins; a control group received no inositol compounds. Animals (49-day-old) were given a single intragastric dose of DMBA (5 mg/rat) in 1 ml of corn oil administered by oral intubation. After 45 weeks of treatment, the animals in all the three treatment regimens showed a significant reduction (P < 0.05) in tumor incidence. Tumor number, multiplicity and tumor burden were also significantly (P < 0.05) reduced by InsP6 +/- Ins. When all the parameters were taken into consideration, the best results were obtained by the combination treatment of InsP6 + Ins. Four additional groups not receiving DMBA, but drinking tap water, InsP6, Ins, or InsP6 + Ins of the same molarity as experimental groups were observed for the duration of the study to monitor for any toxicity following this long-term treatment; no significant toxicity as evaluated by body weight gain, serum and bone mineral levels was detected. We demonstrate that InsP6 +/- Ins reproducibly inhibits experimental mammary carcinoma, therefore having great potential as a chemopreventive and adjuvant therapeutic agent for this disease as well.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Inositol hexaphosphate inhibits growth and induces differentiation of PC-3 human prostate cancer cells.

We investigated the effects of inositol hexaphosphate (InsP6) on growth inhibition and differentiation of human prostate cancer cells PC-3 in vitro. A significant dose- and time-dependent growth inhibition was observed as tested by the MTT-incorporation assay (P < 0.05 at 1 mM InsP6 after 24 h treatment, P < 0.01 at 0.1 mM after 3 days). DNA synthesis as determined by [3H]thymidine incorporation assay was also suppressed by InsP6 in a dose-dependent manner, occurring as early as 3 h after treatment and continuing up to 48 h (P < 0.01 at 1 mM InsP6). A 9- to 10-fold increase (P < 0.01) in expression of HLA class I molecule associated with tumor immunosurveillance and cell differentiation was induced by InsP6. The marker for prostatic cell differentiation, prostate acid phosphatase, was significantly (P < 0.05) increased after 48 h treatment at 0.5-5 mM InsP6. Since InsP6 strongly inhibits growth and induces differentiation in human prostate cancer cells in vitro, in vivo studies using a tumor xenograft model and a prostate carcinogenesis model are warranted to validate the efficacy of InsP6 in the treatment and prevention of prostate cancer.

Acid Phosphatase↗
PubMed1995

Inositol phosphates have novel anticancer function.

Inositol hexaphosphate (InsP6, phytic acid) is ubiquitous in the plant kingdom and is abundant in cereals and legumes. In much smaller amounts InsP6 and its lower phosphorylated forms (InsP1-5) are contained in most mammalian cells, where they are important in regulating vital cellular functions. Both in vivo and in vitro experiments have suggested striking anticancer potential (preventive as well as therapeutic) for InsP6 with and without inositol. In addition to reduce cell proliferation, InsP6 increases differentiation of malignant cells often resulting in reversion to the normal phenotype. InsP6 is quickly absorbed from the rat stomach and upper intestine and distributed as inositol and InsP1. In vitro it is instantaneously taken up by malignant cells undergoing variable dephosphorylation to inositol and InsP1-5, pointing toward their role in mediating the action of InsP6. Because InsP6 is high in high-fiber diets, our studies also may explain, at least in part, the epidemiologic observation showing high-fiber diets are associated with a lower incidence of certain cancers. Although further studies are needed to elucidate the mechanism(s) of this action, inclusion of InsP6 in our strategies for cancer prevention and therapy is warranted.

Animals↗
PubMed1995

A new murine monoclonal antibody, CMU10, as a marker for colonic carcinoma and precancerous conditions.

OBJECTIVE: To investigate the usefulness of a cancer-associated mucin antigen using a new monoclonal antibody, CMU10, as a tumor marker. Expression was assessed in normal adult, fetal, hyperplastic, preneoplastic, and neoplastic tissues of colon. DESIGN: CMU10 monoclonal antibody recognizes a mucin antigen that is not expressed in normal fetal and adult large intestine, but is rather commonly expressed in cancerous and precancerous lesions. Immunocytochemical analysis was performed on human tissues obtained at surgery or at autopsy. RESULTS: Expression of this mucin antigen was observed in 27 (98.4%) of 28 cases of colorectal carcinoma, 24 (96%) of 25 cases of adenomatous polyps, 9 (75%) of 12 cases of ulcerative colitis, and 9 (100%) of 9 cases of hyperplastic polyps. In cancerous specimens, the antigen distribution was mainly localized in the secretory mucin and surface membrane, whereas in precancerous lesions it was located in dysplastic, dilated, and distorted crypts. CONCLUSIONS: Because CMU10 differentially recognizes an antigen in cancerous and precancerous tissues, but not in normal tissues, it may be useful as a tumor marker for immunodiagnosis and, hence, early detection.

Adenomatous Polyps↗
PubMed1994

[3H]inositol hexaphosphate (phytic acid) is rapidly absorbed and metabolized by murine and human malignant cells in vitro.

To test the hypothesis that the antineoplastic activity of phytic acid [inositol hexaphosphate (InsP6)] is a result of rapid intake by the cells and its conversion to lower inositol phosphates (InsP1-5), thereby affecting the intracellular inositol phosphate pool, YAC-1 (mouse T cell leukemia), K562 (human erythroleukemia) and HT-29 (human colon adenocarcinoma) cell lines were incubated at 37 degrees C with [3H]InsP6. After 1 h, 31.3 +/- 3.1% of administered radio-activity was taken up by YAC-1 cells, 6.2 +/- 0.9% by K562 cells and 6.6 +/- 3.8% by HT-29 cells. Differential centrifugation and high resolution subcellular fractionation of cell homogenates demonstrated that within the various cellular compartments, 80% (HT-29) to 97% (YAC-1) of the total radioactivity was in the cytosol. Kinetic study showed that the peak of the total absorption was obtained after 30 min of cell exposure to radiolabeled InsP6, after with a plateau was reached. Analysis of the radioactivity accumulated within the cells showed variable proportions of myo-inositol and InsP1-6, with a preponderance of InsP1 and InsP2. The presence of [3H]myo-inositol and [3H]InsP1-6 suggests that InsP6 may, in some cells at least, be absorbed as such and that a variable degree of dephosphorylation of InsP6 takes place both extra- and intracellularly.

Adenocarcinoma↗
PubMed1994

Expression of the tumor marker D-galactose-beta-[1-->3]-N-acetyl-D-galactosamine by premalignant and malignant prostate.

Accurate and consistent discrimination of prostatic carcinomas from benign lesions and vice versa continues to be a vexing problem in diagnostic pathology. We have tested the usefulness of the tumor marker D-galactose-beta-[1-->3]-N-acetyl-D-galactosamine in differentiating the benign from the malignant and premalignant lesions of the prostate. A sequential galactose oxidase technique (overnight incubation), followed by Schiff's reaction (15 minutes), was done on deparaffinized tissue sections of 65 carcinomas, 25 hyperplasias, 11 foci of adenosis, and 10 normal specimens. While none of the 35 benign prostates and 11 foci of adenosis expressed D-galactose-beta-[1-->3]-N-acetyl-D-galactosamine (100% specificity), 62 (95.4% sensitivity) of 65 adenocarcinomas variably expressed the marker. We therefore propose that this simple technique may have potential use in routine histopathological analysis of prostatic specimens. This marker may also serve as the basis of assays for early detection of prostatic malignancies.

Adult↗
PubMed1993

Inhibition of rat mammary carcinogenesis by inositol hexaphosphate (phytic acid). A pilot study.

Since phytic acid (inositol hexaphosphate, InsP6) and inositol (Ins) have been demonstrated to have anti-tumor and anti-cell proliferative action in several experimental models of carcinogenesis, in a pilot study we have examined their effect on 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumor model. Starting a week prior to induction with DMBA, the drinking water of female Sprague-Dawley rats was supplemented with either: 15 mM InsP6, 15 mM Ins, or 15 mM InsP6 + 15 mM Ins; a control group received no inositol compounds. Animals (55-day-old) were given a single dose of DMBA (20 mg) in 1 ml of sesame oil by oral intubation. Four additional groups not receiving DMBA, but drinking tap water, InsP6, Ins, or InsP6 + Ins of the same molarity as experimental groups were observed for the duration of the study to monitor for any putative toxicity following this long-term treatment. As opposed to the DMBA-only group, rats treated with InsP6 +/- Ins showed a 48% reduction in the number of tumors/tumor bearing animal (tumor multiplicity) and a 40% reduction in the number of tumors/rat. In contrast to 20% rats in DMBA-only group, only 0-8% animals in the treatment group had 5 or more tumors. Likewise, the tumor incidence was reduced by 19% in InsP6 +/- Ins as compared to control untreated animals. The tumors in the treated groups were also 16% smaller in size. Data from this pilot study suggest that in addition to being effective against colon cancer, InsP6 +/- Ins may be protective against mammary carcinoma as well; additional studies are however warranted.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

Tumor promotion by fecapentaene-12 in a rat colon carcinogenesis model.

Fecapentaenes are a group of fecal mutagens produced by anaerobic microflora of the colon. The potential of fecapentaene-12 (FP-12) to promote tumor development was tested in a rat colon carcinogenesis model using N-methyl-N-nitrosourea (MNU) as the initiating agent. Two groups of female F-344 rats were initiated by intrarectal instillations of MNU (2 mg in 0.5 ml H2O, 3 times a week, for 3 weeks; MNU and MNU + FP-12 groups). Two additional groups (FP-12 and Control) were given H2O without carcinogen. In the post-initiation phase, rats of the MNU + FP-12 and FP-12 groups were intrarectally administered 400 ng of FP-12 in 0.5 ml T-E buffer, twice a week, for 24 weeks, whereas the MNU and Control groups received the vehicle only. Tumors were found only in the MNU and MNU + FP-12 groups, their number being higher in the latter. The number of carcinoma bearing rats as well as the average number of carcinomas per rat were significantly higher (P < 0.05) in the MNU + FP-12 group as compared to the MNU-alone values. Aberrant crypt foci (ACF) were found in all carcinogen-treated rats, including those that did not contain tumors, whereas none were observed in the FP-12 and Control groups. The average number of ACF/cm2 was also significantly higher in the MNU+FP-12 group, as was the case for the average number of ACF containing > 10 aberrant crypts per focus. These findings suggest that FP-12 can express promoting activity in chemical induced colon carcinogenesis.

Animals↗
PubMed1993

Growth inhibition and differentiation of HT-29 cells in vitro by inositol hexaphosphate (phytic acid).

Inositol hexaphosphate (InsP6 or phytic acid) has been shown to have antineoplastic action in in vivo models of colon carcinogenesis. We therefore investigated its effect on proliferation and differentiation of the human colon cancer cell line HT-29 in vitro. Proliferation was evaluated by neutral red incorporation assay, and differentiation was assessed by expression of the markers, cytokeratin, carcinoembryonic antigen (CEA) and beta-D-galactose-[1-->3]-N-acetyl-galactosamine (Gal-GalNAc). InsP6 in the culture media (0.66-10 mM) inhibited cell proliferation in a dose-dependent manner (P < 0.001), while inositol or inositol hexasulfate used as controls or media without InsP6 did not show any suppressive effect. The expression of the tumor marker, Gal-GalNac, was augmented (100.7% increase) by low dose (0.66 mM) of InsP6 but was subsequently suppressed with higher concentrations of InsP6. The expression of cytokeratin and CEA were both augmented by either InsP6 or inositol at all concentrations tested, although the degree of augmentation was milder with inositol than with InsP6. The combination of InsP6 and inositol (both 0.66 mm) resulted in augmentation (P < 0.001) of cytokeratin expression, while that of CEA remained unchanged. The inhibitory effect of InsP6 on cell proliferation was not altered by combination with additional inositol at any concentrations tested. Our results show that InsP6 inhibits cell proliferation and concomitantly increases differentiation and is therefore a candidate chemopreventive and chemotherapeutic agent for human large intestinal cancer.

Adenocarcinoma↗
PubMed1993

[3H]phytic acid (inositol hexaphosphate) is absorbed and distributed to various tissues in rats.

To understand the mechanism of antineoplastic action of phytic acid, we investigated the absorption and distribution of myo-[inositol-2-3H(N)] hexakisphosphate in rats. The radioactivity was measured in urine, feces, blood, gastrointestinal tract contents and various organs and tissues at 1 and 24 h after intragastric administration. Of the total radioactivity, 79.0 +/- 10.0% was absorbed and at least 26.6% was degraded during the 24-h period following ingestion. The absorption was rapid; 11.0 +/- 2.6% of the radioactivity was detected in the wall of the stomach (4.4 +/- 3.7%) and upper small intestine (6.6 +/- 1.9%), 6.5 +/- 2.6% in the skeletal muscle and 4.0 +/- 1.5% in the skin after 1 h. Much of the radioactivity after 24 h was in the liver (4.0 +/- 0.9%), kidneys (2.2 +/- 1.1%), muscle (18.1 +/- 3.4%) and skin (10.1 +/- 3.3%). Analysis of plasma and urine demonstrated that most of the radioactivity was due to myo-inositol and small amounts of inositol monophosphate (InsP1). Gastric epithelial cells, however, contained inositol and various inositol phosphates (InsP1-6). Our data suggest that soluble InsP6 when administered in drinking water is rapidly absorbed through the stomach and upper small intestine, becomes quickly dephosphorylated within the mucosal cells and is distributed to various organs as inositol and InsP1.

Animals↗
PubMed1992

Antitumor activity of phytic acid (inositol hexaphosphate) in murine transplanted and metastatic fibrosarcoma, a pilot study.

We have previously reported that phytic acid (inositol hexaphosphate or InsP6), a natural constituent of cereal diet, when administered in drinking water exerts a consistent antitumor effect on experimental colon cancer in vivo. The objective of this study was to determine whether InsP6 has similar anti-neoplastic effect on other tumor models, such as murine fibrosarcoma. We report that intraperitoneal injection of InsP6 reduces growth of subcutaneously transplanted fibrosarcoma (FSA-1) in mice, prolongs survival of tumor-bearing mice and reduces the number of pulmonary metastases. Since InsP6 is a common constituent of our diet and has very little or no toxic effects, in addition to being chemopreventive, it could have potential use in therapy of cancer as well.

Animals↗
PubMed1992

Effects of inositol hexaphosphate on growth and differentiation in K-562 erythroleukemia cell line.

Inositol hexaphosphate (InsP6) has recently been shown to inhibit experimental cancers in vivo. Since the lower phosphorylated forms of InsP6 are important in cell growth in a wide variety of mammalian cells, we tested the efficacy of InsP6 in growth reduction of K-562 human erythroleukemia cells in vitro. We report that InsP6 decreases the K-562 cell population by 19-36% (P less than 0.001) concomitant to an increased differentiation as evidenced by ultrastructural morphology and increased hemoglobin synthesis. Pilot experiments to study the mechanism of action of InsP6 show that following treatment with InsP6, the concentration of intracellular [Ca2+] ([Ca2+]i) is increased by 57% (P less than 0.02). Likewise, a 41% increase (P less than 0.05) in InsP3 and a 26% decrease (P less than 0.02) in InsP2 were noted 1 h following treatment with InsP6. Contrary to the dogma that cell division is associated with increased [Ca2+]i, our data show that reduced cell growth and enhanced differentiation is associated with increased [Ca2+]i and increased InsP3 in the presence of InsP6.

Cell Differentiation↗
PubMed1992

Long-term culture of normal human colonic epithelial cells in vitro.

Studies of normal cellular function as well as the understanding of cellular mechanisms of carcinogenesis and other diseases of the large intestine have been limited, particularly due to the lack of long-term culture of normal human large intestinal epithelial cells (NHLIEC). Using the epithelia from surgically resected human colon, we have dissociated a sufficient number of viable NHLIEC and maintained them in in vitro culture for up to 5 months. Normal-appearing human large intestinal mucosal fragments (1 mm2) were treated with 0.01 mg/ml trypsin, 0.2 mg/ml collagenase + 0.1 mM EGTA or 0.1 mg/ml trypsin + 0.1 mM EGTA in a Stomacher laboratory blender to isolate the cells. Compared with other methods, the use of the Stomacher blender combined with low concentrations of proteolytic enzymes yielded greater numbers of cells per gram of tissue, with up to 84% viable cells. Primary and serially passaged NHLIEC were cultured in CMRL-1066, MEM with 5% serum, and serum-free KGM. These media were all supplemented with insulin, hydrocortisone, epithelial growth factor, and bovine pituitary extract. CMRL-1066 was found to be the best medium for NHLIEC. Contaminating fibroblasts were selectively removed by briefly allowing the cells to adhere to the culture vessel and adding 25 U/ml collagenase to the culture media at the first subculture treatment. The epithelial nature and secretory function of the established cells were confirmed by morphological criteria (light microscopy, phase contrast microscopy and electron microscopy), immunoreactivity to cytokeratin, and positive mucin cytochemistry. We propose that using this methodology for the culture and maintenance of NHLIEC for an extended period of time would serve as a valuable model for a variety of investigations.

Cell Division↗