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Biomedical subjects

Laurence M Demers

Publications and source records attributed to Laurence M Demers.

At least 19 recordsLinked to original sources
PubMed2007

Changes in urine markers and symptoms after bladder distention for interstitial cystitis.

PURPOSE: We evaluated changes in urine markers and symptom scores after bladder distention in patients with interstitial cystitis. MATERIALS AND METHODS: Study subjects were 33 new patients who had undergone no prior interstitial cystitis treatment. Urine specimens were taken before and 1 month after bladder distention. University of Wisconsin symptom scores were done the same day as the urine specimen collection. Urine marker levels and symptom scores before and after distention were compared. Changes in markers were tested for associations with changes in symptom scores and other markers. Markers and specific symptoms before distention were tested for their association with post-distention symptom improvement. RESULTS: After distention the median total University of Wisconsin score decreased significantly (28.5 before, 20 after, p <0.001). A total of 12 patients (36%) had at least 30% improvement in University of Wisconsin score, and 8 patients (24%) had at least 50% improvement. No pre-distention markers or symptoms predicted which patients would have a good response. There were 2 urine markers that improved significantly after distention: anti-proliferative factor activity (median -96% before, -17% after, p <0.001) and heparin-binding epidermal growth factor-like growth factor levels (median 0.34 ng/mg creatinine before, 4.1 after, p <0.001). None of the changes in urine markers associated with changes in symptom scores. CONCLUSIONS: The median symptom score for newly diagnosed patients with interstitial cystitis decreased after distention, but only a minority of patients had at least 30% symptom improvement. Bladder distention altered urine anti-proliferative factor activity and heparin-binding epidermal growth factor-like growth factor levels toward normal, but the mechanism of symptom relief after distention is still unknown.

Adult↗
PubMed2006

Effects of polyamine depletion by alpha-difluoromethylornithine on in vitro and in vivo biological properties of 4T1 murine mammary cancer cells.

Increased polyamine synthesis has been associated with proliferation and progression of breast cancer, and thus, is a potential target for anti-cancer therapy. Polyamine depletion by DFMO has been shown to decrease pulmonary and bone metastasis from human breast cancer cell xenografts. Following these observations, this study was designed to test the effects of DFMO on in vitro and in vivo features of the highly invasive and metastatic 4T1 murine mammary cancer cells. DFMO inhibited proliferation, caused G1-S arrest, and suppressed in vitro invasiveness of 4T1 cells. In contrast to our previous findings with MDA-MB-435 cells, DFMO did not affect the activation of STAT3, JNK, and ERK, but decreased phosphorylation of p38. DFMO did not alter the expression of Twist. DFMO delayed the orthotopic growth of 4T1 xenografts in association with suppressed putrescine and spermidine levels but increased levels of spermine. DFMO did not affect pulmonary metastasis when primary tumors of control and DFMO-treated mice were matched for size. Interestingly, DFMO reduced Ki-67 expression only in the primary tumors but did not affect its expression in the metastatic tumors in the lung. Cleaved caspase-3 expression was not affected by DFMO in either the primary tumors or pulmonary metastasis. In summary, DFMO treatment markedly inhibited in vitro proliferation and invasiveness of 4T1 cells and retarded the growth of orthotopic xenografts in mice. The failure of DFMO to inhibit pulmonary metastasis in this system appears to be due, at least in part, to its lack of anti-proliferative effect at the metastatic sites.

Animals↗
PubMed2006

Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer.

PURPOSE: Androgen deprivation therapy in patients with prostate cancer is associated with bone loss and an increased risk of fractures. Zoledronic acid protects against bone mineral density loss when initiated concurrently with androgen deprivation therapy. We evaluated the effect of zoledronic acid initiated subsequent to androgen deprivation therapy on bone mineral density and biochemical markers of bone turnover. MATERIALS AND METHODS: Patients with prostate cancer without bone metastases who had received androgen deprivation therapy for 12 months or less were randomized to 4 mg zoledronic acid or placebo intravenously every 3 months for 1 year. Patients were stratified according to androgen deprivation therapy duration (less than 6 vs 6 to 12 months). The primary end point was the change in femoral neck and lumbar spine bone mineral density in the 2 groups. The secondary end point was the change in serum bone specific alkaline phosphatase and urine N-telopeptide levels. Total hip bone mineral density was also measured. RESULTS: The 120 patients with prostate cancer received zoledronic acid (61) or placebo (59). Compared with placebo, zoledronic acid increased femoral neck, total hip and lumbar spine bone mineral density yearly by 3.6% (p = 0.0004), 3.8% (p <0.0001) and 6.7% (p <0.0001), respectively. The effects of zoledronic acid on bone mineral density at these 3 sites were not differentiated according to androgen deprivation therapy duration. Additionally, mean bone specific alkaline phosphatase and N-telopeptide levels were decreased in the zoledronic acid group (each p <0.0001) and were increased in the placebo group (p <0.0001 and p = 0.004, respectively). CONCLUSIONS: Zoledronic acid increased bone mineral density and suppressed bone turnover markers in patients with prostate cancer without bone metastases when initiated during year 1 of androgen deprivation therapy.

Adenocarcinoma↗
PubMed2006

Parathyroid hormone may maintain bone formation in hibernating black bears (Ursus americanus) to prevent disuse osteoporosis.

Mechanical unloading of bone causes an imbalance in bone formation and resorption leading to bone loss and increased fracture risk. Black bears (Ursus americanus) are inactive for up to six months during hibernation, yet bone mineral content and strength do not decrease with disuse or aging. To test whether hibernating bears have biological mechanisms to prevent disuse osteoporosis, we measured the serum concentrations of hormones and growth factors involved in bone metabolism and correlated them with the serum concentration of a bone formation marker (osteocalcin). Serum was obtained from black bears over a 7-month duration that included periods of activity and inactivity. Both resorption and formation markers increased during hibernation, suggesting high bone turnover occurred during inactivity. However, bone formation appeared to be balanced with bone resorption. The serum concentration of parathyroid hormone (PTH) was higher in the hibernation (P=0.35) and post-hibernation (P=0.006) seasons relative to pre-hibernation levels. Serum leptin was lower (P<0.004) post-hibernation relative to pre-hibernation and hibernation periods. Insulin-like growth factor I (IGF-I) decreased (P<0.0001) during hibernation relative to pre-hibernation and reached its highest value during remobilization. There was no difference (P=0.64) in 25-OH vitamin D between the three seasons. Serum osteocalcin (bone formation marker) was significantly correlated with PTH, but not with leptin, IGF-I or 25-OH vitamin D. Osteocalcin and PTH were positively correlated when samples from all seasons were pooled and when only hibernation samples were considered, raising the possibility that the anabolic actions of PTH help maintain bone formation to prevent disuse osteoporosis. Prostaglandin E(2) (PGE(2)) release from MC3T3 osteoblastic cells was significantly affected by treatment with bear serum from different seasons (i.e. hibernation versus active periods). The seasonal changes in PGE(2) release showed trends similar to the seasonal changes in serum IGF-I. Since both PGE(2) and IGF-I are associated with collagenous bone formation, it is possible that seasonal changes in a circulating factor influence IGF-I levels in vivo in bears and PGE(2) release in osteoblastic cells in vitro. The significant decrease in serum leptin following arousal from hibernation may promote bone formation during remobilization, assuming there is a similar decrease in intracerebroventricular leptin. These findings support the idea that seasonal changes in the concentration of circulating molecules help regulate bone formation activity and may be important for preventing disuse osteoporosis in bears.

3T3 Cells↗
PubMed2005

Metastasis of hormone-independent breast cancer to lung and bone is decreased by alpha-difluoromethylornithine treatment.

INTRODUCTION: Polyamines affect proliferation, differentiation, migration and apoptosis of cells, indicating their potential as a target for cancer chemotherapy. Ornithine decarboxylase converts ornithine to putrescine and is the rate-limiting step in polyamine synthesis.alpha-Difluoromethylornithine (DFMO) irreversibly inhibits ornithine decarboxylase and MDA-MB-435 human breast cancer metastasis to the lung without blocking orthotopic tumor growth. This study tested the effects of DFMO on orthotopic tumor growth and lung colonization of another breast cancer cell line (MDA-MB-231) and the effects on bone metastasis of MDA-MB-435 cells. METHODS: MDA-MB-231 cells were injected into the mammary fat pad of athymic mice. DFMO treatment (2% per orally) began at the day of tumor cell injection or 21 days post injection. Tumor growth was measured weekly. MDA-MB-231 cells were injected into the tail vein of athymic mice. DFMO treatment began 7 days prior to injection, or 7 or 14 days post injection. The number and incidence of lung metastases were determined. Green fluorescent protein-tagged MDA-MB-435 cells were injected into the left cardiac ventricle in order to assess the incidence and extent of metastasis to the femur. DFMO treatment began 7 days prior to injection. RESULTS: DFMO treatment delayed MDA-MB-231 orthotopic tumor growth to a greater extent than growth of MDA-MB-435 tumors. The most substantial effect on lung colonization by MDA-MB-231 cells occurred when DFMO treatment began 7 days before intravenous injection of tumor cells (incidence decreased 28% and number of metastases per lung decreased 35-40%). When DFMO treatment began 7 days post injection, the incidence and number of metastases decreased less than 10%. Surprisingly, treatment initiated 14 days after tumor cell inoculation resulted in a nearly 50% reduction in the number of lung metastases without diminishing the incidence. After intracardiac injection, DFMO treatment decreased the incidence of bone metastases (55% vs 87%) and the area occupied by the tumor (1.66 mm2 vs 4.51 mm2, P < 0.05). CONCLUSION: Taken together, these data demonstrate that DFMO exerts an anti-metastatic effect in more than one hormone-independent breast cancer, for which no standard form of biologically-based treatment exists. Importantly, the data show that DFMO is effective against metastasis to multiple sites and that treatment is generally more effective when administered early.

Animals↗
PubMed2005

The Human mineral dust-induced gene, mdig, is a cell growth regulating gene associated with lung cancer.

Environmental or occupational exposure to mineral dusts, mainly silica and asbestos, is associated with an increased incidence of lung inflammation, fibrosis, and/or cancer. To better understand the molecular events associated with these pulmonary diseases, we attempted to identify genes that are regulated by mineral dusts. Using a differential display reverse transcription polymerase chain reaction technique and mRNAs of alveolar macrophages from both normal individuals and coal miners, we identified a novel mineral dust-induced gene named mdig, which had not been fully characterized. The expression of mdig mRNA was detected in alveolar macrophages from coal miners but not from normal subjects. The inducible expression of mdig could be observed in A549 cells exposed to silica particles in a time-dependent manner. The full-length mdig mRNA was expressed in human lung cancer tissues but was barely detectable in the adjacent normal tissues. In addition, a number of lung cancer cell lines constitutively express mdig. Alternative spliced transcripts of mdig were detected in some lung cancer cell lines. Silencing mdig mRNA expression in A549 lung cancer cells by siRNA-mediated RNA interference inhibits cell proliferation and sensitizes the cells to silica-induced cytotoxicity. These results suggest that the mdig gene may be involved in the regulation of cell growth and possibly the development of cancer.

Alternative Splicing↗
PubMed2005

Effects of polyamine synthesis inhibitors on primary tumor features and metastatic capacity of human breast cancer cells.

We have previously reported that inhibition of polyamine biosynthesis with alpha-difluoromethylornithine (DFMO) reduces pulmonary metastasis from MDA-MB-435 human breast cancer xenografts without affecting the volume of the primary tumors (Manni et al. Clin Exp Mets 20:321, 2003). In these experiments, we show that DFMO treatment (2% in drinking H(2)O) reduced the growth fraction of the primary tumors by 60%. However, this effect was counter-balanced by a similar reduction in non-apoptotic necrosis, thus accounting for the preservation of tumor volume in DFMO-treated mice. DFMO treatment caused a 4-fold increase in cytoplasmic staining for cleaved caspase-3 (as opposed to the nuclear staining observed in control tonsil tissue) in the absence of histologic evidence of apoptosis. DFMO treatment reduced the number of mice with pulmonary metastasis by approximately 80% and the number of metastasis per mouse by >90% in association with a reduction in invasiveness of the primary tumor in the surrounding dermis and muscle by approximately 30%. DFMO treatment increased ERK phosphorylation in the tumors, an effect that has been found by us in vitro to be causally linked to the anti-invasive effect of the drug (Manni et al. Clin Exp Metast 2004; 21: 461]. DFMO also increased tyrosine phosphorylation of STAT-3 and expression of STAT-1 and JNK proteins. Administration of SAM486A (1 mg/kg/i.p. daily), an inhibitor of S-adenosylmethionine decarboxylase, either individually or in combination with DFMO, was not found to exert any biological or biochemical effects, most likely as a result of its failure to suppress tissue polyamine levels under these experimental conditions.

Amidines↗
PubMed2005

Do the National Institute of Diabetes and Digestive and Kidney Diseases cystoscopic criteria associate with other clinical and objective features of interstitial cystitis?

PURPOSE: We compared urine markers, bladder biopsy findings and clinical features of patients with symptoms of interstitial cystitis (IC) who did or did not meet the cystoscopic criteria defined by the National Institute of Diabetes and Digestive and Kidney Diseases. MATERIALS AND METHODS: Urine markers and symptom questionnaires were measured before and 1 month after bladder distention for IC. Bladder biopsies were taken at the time of distention. At distention patients were defined as meeting or not meeting the National Institute of Diabetes and Digestive and Kidney Diseases established cystoscopic criteria for IC. The 2 patient groups were compared. RESULTS: Urine marker levels were similar for the 2 groups, including antiproliferative factor, epidermal growth factor, heparin binding epidermal growth factor-like growth factor, cyclic guanosine monophosphate, interleukins 6 and 8, and methylhistamine. Bladder biopsy features were similar for the 2 groups. Bladder capacity with the patients under anesthesia was higher in those who did not meet the criteria (median 750 vs 1,000 ml, p = 0.005). Median age at symptom onset was 26 years in both groups. On the University of Wisconsin symptom scale patients who met the criteria had higher scores for daytime frequency (p = 0.002) and nocturia (p = 0.01). Symptom characteristics and symptom response after bladder distention were similar for the 2 groups. CONCLUSIONS: Patients who met the cystoscopic criteria had worse daytime frequency and nocturia, and lower bladder capacity under anesthesia. However, the 2 groups had similar urine markers and bladder biopsy findings. The cystoscopic criteria do not appear to identify a distinct pathophysiological subset of patients with IC symptoms.

Adult↗
PubMed2005

Effects of supplemental oxygen administration on coronary blood flow in patients undergoing cardiac catheterization.

Patients with heart disease are frequently treated with supplemental oxygen. Although oxygen can exhibit vasoactive properties in many vascular beds, its effects on the coronary circulation have not been fully characterized. To examine whether supplemental oxygen administration affects coronary blood flow (CBF) in a clinical setting, we measured in 18 patients with stable coronary heart disease the effects of breathing 100% oxygen by face mask for 15 min on CBF (via coronary Doppler flow wire), conduit coronary diameter, CBF response to intracoronary infusion of the endothelium-dependent dilator ACh and to the endothelium-independent dilator adenosine, as well as arterial and coronary venous concentrations of the nitric oxide (NO) metabolites nitrotyrosine, NO(2)(-), and NO(3)(-). Relative to breathing room air, breathing of 100% oxygen increased coronary resistance by approximately 40%, decreased CBF by approximately 30%, increased the appearance of nitrotyrosine in coronary venous plasma, and significantly blunted the CBF response to ACh. Oxygen breathing elicited these changes without affecting the diameter of large-conduit coronary arteries, coronary venous concentrations of NO(2)(-) and NO(3)(-), or the coronary vasodilator response to adenosine. Administering supplemental oxygen to patients undergoing cardiac catheterization substantially increases coronary vascular resistance by a mechanism that may involve oxidative quenching of NO within the coronary microcirculation.

Acetylcholine↗
PubMed2004

Recombinant cell ultrasensitive bioassay for measurement of estrogens in postmenopausal women.

A recent analysis of data from nine studies provided convincing evidence that plasma estradiol measurements predict the risk of breast cancer in normal postmenopausal women. However, the median values detected by the various assays used in this study varied by 5-fold. These and other published data in normal postmenopausal women suggest that assays measuring low plasma estradiol concentrations suffer from problems of sensitivity, specificity, and precision. Availability of a practical, low-cost, specific, precise, and ultrasensitive estrogen assay might allow enhanced prediction of the risk of breast cancer and provide an objective means of selecting postmenopausal women for breast cancer prevention. A recombinant cell ultrasensitive bioassay (RCUB) for estrogen was recently validated for use in prepubertal children. We postulated that the RCUB might also prove useful for measurement of postmenopausal levels and designed the present study to examine this possibility. Thirty normal postmenopausal volunteers provided blood samples for measurement of estrogen by RCUB and, for comparison, by RIA. The estrogenic activity measured by RCUB [mean +/- sd, 11.9 +/- 10.9 pmol/liter (SI units, 3.23 +/- 2.96 pg/ml] was significantly lower than estradiol levels measured by RIA [43.7 +/- 44.0 pmol/liter (11.9 +/- 12.0 pg/ml)] in our volunteer subjects (P < 0.00001). Nonetheless, plasma estradiol levels measured by bioassay were significantly correlated with the estrogenic activity measured by RIA (r = 0.84) and by gas chromatography/tandem mass spectrometry (r = 0.85). To obtain biological evidence of the validity of the RCUB, we related plasma estrogen levels to body weight and body mass index and found highly significant correlations (r = 0.54 and r = 0.53, respectively). Surprisingly, 28 of 30 postmenopausal women were found to have estrogen levels in the prepubertal range with the RCUB. The levels detected by RCUB were similar to those previously reported using an ultrasensitive but less practical yeast bioassay. These results provide validation for the RCUB in postmenopausal women and suggest that it might prove useful for selection of women for drug therapy to prevent breast cancer.

Aged↗
PubMed2004

Thyroid disease: pathophysiology and diagnosis.

The thyroid is a butterfly-shaped gland that is located in the front of the neck just above the trachea; it weighs approximately 15 g to 20 g in the adult human. The thyroid produces and releases into the circulation at least two potent hormones, thyroxine (T4) and triiodothyronine (T3), that influence basal metabolic processes or enhance oxygen consumption in nearly all body tissues. Thyroid hormones also influence linear growth; brain function, including intelligence and memory; neural development; dentition; and bone development.

Humans↗
PubMed2004

A randomized trial of the effects of two types of short-term hypocaloric diets on weight loss in women with polycystic ovary syndrome.

OBJECTIVE: We performed this study as a pilot experiment to investigate the short term effects of two diets of varying composition on weight loss as the primary outcome in obese women with polycystic ovary syndrome (PCOS) seeking fertility. DESIGN: Randomized clinical trial. SETTING: Academic medical center. PATIENT(S): Thirty-five obese women with PCOS. INTERVENTION(S): We examined the effects of a 1-month dietary intervention on the PCOS phenotype. Participants were randomized to one of two energy-restricted diets; high protein (HP: 30% protein, 40% carbohydrate, and 30% fat) or high carbohydrate (HC: 15% protein, 55% carbohydrate, and 30% fat). The fat content was held constant in both diets. MAIN OUTCOME MEASURE(S): Primary - change in body weight; Secondary - biometric, hormonal, lipid and lipoprotein, and markers of glucose homeostasis and energy metabolism. RESULT(S): Twenty-six women completed the study. Both the HP (-3.7 +/- 1.9 kg) and HC (-4.4 +/- 1.5 kg) diets resulted in significant weight loss, but there was no significant difference in mean weight loss between the two groups. There were also no differences between diets on a variety of measures including circulating androgens, measures of glucose metabolism, and leptin. However, the effects of a hypocaloric diet per se on improving metabolic and reproductive abnormalities in a group of PCOS women were marked by a decline in circulating androgens (P=.03), fasting and area under the curve (AUC) insulins (P<.05) on a 3-hour oral glucose tolerance test (OGTT), and fasting and AUC leptin levels (P<.0001). There was a high prevalence of menstrual bleeding during the trial (14 out of 26 patients). CONCLUSION(S): Those who completed the short-term hypocaloric diet had a significant weight loss and a significant improvement in their reproductive and metabolic abnormalities. There was no increased benefit to a high-protein diet. Future diet studies evaluating the ideal composition of a hypocaloric diet in women with PCOS will require a large study population, and will most likely require a multicenter trial.

Adult↗
PubMed2004

Is urine methylhistamine a useful marker for interstitial cystitis?

PURPOSE: We determined whether urine methylhistamine (MH) is associated with other clinical features and bladder biopsy findings in interstitial cystitis (IC). MATERIALS AND METHODS: Urine MH and University of Wisconsin symptom scores were measured before and 1 month after bladder distention for IC. Bladder biopsies were done at the time of distention. In new patients with IC who met cystoscopic criteria urine MH was compared before and after distention, and changes in urine MH were compared with changes in symptom scores. Pre-distention urine MH was tested for associations with the results of a symptom questionnaire, symptom response after distention, cystoscopic findings and bladder biopsy findings. RESULTS: There were no significant associations between urine MH and symptom scores, response to bladder distention, cystoscopic findings or bladder biopsy features, including mast cell count by tryptase staining. Urine MH was similar in new patients with IC who did vs did not meet cystoscopic criteria. Urine MH was similar in new vs chronically treated patients with IC. CONCLUSIONS: Urine MH is unlikely to be useful as an objective marker of the response to bladder distention, as a method to predict which patients will respond to bladder distention or as a noninvasive substitute for bladder biopsy and mast cell counts by tryptase staining.

Adult↗
PubMed2004

Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry.

The diagnosis of male hypogonadism requires the demonstration of a low serum testosterone (T) level. We examined serum T levels in pedigreed samples taken from 62 eugonadal and 60 hypogonadal males by four commonly used automated immunoassay instruments (Roche Elecsys, Bayer Centaur, Ortho Vitros ECi and DPC Immulite 2000) and two manual immunoassay methods (DPC-RIA, a coated tube commercial kit, and HUMC-RIA, a research laboratory assay) and compared results with measurements performed by liquid chromatography-tandem mass spectrometry (LC-MSMS). Deming's regression analyses comparing each of the test results with LC-MSMS showed slopes that were between 0.881 and 1.217. The interclass correlation coefficients were between 0.92 and 0.97 for all methods. Compared with the serum T concentrations measured by LC-MSMS, the DPC Immulite results were biased toward lower values (mean difference, -90 +/- 9 ng/dl) whereas the Bayer Centaur data were biased toward higher values (mean difference, +99 +/- 11 ng/dl) over a wide range of serum T levels. At low serum T concentrations (<100 ng/dl or 3.47 nmol/liter), HUMC-RIA overestimated serum T, Ortho Vitros ECi underestimated the serum T concentration, whereas the other two methods (DPC-RIA and Roche Elecsys) showed differences in both directions compared with LC-MSMS. Over 60% of the samples (with T levels within the adult male range) measured by most automated and manual methods were within +/- 20% of those reported by LC-MSMS. These immunoassays are capable of distinguishing eugonadal from hypogonadal males if adult male reference ranges have been established in each individual laboratory. The lack of precision and accuracy, together with bias of the immunoassay methods at low serum T concentrations, suggests that the current methods cannot be used to accurately measure T in females or serum from prepubertal subjects.

Adult↗
PubMed2004

Biological activity of the S-adenosylmethionine decarboxylase inhibitor SAM486A in human breast cancer cells in vitro and in vivo.

The antitumor activity of the S-adenosylmethionine decarboxylase (SAMDC) inhibitor SAM486A in human breast cancer cells was investigated. Our in vitro study focused on testing the effects of SAM486A on the proliferation, clonogenicity, invasiveness, cell signaling and PA levels of hormone-independent MDA-MB-435 human breast cancer cells. We also investigated the antitumor action, effects on polyamine pools and tolerability of SAM486A administered to nude mice carrying MDA-MB-435 xenografts. SAM486A suppressed anchorage-independent and -dependent growth and invasiveness of breast cancer cells and the inhibition of cell growth was associated with suppression of spermine synthesis. Combined administration of SAM486A and alpha-difluoromethylornithine (DFMO), a selective inhibitor of ornithine decarboxylase (ODC), exerted greater antiproliferative and anti-invasive effects and induced an overall greater suppression of cellular PA levels than the individual treatments. Both SAM486A and DFMO increased phosphorylation of STAT-1, -3, ERK1/2 and p38, thus indicating activation of both STAT signaling and the MAPK pathway. SAM486A (1 mg/kg) significantly suppressed the growth and spermine levels of established MDA-MB435 breast tumors in nude mice. SAM486A exerts a potent antitumor action in MDA-MB-435 breast cancer cells both in vitro and in vivo. Inhibition of cellular spermine is consistently observed with SAM486A treatment and may mediate its antitumor action. Combination treatment with DFMO may allow the use of lower and, hence, less toxic doses of each compound with preservation of optimal therapeutic effect. The role of activation of STAT signaling and the MAPK pathway in the antitumor action of SAM486A remains to be determined.

Adenosylmethionine Decarboxylase↗
PubMed2003

Bone markers in the management of patients with skeletal metastases.

BACKGROUND: Biochemical markers of bone remodeling have been used as surrogate markers to manage patients with metastatic bone disease. Markers of the bone resorptive process, such as the bone collagen breakdown products N-telopeptide and C-telopeptide, are useful markers for monitoring the response and efficacy of antiresorptive therapy and to assess disease progression in patients with osteolytic bone disease. Recently discovered markers of osteoclastogenesis, osteoprotegerin (OPG) and the soluble form of the receptor activator for nuclear factor (NF)-kappaB (RANK-L), also are candidate markers of the bone metastases process and offer potential as surrogate markers of tumor-induced osteoclastogenesis. METHODS: Immunoassays have been developed that can determine blood and urine levels of the telopeptides associated with bone collagen breakdown. In addition, immunoassays now are available that can measure both OPG and the soluble form of RANK-L in blood and tissues as markers of osteoclastogenesis. RESULTS: The measurement of bone collagen breakdown products and specific factors associated with the process of osteoclastogenesis have been applied to the management and assessment of patients with metastatic bone disease. Results indicate that these surrogate markers can be useful in determining response to antiresorptive therapy, in selecting optimal dosage, and as markers of disease progression. CONCLUSIONS: Although they show promise, questions remain whether blood measurements of surrogate markers of osteoclastogenesis, like OPG and RANK-L, will be useful in both assessing and managing patients with metastatic bone disease.

Biomarkers, Tumor↗
PubMed2003

Effects of alpha-difluoromethylornithine on local recurrence and pulmonary metastasis from MDA-MB-435 breast cancer xenografts in nude mice.

We have recently shown that administration of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine (PA) biosynthesis reduces pulmonary metastasis from MDA-MB-435 breast cancer xenografts in nude mice. The present experiments were designed to further explore PA involvement in breast cancer metastasis, using GFP-tagged MDA-MB-435 cells that can be tracked at the single cell level. Administration of DFMO significantly reduced the number of mice with pulmonary metastasis as well as the number of metastases per mouse. Both single-cell and multicellular metastatic deposits were similarly suppressed, thus suggesting that DFMO was inhibiting lung colonization by tumor cells rather than preventing progression of single-cell deposits to overt metastasis. DFMO administration also significantly reduced local recurrences following removal of the primary tumor. Prolongation of DFMO treatment to 14 weeks did not yield a superior antimetastatic effect beyond that provided by a 10-week course of therapy. Discontinuation of DFMO, on the other hand, was associated with local regrowth of the tumors and, possibly, recurrence of pulmonary metastasis. These data provide a rationale for testing the efficacy of anti-PA treatment within the context of adjuvant therapy of breast cancer.

Animals↗