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Biomedical subjects

D Heber

Publications and source records attributed to D Heber.

At least 55 records · Page 3Linked to original sources
PubMed1999

Decreased growth of human prostate LNCaP tumors in SCID mice fed a low-fat, soy protein diet with isoflavones.

Epidemiological studies suggest that high intake of dietary fat is a risk factor for the development of clinical prostate cancer. Soy protein has also been proposed to play a role in the prevention of prostate cancer, and one of the isoflavones in soy protein, genistein, inhibits the growth of human prostate cancer cell lines in vitro. This study was designed to evaluate whether altering dietary fat, soy protein, and isoflavone content affects the growth rate of a human androgen-sensitive prostate cancer cell line (LNCaP) grown in severe-combined immunodeficient (SCID) mice. SCID mice were randomized into four dietary groups: high-fat (42.0 kcal%) + casein, high-fat (42.0 kcal%) + soy protein + isoflavone extract, low-fat (12.0 kcal%) + casein, and low-fat (12.0 kcal%) + soy protein + isoflavone extract. After two weeks on these diets, the mice were injected subcutaneously with 1 x 10(5) LNCaP tumor cells and placed in separate cages (1 mouse/cage) to strictly control caloric intake. Isocaloric diets were given 3 days/wk, and tumor sizes were measured once per week. The tumor growth rates were slightly reduced in the group that received the low-fat + soy protein + isoflavone extract diet compared with the other groups combined (p < 0.05). In addition, the final tumor weights were reduced by 15% in the group that received the low-fat + soy protein + isoflavone extract diet compared with the other groups combined (p < 0.05). In this xenograft model for prostate cancer, there were statistically significant effects on tumor growth rate and final tumor weight attributable to a low-fat + soy protein + isoflavone extract diet.

Animals↗
PubMed1998

Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice.

Induction of differentiation and apoptosis in cancer cells through ligands of nuclear hormone receptors (NHRs) is a novel and promising approach to cancer therapy. All-trans-retinoic acid (ATRA), an RA receptor-specific NHR ligand, is now used for selective cancers. The NHR, peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in breast cancer cells. Activation of PPARgamma through a synthetic ligand, troglitazone (TGZ), and other PPARgamma-activators cause inhibition of proliferation and lipid accumulation in cultured breast cancer cells. TGZ (10(-5) M, 4 days) reversibly inhibits clonal growth of MCF7 breast cancer cells and the combination of TGZ (10(-5) M) and ATRA (10(-6) M, 4 days) synergistically and irreversibly inhibits growth and induces apoptosis of MCF7 cells, associated with a dramatic decrease of their bcl-2 protein levels. Similar effects are noted with in vitro cultured breast cancer tissues from patients, but not with normal breast epithelial cells. The observed apoptosis mediated by TGZ and ATRA may be related to the striking down-regulation of bcl-2, because forced over-expression of bcl-2 in MCF7 cells cultured with TGZ and ATRA blocks their cell death. TGZ significantly inhibits MCF7 tumor growth in triple immunodeficient mice. Combined administration of TGZ and ATRA causes prominent apoptosis and fibrosis of these tumors without toxic effects on the mice. Taken together, this combination may provide a novel, nontoxic and selective therapy for human breast cancers.

Adenocarcinoma↗
PubMed1998

Preadipocytes stimulate breast cancer cell growth.

Mammary fat may affect human breast cancer development. In this study a novel coculture system was used to investigate stromal-epithelial cell interactions in vitro. The extent of differentiation of a feeder layer of 3T3-L1 preadipocytes affected the clonal growth of breast cancer cells under anchorage-independent conditions. When the feeder-layer preadipocytes were proliferating, the clonal growth of estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB-231 and MDA-MB-436 cells was stimulated by 100%, 43%, and 60%, respectively. In contrast, after differentiation the feeder layer of mature adipocytes inhibited clonal growth of breast cancer cell lines by 60%. No clonal growth stimulation of human pancreatic (Panc-1) or prostatic (PC-3) cancer cells was noted when these cells were grown under identical conditions with a proliferating 3T3-L1 cell feeder layer. These findings suggest that proliferating preadipocytes may be associated with factors that specifically stimulate breast cancer cell growth.

3T3 Cells↗
PubMed1997

Dietary modulation of omega-3/omega-6 polyunsaturated fatty acid ratios in patients with breast cancer.

BACKGROUND: Polyunsaturated fatty acids of the omega-6 (omega-6) class, as found in corn and safflower oils, can act as precursors for intermediates involved in the growth of mammary tumors when fed to animals, whereas polyunsaturated fatty acids of the omega-3 (omega-3) class, as found in fish oil, can inhibit these effects. The effects of dietary intervention on the ratios of these fatty acids in breast and other adipose tissues have not previously been prospectively studied. PURPOSE: The present investigation was conducted to study the impact on the ratio of omega-3 and omega-6 polyunsaturated fatty acid in plasma and in adipose tissue of the breast and buttocks when women with breast cancer consume a low-fat diet and fish oil supplements. METHODS: Twenty-five women with high-risk localized breast cancer were enrolled in a dietary intervention program that required them to eat a low-fat diet and take a daily fish oil supplement throughout a 3-month period. Breast and gluteal fat biopsy specimens were obtained from each woman before and after dietary intervention. The fatty acid compositions of specimens of plasma, breast fat, and gluteal fat were determined by gas-liquid chromatography. Statistical analysis involved use of a two-sided paired t test. RESULTS: After dietary intervention, a reduction in the level of total omega-6 polyunsaturated fatty acids in the plasma was observed (P<.0003); moreover, total omega-3 polyunsaturated fatty acids increased approximately three-fold (P<.0001) and the omega-3/omega-6 polyunsaturated fatty acids ratio increased approximately fourfold (i.e., mean values increased from 0.09 to 0.41; P = .0001). An increase in total omega-3 polyunsaturated fatty acids in breast adipose tissue was observed following dietary intervention (P = .04); the omega-3/omega-6 polyunsaturated fatty acid ratio increased from a mean value of 0.05 to 0.07 (P = .0001). An increase in total omega-3 polyunsaturated fatty acids was observed in gluteal adipose tissue following the intervention (P = .05); however, the ratio of omega-3 to omega-6 polyunsaturated fatty acids (mean ratio values of 0.036-0.045; P = .06) was unchanged. CONCLUSION: Short-term dietary intervention can lead to statistically significant increases in omega-3/omega-6 polyunsaturated fatty acid ratios in plasma and breast adipose tissue. Breast adipose tissue changed more rapidly than gluteal adipose tissue in response to the dietary modification tested in this study. Therefore, gluteal adipose tissue may not be a useful surrogate to study the effect of diet on breast adipose tissue.

Adipose Tissue↗
PubMed1997

Effects of potent vitamin D3 analogs on clonal proliferation of human prostate cancer cell lines.

BACKGROUND: Management of prostate cancer that has spread outside of the prostate capsule is a difficult problem. Innovative, non-toxic approaches to the disease are required. New, relatively non-toxic vitamin D3 analogs have recently been synthesized. We report that several of these compounds have marked antiproliferative effects on prostate cells. METHODS: The clonal antiproliferative activity of five novel analogs of 1,25 dihydroxyvitamin D3 [1,25(OH)2D3, (cmpd C)] as well as 1,25(OH)2D3 itself was tested on three human prostate cancer cell lines (PC-3, LNCaP, and DU-145). The analogs were 20-epi-22oxa-24a,26a,27a-tri-homo-1 alpha,25(OH)2D3 (code name: KH 1060); 24a26a27a-tri-homo-22,24-diene-1 alpha,25(OH)2D3 (code name: EB 1089); 1,25(OH)2-16ene-D3 (code name: HM); 1,25(OH)2-16ene-23yne-D3 (code name: V); 1,25(OH)2-20-epi-D3 (code name: MC 1288)]. RESULTS: With the parent compound [1,25(OH)2D3], the effective dose that inhibited 50% clonogenic growth of PC-3 and LNCaP was 10(-8)M and 7 x 10(-9)M, respectively. For these prostate cancer cell lines, KH 1060 was the most potent analog by an order of 25- to 35-fold as compared to cmpd C. The second and third most potent analogs were HM and MC 1288. DU-145 was resistant to all the vitamin D3 analogs. The major side-effect of 1,25(OH)2D3 is the production of hypercalcemia. The relative inhibitory index (RII) was determined by comparing the antiproliferative activity of the analog to its ability to produce hypercalcemia in mice injected intraperitoneally every other day. The KH 1060 had the best RTI: 50- to 70-fold greater than 1,25(OH)2D3 for PC-3 and LNCaP, respectively. CONCLUSIONS: A trial of one or more of these innovative compounds should be considered for treatment of minimal residual disease of prostate cancer.

Animals↗
PubMed1997

NADPH-cytochrome P-450 reductase, cytochrome P-450 2C11 and P-450 1A1, and the aryl hydrocarbon receptor in livers of rats fed methyl-folate-deficient diets.

We investigated three hepatic cytochrome P-450 isozymes and the aryl hydrocarbon (Ah) receptor in rats fed one of the following three diets for 15 months: a diet containing the AIN vitamin mixture (control), the control diet devoid of choline and folate (CFD), or the CFD diet devoid of niacin (CFND). Hepatic tumors developed in all CFD- and CFND-fed rats. Western blot analyses of nontumor hepatic tissue showed that NADPH-cytochrome P-450 reductase (P-450 reductase) increased significantly in the CFD and CFND groups compared with the control group. Hepatic cytochrome P-450 2C11 (CYP2C11) was not detectable in the CFD and CFND groups compared with the control group. Ah receptor and cytochrome P-450 1A1 (CYP1A1) were detected in higher amounts in livers of both deficient groups. CYP1A1 is an enzyme associated with bioactivation of exogenous genotoxins. To our knowledge, this is the first time it has been shown that CYP1A1 and the Ah receptor are induced by dietary deficiencies.

Animals↗
PubMed1996

Effects of novel retinoid X receptor-selective ligands on myeloid leukemia differentiation and proliferation in vitro.

The biologic effects of retinoids such as all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid on proliferation and differentiation of hematopoietic cells are mediated by binding and activating two distinct families of transcription factors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The RARs require heterodimerization with RXRs; in addition, RXRs can form homodimers, which can bind to DNA response elements that are either distinct or the same as those bound by the RAR/RXR heterodimers. Therefore, the two retinoid pathways provide sequences that are specific for effective DNA binding and activation of target genes. We have developed several series of novel synthetic retinoids that selectively interact with RXR/RXR homodimers and RAR/RXR heterodimers. We show here that SR11236 and SR11246, which are RXR-selective analogs, had little ability to inhibit clonal growth and induce differentiation of leukemic cells (HL-60 cells and fresh acute myeloid leukemia cells). However, SR11249, SR11256, and LGD1069, which activated both RXR/RXR homodimers and RAR/RXR heterodimers, could inhibit clonal growth and induce differentiation of HL-60 cells as well as leukemic cells from patients, including those with acute promyelocytic leukemia (APL). This is similar to results observed with RAR/RXR-specific ligands. Interestingly, the combination of ATRA and either SR11249, SR11256, or LGD1069 showed synergistic effects in inducing differentiation of HL-60 cells. A retinoid (SR11238) with strong anti-AP-1 activity that did not activate the RARs and RXRs for gene transcription from the response element TREpal was inactive in our assay systems, suggesting that the antiproliferative effects of retinoids on leukemic cells is not mediated by inhibiting the AP-1 pathway. We conclude that the RAR/RXR pathway is more important than RXR/RXR pathway for differentiation and proliferation of acute myeloid leukemic cells, and certain retinoids or combination of retinoids with both RAR and RXR specificities may synergistically enhance the differentiation activity of ATRA, which may be relevant in several clinical situations.

Bexarotene↗
PubMed1996

Synthesis, opioid receptor affinity, and enzymatic hydrolysis of sterically hindered morphine 3-esters.

With the intention of preparing prodrugs, 10 morphine 3-esters were synthesized and evaluated in vitro for opioid receptor binding and enzymatic hydrolysis. The results of binding assays performed on homogenates of guinea pig brain demonstrate a loss in affinity of morphine to mu-, delta-, and kappa-receptors by esterification at the 3-position. The conversion of the esters to morphine was determined in human plasma by HPLC analysis. The half-lives of hydrolysis ranged from 0.5 to > 300 h. The investigations indicate that esterification at the 3-position results in morphine prodrugs with variable hydrolytic stability. Sterically hindered morphine 3-esters may be a promising approach to manipulate the rate of release of morphine.

Animals↗
PubMed1996

Clinical detection of sarcopenic obesity by bioelectrical impedance analysis.

To assess whether bioelectrical impedance analysis (BIA) provides clinically useful information on body composition beyond that obtained from measuring height and weight, we clinically classified 306 obese patients (233 females and 73 males) into tertiles of increasing fat-free mass estimated by BIA. Because fat-free mass by BIA is an estimate of lean body mass, the lowest tertile was clinically defined as sarcopenic obesity (reduced lean body mass), as contrasted with proportionate or muscular obesity in the next two tertiles. Fat mass in patients in each of the above tertiles based on BIA was then compared with fat mass estimated by using the equations of Garrow and Webster with body mass index (weight/height2). BIA-estimated fat mass was 4.3 kg greater in the sarcopenic group (n = 102) than predicted from body mass index. Fat mass predicted by BIA in the proportionate (n = 102) and muscular (n = 102) groups differed by less than the SEE of fat mass predicted by BMI. In premenopausal women at increased risk of breast cancer BIA showed a high prevalence of sarcopenic obesity (28/30) in these women at normal body mass indexes. Thus, BIA may be clinically useful for demonstrating sarcopenic obesity, but additional studies are needed to determine the metabolic and clinical significance of sarcopenic obesity.

Adipose Tissue↗
PubMed1996

Metabolic effects of triiodothyronine replacement during fasting in obese subjects.

The adaptation to fasting reduces muscle protein breakdown by switching from a carbohydrate to fat fuel economy in normal man. With the discovery of T3 and the observation that its formation from T4 was reduced significantly during starvation, it was proposed that T3 mediated many of these changes. To examine this possibility, otherwise healthy, obese subjects were fasted for 10 days and supplemented with T3 the last 3 days of the fast to bring circulating T3 levels within normal prefasting (weight maintenance) levels. The effects of the same dose of T3 for 3 days were tested during the last 3 days of a 10-day weight maintenance diet for comparison. Both metabolic rate and CO2 production decreased as expected with fasting and did not increase after T3 supplementation. Hepatic glucose appearance rates fell with fasting and increased significantly during T4 supplementation, but not to prefasting levels. Urinary urea nitrogen excretion decreased significantly with fasting and decreased further with T3 supplementation. Lysine appearance did not change during fasting or T3 supplementation, but leucine appearance decreased with T3 supplementation during fasting. These observations suggest that the fall in serum T3 during fasting may not mediate the observed decreases in protein breakdown that occur during fasting and prolonged starvation, but may instead initiate the fall in hepatic glucose appearance.

Adult↗
PubMed1995

Effects of a very low fat, high fiber diet on serum hormones and menstrual function. Implications for breast cancer prevention.

BACKGROUND: Low fat, high fiber dietary interventions that decrease blood estrogen levels may reduce breast cancer risk. Asian women consuming their traditional low fat, high fiber diets have lower blood estrogen levels before and after menopause and lower rates of breast cancer compared with Western women. The current controlled feeding study of premenopausal women was designed to determine the effects of a very low fat (10% of calories) and high fiber (35-45 g/day) diet on blood estrogen levels and menstrual function. METHOD: Twelve healthy premenopausal women with regular ovulatory cycles were followed for 3 months. Subjects consumed a diet providing 30% of their energy from fat and 15-25 g of dietary fiber per day for 1 month, and they consumed a very low fat, high fiber and libitum diet providing 10% of their energy from fat and 25-35 g of dietary fiber per day for 2 months. RESULTS: At the end of the second month of the very low fat, high fiber diet, there was a significant reduction in serum estrone and estradiol levels during the early follicular and late luteal phases. There were no significant changes observed in serum estrone sulfate, sex hormone binding globulin, or progesterone. Despite a significant decrease in serum estradiol and estrone levels after 2 months of a very low fat, high fiber diet, there was no interference with ovulation or the magnitude of the mid-cycle leuteinizing hormone surge. Small changes in menstrual cycle length of up to 3 days were not ruled out due to the small sample size of the study. CONCLUSIONS: A very low fat, high fiber diet in healthy premenopausal women can reduce estradiol and estrone levels without affecting ovulation, thereby providing a rationale for the prevention of breast cancer through a very low fat, high fiber diet.

Adult↗
PubMed1995

20-epi-vitamin D3 analogues: a novel class of potent inhibitors of proliferation and inducers of differentiation of human breast cancer cell lines.

We have studied the in vitro biological activities and mechanism of action of 1,25-dihydroxyvitamin D3 (1,25D3) and four potent 1,25D3 analogues [20-epi-22oxa-24a,26a,27a-tri-homo-1,25(OH)2D3 (KH 1060); 20-epi-1,25(OH)2D3; 1,25(OH)2-16ene-D3; and 1,25(OH)2-16ene-23yne-D3] on proliferation and differentiation of estrogen receptor-negative (MDA-MB-436, BT-20, SK-BR-3, and MDA-MB-231), estrogen receptor-weakly positive (BT474), and estrogen receptor-positive (MCF-7) breast cancer cell lines. Dose-response studies showed that KH 1060 was the most potent analogue, because it was able to induce differentiation in all seven breast cancer cell lines (measured by lipid staining) and to suppress more than 50% clonal proliferation (ED50) at 10(-10) M in all cell lines, except MDA-MB-436 and BT-20. To explore how these compounds mediated antiproliferative actions, their effects on the cell cycle, on expression of bcl-2 and p53, and on apoptosis were assessed. Five of six cell lines have a mutant p53 gene, whereas MCF-7 has wild-type p53. Immunohistochemical staining showed that the p53 protein was predominantly localized in the nucleus in each of the breast cancer cell lines except for MCF-7, which expressed the protein predominantly in the cytoplasm. After incubation with KH 1060 (3 days; 10(-7) M), expression of bcl-2 protein as determined by immunohistochemical localization was markedly decreased in BT-474, MCF-7, and MDA-MB-231; these same cells were profoundly inhibited in their clonal proliferation and arrested in the G0/G1 phase of the cell cycle when cultured with KH 1060. In contrast, BT-20 and MDA-MB-436 cells that were refractory to the antiproliferative effect of KH 1060 (ED50 < 10(-6) M) had no down-regulation of their bcl-2 expression and no cell cycle changes after exposure to KH 1060. MCF-7 showed morphological changes and DNA fragmentation, indicative of apoptosis after 48 h incubation with KH 1060 (10(-6) M), during which time p53 protein accumulated in the nucleus and decreased in the cytoplasm. In contrast, no apoptosis was detected in three other breast lines (MDA-MB-231, SK-BR-3, and BT-474) that had a mutated p53. In conclusion, the data indicate that KH 1060 is an extremely potent 1,25D3 analogue inducing differentiation of all six breast cancer lines and potently inhibiting clonal growth of four of them with concomitant decreased bcl-2 and cell cycle arrest at G0/G1.(ABSTRACT TRUNCATED AT 400 WORDS)

Apoptosis↗