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Biomedical subjects

A Lipton

Publications and source records attributed to A Lipton.

At least 55 records · Page 3Linked to original sources
PubMed1996

Serial serum c-erbB-2 levels in patients with breast carcinoma.

BACKGROUND: Recently, the extracellular domain of the c-erbB-2 oncogene product (HER-2/neu) has been reported to be elevated in the serum of one-fourth of patients with metastatic breast carcinoma. The role of serum c-erbB-2 as a tumor marker, however, is still poorly defined. The purpose of this study was to evaluate the utility of serial serum c-erbB-2 levels as a tumor marker in patients with metastatic breast carcinoma. METHODS: c-erbB-2 levels in the sera of patients with breast carcinoma were determined by an enzyme immunoassay that detects the extracellular domain of c-erbB-2. Serum c-erbB-2 levels were evaluated prior to treatment as well as throughout the course of treatment with second-line hormonal therapy employing either megestrol acetate or fadrozole, an experimental aromatase inhibitor. RESULTS: Fifty-eight of 300 patients (19.3%) had elevated pretreatment serum c-erbB-2 levels. Of these 58 patients with elevated pretreatment c-erbB-2, 48 had more than 1 visit which enabled us to quantitate serial c-erbB-2 levels throughout the course of treatment. Of these 48 patients, 28 (58.3%) had serial c-erbB-2 values that correlated with the clinical course. CONCLUSIONS: Serial serum c-erbB-2 levels did not show a high overall correlation with the clinical course in this group of patients with metastatic breast carcinoma treated with second-line hormonal therapy.

Aged↗
PubMed1996

Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group.

BACKGROUND: Skeletal complications are a major clinical manifestation of multiple myeloma. These complications are caused by soluble factors that stimulate osteoclasts to resorb bone. Bisphosphonates such as pamidronate inhibit osteoclastic activity and reduce bone resorption. METHODS: Patients with stage III multiple myeloma and at least one lytic lesion received either placebo or pamidronate (90 mg) as a four-hour intravenous infusion given every four weeks for nine cycles in addition to antimyeloma therapy. The patients were stratified according to whether they were receiving first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy at entry into the study. Skeletal events (pathologic fracture, irradiation of or surgery on bone, and spinal cord compression), hypercalcemia (symptoms or a serum calcium concentration > or = 12 mg per deciliter [3.0 mmol per liter]), bone pain, analgesic-drug use, performance status, and quality of life were assessed monthly. RESULTS: Among 392 treated patients, the efficacy of treatment could be evaluated in 196 who received pamidronate and 181 who received placebo. The proportion of patients who had any skeletal events was significantly lower in the pamidronate group (24 percent) than in the placebo group (41 percent, P < 0.001), and the reduction was evident in both stratum 1 (P = 0.04) and stratum 2 (P = 0.004). The patients who received pamidronate had significant decreases in bone pain and no deterioration in performance status and quality of life. Pamidronate was tolerated well. CONCLUSIONS: Monthly infusions of pamidronate provide significant protection against skeletal complications and improve the quality of life of patients with stage III multiple myeloma.

Aged↗
PubMed1996

NDF induces expression of a novel 46 kD protein in estrogen receptor positive breast cancer cells.

Most human breast tumors start as estrogen-dependent, but during the course of the disease become refractory to hormone therapy. The transition of breast tumors from estrogen dependent to independent behavior may be regulated by autocrine and/or paracrine growth factor(s) that are independent of the estrogen receptor (ER). We have investigated the role(s) of NDF (neu-differentiation factor) in the biology of estrogen positive breast cancer cells by using MCF-7 cells as a model system. Treatment of MCF-7 cells with human recombinant NDF-beta 2 (NDF) inhibited the ER expression by 70% and this was associated with growth stimulation in an estrogen-independent manner. To explore the mechanism(s) of action of NDF in MCF-7 cells, we examined the expression of NDF-inducible gene products. We report here that NDF stimulated the levels of expression of a 46 kD protein (p46) (in addition to few minor proteins) in ER positive breast cancer cells including MCF-7, T-47-D, and ZR-75-R cells but not in ER negative breast cancer cells including MDA-231, SK-BR-3, and MDA-468 cells. This effect of NDF was due to induction in the rate of synthesis of new p46. The observed NDF-mediated induction of p46 expression was specific as there was no such effect by epidermal growth factor or 17-beta-estradiol, and inclusion of actinomycin D partially inhibited the p46 induction elicited by NDF. NDF-inducible stimulation of p46 expression was an early event (2-6 h) which preceded the period of down-regulation of ER expression by NDF. These results support the existence of NDF-responsive specific cellular pathway(s) that may regulate ER, and these interactions could play a role(s) in hormone-independence of ER positive breast cancer cells.

Gene Expression Regulation, Neoplastic↗
PubMed1996

Phase I trial of recombinant platelet factor 4 (rPF4) in patients with advanced colorectal carcinoma.

BACKGROUND: Recombinant platelet factor 4 (rPF4) is a naturally occurring protein found in platelet alpha granules that can inhibit angiogenesis. METHODS: In this Phase I trial, 9 patients with metastatic colorectal cancer who had failed 5-FU treatment received rPF4 at doses ranging from 0.3 to 3.0 mg/kg via 30-minute infusion. Three additional patients were treated with the 3 mg/kg dose over a 6-hour period of infusion. RESULTS: The only toxicity encountered was mild leg twitching in 2/3 patients treated with the 6-hour infusion. One patient with a history of phlebitis developed a lower extremity deep venous thrombosis after the first dose of rPF4. A mild rise in fibrinogen level was noted in several patients. Of the 11 evaluable patients, there were no clinical responses to treatment. CONCLUSIONS: rPF4 is well tolerated at the doses and schedules tested. No clinical responses were observed. Prolonged infusion schedules should be investigated.

Adult↗
PubMed1996

The role of bisphosphonates in the treatment of bone metastases--the U.S. experience.

Frequent complications of bone metastases include pain, pathologic fracture, hypercalcemia and spinal cord compression. Lytic bone metastases result from excessive activation of osteoclasts by tumor-produced cytokines. Aredia (pamidronate) is a potent bisphosphonate that inhibits osteoclast activation. In two dose-seeking phase I trials in patients with breast cancer and prostate cancer, repeated intravenous infusion of Aredia was shown to be safe and effective in reducing bone resorption and pain. In a randomized phase III trial of 377 patients with multiple myeloma, Aredia was administered in a dosage of 90 mg i.v. every 4 weeks. Compared with placebo, treatment with Aredia was associated with a significant decrease in bone pain and in the incidence and time to development of all skeleton-related events. Data from two phase III breast cancer trials each involving 300 patients are now being analyzed. The newer bisphosphonates can safely be used together with standard anticancer therapy to provide effective palliation of symptoms caused by lytic bone metastases.

Antineoplastic Agents↗
PubMed1996

Overexpression of HER2 modulates bcl-2, bcl-XL, and tamoxifen-induced apoptosis in human MCF-7 breast cancer cells.

Overexpression of HER2 in estrogen receptor (ER)-positive human breast tumors has been associated with resistance to endocrine therapy. Here we investigated the effects of HER2 on expression of apoptotic pathways and modulation of tamoxifen-induced apoptosis in ER-positive MCF-7 breast cancer cells. We report that HER2 overexpression in MCF-7 cells is accompanied by up-regulation of antiapoptotic Bcl-2 and Bcl-XL proteins and suppression of tamoxifen-induced apoptosis. In addition, human tumor cell lines that are both ER positive and overexpress HER2 also express enhanced levels of Bcl-2 compared to cells that are either ER positive or overexpress HER2 alone. Our findings suggest that possible deregulation of antiapoptotic Bcl-2 and Bcl-XL may be associated with the enhanced survival of HER2-overexpressing and ER-positive breast cancer cells treated with antiestrogens.

Apoptosis↗
PubMed1995

On the use of local statistical properties in focusing microscopy images.

Techniques to extract focus properties of microscopy images are many and varied. Many of them, however, rely on the summation of local statistical properties. Presented here is an examination of conventional focus determination algorithms, and a new method based on planar histograms of these local statistical properties. It is shown that this new method provides finer discernment of the focus properties of an image, and provides a means to extend the focus of an optical microscopy system.

Algorithms↗
PubMed1995

Letrozole (CGS 20267). A phase I study of a new potent oral aromatase inhibitor of breast cancer.

BACKGROUND: Letrozole (CGS 20267), a triazole derivative, is a new, once-daily, oral nonsteroidal inhibitor of aromatase activity. METHODS: In this Phase I trial, 23 heavily pretreated postmenopausal patients with metastatic breast cancer received letrozole at doses ranging from 0.1 to 5.0 mg once daily. RESULTS: No hematologic, biochemical, or significant clinical toxicity was encountered. Serial steroid measurements were determined in 19 of these patients. Letrozole at all doses tested produced a marked suppression of plasma estrone, estradiol, estrone sulfate, and urine estrone and estradiol. This was observed within 24 hours of the initial dose of letrozole and resulted in a greater than 90% suppression of plasma and urinary estrogen levels within 2 weeks. Letrozole appears to be highly selective in its action and does not compromise glucocorticoid or mineralocorticoid production or thyroid function. Of the 21 evaluable patients, there were 2 with partial responses and 7 with stable disease. CONCLUSIONS: Letrozole is a well tolerated, potent, and specific inhibitor of estrogen biosynthesis in postmenopausal patients with metastatic breast cancer.

Adult↗
PubMed1995

Aromatase inhibitor development for treatment of breast cancer.

Inhibition of estrogen production provides effective therapy for patients with hormone-dependent breast cancer. The source of estrogens in premenopausal women is predominantly the ovary, but after the menopause, estradiol is synthesized in peripheral tissues through the aromatization of androgens to estrogens. Uptake from plasma is the primary mechanism for maintenance of estradiol concentrations in breast cancer tissue in premenopausal women, whereas several steps may be operant in postmenopausal women. These include enzymatic synthesis of estradiol via sulfatase, aromatase, and 17 beta-hydroxysteroid dehydrogenase in the tumor itself. Aromatization of androgens secreted by the adrenal to estrogens in peripheral tissues and transport to the tumor via circulation in the plasma provides another means of maintaining breast tumor estradiol levels in postmenopausal women. These various sources contribute to the high tissue estrogen levels measured in breast tumor tissue. To effectively suppress tissue concentrations of estrogens and circulating estradiol in postmenopausal patients, various aromatase inhibitors have been developed recently. These include steroidal inhibitors such as 4-hydroxy-androstenedione as well as non-steroidal compounds with imidazole and triazole structures. The most potent of these, CGS 20267, is reported to suppress levels of active estrogens (i.e., estrone, estrone sulfatase, and estradiol) by more than 95%. This compound can suppress both serum and 24-hr urine estrogens to a greater extent than produced by the second generation inhibitor, CGS 16949A. CGS 20267 is highly specific since it does not affect cortisol and aldosterone serum levels during ACTH stimulation tests nor sodium and potassium balance in 24-hr urine samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Aromatase Inhibitors↗
PubMed1995

Calcium absorption, endogenous excretion, and endocrine changes during and after long-term bed rest.

Negative calcium balance is a known consequence of bed rest, and is manifested in elevated urine and fecal calcium (Ca). Elevated fecal Ca can result from either decreased absorption, increased endogenous fecal excretion, or both. We measured the Ca absorption and endogenous fecal excretion in eight healthy male volunteers before and during 4 months of bed rest. Dual isotope (n = 6) or single isotope (n = 2) methods in conjunction with Ca balance were used to calculate true and net Ca absorption and endogenous fecal excretion. Stool Ca increased from 797 mg/day (mean intake 991 mg/day) to 911 mg/day during bed rest, whereas urine Ca excretion increased from 174 to 241 mg/day. True Ca absorption decreased from 31 +/- 7% of Ca intake pre-bed rest to 24 +/- 2% during bed rest, (p < 0.05) and returned toward pre-bed rest values within 5-6 weeks following reambulation. Endogenous fecal excretion did not change significantly, and therefore, most of the increased fecal Ca resulted from changes in absorption. However, in one individual, endogenous fecal Ca excretion was the major contributor to Ca loss. Ionized Ca and pyridinium crosslinks increased and 1,25(OH)2 vitamin D decreased during bed rest, similar to the decrease in Ca absorption; parathyroid hormone (PTH), calcitonin, serum albumin, phosphorus, and total serum Ca were unchanged. Although alkaline phosphatase, osteocalcin, and PTH were unchanged during bed rest, they were elevated during reambulation. These changes accompanied by increased Ca absorption and balance and decreased ionized and total serum Ca suggest a rebound in bone formation following immobilization.

Absorption↗
PubMed1995

Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of breast cancer.

PURPOSE: Decisions concerning the use of hormone therapy to treat metastatic breast cancer are made on the basis of the presence of estrogen receptor (ER). Despite the presence of ER, half of patients will not respond to hormone treatment. The purpose of this study was to determine the effect of overexpression of HER-2/neu on the response to hormone therapy. PATIENTS AND METHODS: Sera from 300 metastatic breast cancer patients with ER-positive (ER+), ER status unknown, or ER-/progesterone receptor-positive (PR+) randomized to receive second-line hormone therapy with either megestrol acetate or fadrozole were evaluated. An enzyme immunoassay (EIA) specific for the extracellular domain of the c-erbB-2 (HER-2/neu) oncogene product was used to detect serum levels. RESULTS: Fifty-eight patients (19.3%) had elevated serum c-erbB-2 protein levels, using a selected cut-point of 30 U/mL. The response rate (complete responses [CRs] plus partial responses [PRs] plus stable disease [S]) to endocrine therapy was 40.9% in 242 patients with low serum c-erbB-2 levels and only 20.7% in 58 patients with elevated serum c-erbB-2 levels (P = .004). The median duration of treatment response was longer in the group with low serum c-erbB-2 levels (15.5 months) compared with the group with elevated serum c-erbB-2 levels (11.6 months). Survival was also significantly shorter in patients with elevated serum c-erbB-2 levels (P < .0001). CONCLUSION: Patients with ER+/c-erbB-2+ metastatic breast cancer are less likely to respond to hormone treatment than ER+/c-erbB-2- patients. Their survival duration is also shorter.

Adult↗
PubMed1995

Biochemical markers of bone turnover in patients with metastatic bone disease.

Several biochemical markers of bone formation and bone resorption have recently been developed. These markers have been evaluated for clinical utility in patients with metabolic bone disease, including Paget disease and osteoporosis, and for their potential use in cancer patients whose disease has metastasized to bone. We have evaluated seven markers of bone turnover in the plasma and urine of 94 patients with newly diagnosed or progressive malignancy with and without clinical evidence of bone metastases. As determined by a positive bone scan and (or) bone survey, 30 patients had metastases to bone; 51 patients had metastatic cancer without overt bony involvement; and 13 patients had local disease without bone metastases. To evaluate the predictive value of these markers in the metastatic population, we utilized a "Z-score" and logistic regression analysis to distinguish patients with documented bone metastatic disease from those patients without clinical evidence of bone metastases. The higher the Z-score, the better the marker predicts the presence of bone metastases. With this statistical approach, urine N-telopeptide measurements had the highest Z-score and the most significant association with the probability of bone metastases. Urine deoxypyridinoline was the second most predictive marker of bone metastases. Thus, biochemical markers of bone resorption might be of use to predict the presence of bone metastases in cancer patients and to monitor the efficacy of antiresorptive therapy in patients treated for metastatic bone disease.

Alkaline Phosphatase↗
PubMed1995

Bone markers in osteoporosis and malignancy.

Normal bone turnover is characterized by a balance (coupling) between the formation of new bone by osteoblasts and the resorption of old bone by osteoclasts. This bone remodeling takes place at discrete sites in the skeleton called bone remodeling units. Initially, the cells that line bone are replaced by osteoclasts that bring about resorption of the surface of bone. Next, osteoclasts are replaced by osteoblasts that gradually refill this space. This balance between bone formation and bone resorption is altered in most metabolic bone diseases (uncoupling). Over the past two decades many investigators have attempted to develop both sensitive and specific assays for the noninvasive assessment of bone turnover. Biochemical markers of bone formation include total and bone-specific alkaline phosphatase, serum osteocalcin (bone gla protein), and more recently procollagen I extension peptides. During the extracellular processing of type I collagen, there is a cleavage of the aminoterminal (p-coll-I-N) and carboxyterminal (p-coll-I-C) extension peptides prior to fibril formation. These peptides circulate in blood and could be useful markers of bone formation.

Alkaline Phosphatase↗
PubMed1995

Epidermal growth factor receptor ectodomain in the urine of patients with squamous cell carcinoma.

In this study we determined the levels of the epidermal growth factor receptor (EGFR) in the urine of patients with squamous cell carcinoma compared to levels in the urine of normal volunteers and patients with nonsquamous cell carcinoma. A 24-h urine specimen was collected from 50 normal volunteers, 50 patients with nonsquamous cell carcinoma, and 42 patients with squamous cell carcinoma. An ELISA using mAbs to the external domain of the EGFR was used to measure levels of the receptor in the urine samples. Measurement of the EGFR ectodomain in the 24-h urine specimens showed detectable levels in 15 (36%) of 42 squamous cell carcinoma patients compared to 3 (6%) of 50 controls and 8 (16%) of 50 nonsquamous patients. It was also observed that 10 (53%) of 19 patients with metastatic squamous cell carcinoma had detectable EGFR ectodomain levels compared to 5 (22%) of 23 squamous cell patients with localized disease. Thus, we concluded that the EGFR ectodomain was detectable in the urine in a significantly higher number of patients with squamous cell carcinoma than normal volunteers or patients with nonsquamous cell carcinoma.

3T3 Cells↗
PubMed1994

Intravenous pamidronate disodium treatment of bone metastases in patients with breast cancer. A dose-seeking study.

BACKGROUND: Treatment of the symptoms of bone metastases currently involves the use of narcotic medication, radiation therapy, or hormonal therapy. Pamidronate disodium, a bisphosphonate, may prove helpful in the palliative treatment of bone metastases in patients with breast cancer as demonstrated in this multicenter, dose-ranging trial. METHODS: Ambulatory female patients age 18 years or older with breast cancer metastatic to bone and a life expectancy of at least 3 months were eligible for the study. Bone metastases were confirmed by bone scan or bone survey within 6 months of enrollment. Sixty-one patients were treated as outpatients and were randomized to receive one of four intravenous pamidronate regimens for 12 weeks: 30 mg administered every 2 weeks, 60 mg every 4 weeks, 60 mg every 2 weeks, or 90 mg every 4 weeks. The primary efficacy parameter for this study was pain score. The change from baseline in pain score was determined for each patient at each study visit and at endpoint, defined as the last postbaseline evaluation for each patient before or at week 12. Secondary efficacy variables included narcotic scores, urinary calcium/creatinine and hydroxyproline/creatinine ratios, serum osteocalcin and bone alkaline phosphatase concentrations, and bone lesion (radiologic) response. RESULTS: At 3 months, the regimens of 60 mg every 4 weeks, 60 mg every 2 weeks, and 90 mg every 4 weeks resulted in significant reduction in bone pain beginning by week 6 of treatment. The regimen of 30 mg every 2 weeks was not effective. Narcotic use, as reflected by narcotic scores, did not parallel the pain scores, because there was little evidence of any effect for any of the treatment groups. Reduction in bone pain was accompanied by decreases in urinary calcium/creatinine and hydroxyproline/creatinine ratios, and bone alkaline phosphatase concentrations. Side effects of pamidronate were mild and transient. Radiographic changes consistent with healing of lytic lesions were observed in 15 patients (25%). CONCLUSION: Intravenous pamidronate is a well tolerated treatment that produced significant relief of bone pain in the majority of patients with metastatic breast cancer at the three highest doses tested.

Adolescent↗