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Biomedical subjects

T J Smith

Publications and source records attributed to T J Smith.

At least 127 records · Page 7Linked to original sources
PubMed1999

A rural cancer outreach program lowers patient care costs and benefits both the rural hospitals and sponsoring academic medical center.

The Rural Cancer Outreach Program (RCOP) between two rural hospitals and the Medical College of Virginia's Massey Cancer Center (MCC) was developed to bring state-of-the-art cancer care to medically underserved rural patients. The financial impact of the RCOP on both the rural hospitals and the MCC was analyzed. Pre- and post-RCOP financial data were collected on 1,745 cancer patients treated at the participating centers, two rural community hospitals and the MCC. The main outcome measures were costs (estimated reimbursement from all sources), revenues, contribution margins and profit (or loss) of the program. The RCOP may have enhanced access to cancer care for rural patients at less cost to society. The net annual cost per patient fell from $10,233 to $3,862 associated with more use of outpatient services, more efficient use of resources, and the shift to a less expensive locus of care. The cost for each rural patient admitted to the Medical College of Virginia fell by more than 40 percent compared with only an 8 percent decrease for all other cancer patients. The rural hospitals experienced rapid growth of their programs to more than 200 new patients yearly, and the RCOP generated significant profits for them. MCC benefited from increased referrals from RCOP service areas by 330 percent for cancer patients and by 9 percent for non-cancer patients during the same time period. While it did not generate a major profit for the MCC, the RCOP generated enough revenue to cover costs of the program. The RCOP had a positive financial impact on the rural and academic medical center hospitals, provided state-of-the-art care near home for rural patients and was associated with lower overall cancer treatment costs.

Academic Medical Centers↗
PubMed1999

Improved method to measure urinary alkoxyacetic acids.

OBJECTIVES: To simplify the current preparation of samples, and to improve the specificity and reliability of the conventional analytical methods to measure urinary alkoxyacetic acids. METHODS: Samples containing alkoxyacetic acids including methoxy, ethoxy, and butoxyacetic acids (MAA, EAA, and BAA) were acidified with HCl and extracted with a mixed solvent of methylene chloride and isopropyl alcohol, then analysed by gas chromatography/mass spectrometry (GC/MS). RESULTS: Optimal results were obtained when pH was 1.05-1.45, the ratio of methylene chloride and isopropyl alcohol was 2:1, and when extraction time was 10 minutes. Over the concentration range 0.3-200 micrograms/ml, MAA, EAA, and BAA could be determined with a pooled coefficient of variation (nine concentrations, six replicate samples) of 5.55%, 6.37%, and 6.41%, respectively. Urine samples were stable for at least 5 months and 3 freeze-thaw cycles at -20 degrees C. The limits of detection of MAA, EAA, and BAA were 0.055, 0.183, and 0.009 microgram/ml, respectively. The matrix effect of urine samples was negligible for MAA and EAA, but were marginally significant for BAA. The average recoveries of alkoxyacetic acids were 99%-101%. In urine samples MAA from 15 exposed workers showed a strong linear correlation (r = 0.999, slope = 1.01) between the new GC/MS method and Sakai's GC method. CONCLUSIONS: The simplified non-derivatisation pretreatment of samples coupled with GC/MS can provide a specific, sensitive, simple, safe, and reliable method for the biological monitoring of occupational exposure of ethylene glycol ethers.

Acetates↗
PubMed1999

Leukoregulin upregulation of prostaglandin endoperoxide H synthase-2 expression in human orbital fibroblasts.

Human orbital fibroblasts from patients with severe thyroid-associated ophthalmopathy are particularly susceptible to the actions of a variety of proinflammatory molecules. In this study, we demonstrate that the inductions of prostaglandin endoperoxide H synthase-2 (PGHS-2), interleukin (IL)-1alpha, and IL-1beta by leukoregulin, a product of activated T lymphocytes, are far more robust in orbital fibroblasts than those observed in dermal fibroblasts. These actions of leukoregulin are mediated through an intermediate induction of IL-1alpha. In contrast, leukoregulin also induces IL-1-receptor antagonist (IL-1ra) expression in orbital fibroblasts, but this induction is considerably greater in dermal fibroblasts (2.3- vs. 8.5-fold). Interrupting the effects of IL-1alpha, either with a neutralizing antibody or with exogenous IL-1ra, can block the induction of PGHS-2 by leukoregulin. Leukoregulin increases PGHS-2 gene transcription in orbital fibroblasts but exerts the major effect on cyclooxygenase expression by enhancing the stability of mature PGHS-2 mRNA. The cytokine triggers nuclear translocation of nuclear factor-kappaB (NF-kappaB) p50/p50 homodimers and p50/p65 heterodimers, and an inhibitor of this transcriptional factor, pyrrolidinedithiocarbamate, can attenuate the PGHS-2 induction. Thus differential inducibility of the members of the IL-1 family of genes in orbital fibroblasts would appear to underlie, at least in part, the differences in PGHS-2 induction observed in orbital and dermal fibroblasts. NF-kappaB plays an important role in mediating the effects of leukoregulin on PGHS-2 expression.

Anti-Inflammatory Agents↗
PubMed1999

Use of hematopoietic colony-stimulating factors: comparison of the 1994 and 1997 American Society of Clinical Oncology surveys regarding ASCO clinical practice guidelines. Health Services Research Committee of the American Society of Clinical Oncology.

PURPOSE: The American Society of Clinical Oncology (ASCO) Health Services Research Committee sought to assess whether more appropriate patterns of colony-stimulating factor (CSF) use occurred after the publication of ASCO evidence-based practice guidelines in 1994 and 1996 for patients with solid tumors or lymphoma. METHODS: In 1994 and 1997, questionnaires describing clinical scenarios were mailed to ASCO members who practiced medical oncology. Physicians were asked the extent to which they preferred to use a CSF for primary prophylaxis, secondary prophylaxis, or treatment of neutropenic complications. Multiple regression analyses were used to determine predictors of overall propensity to use CSFs and, when using a CSF, propensity to support longer schedules of CSF use. RESULTS: Decreased use of CSFs was shown in the following situations: (1) treatment for febrile neutropenia without localizing signs (39% in 1994 v 29% in 1997) or with a right lower lobe infiltrate (54% v 46%); (2) primary prophylaxis with paclitaxel for ovarian cancer (20% v 11%) or cyclophosphamide, doxorubicin, and vincristine chemotherapy for small-cell lung cancer (8.4% v 4.6%); and (3) secondary prophylaxis after afebrile neutropenia following chemotherapy for germ cell tumors (44.5% v 36.0%). One third fewer physicians supported the extended use of CSFs until an absolute neutrophil count >/= 10,000/mm(3) or a WBC count >/= 10,000/mm(3) was reached, both counts serving as criteria for stopping CSF therapy. However, we observed high rates of CSF use despite ASCO guideline recommendations against use in the following clinical situations: (1) primary prophylaxis in patients at low risk of febrile neutropenia (6% v 16%); (2) secondary prophylaxis late in the course of curative and palliative therapy (80% v 53%); and (3) treatment of afebrile and uncomplicated febrile neutropenia (30% v 60%). In 1994 and 1997, fee-for-service physicians were more likely than other physicians to prefer use of CSF support while maintaining treatment dose and schedule instead of using dose-reduction strategies, and, when using a CSF, they were more likely to support longer CSF treatment schedules (P <.05 for both scenarios). CONCLUSION: Decreased use and more appropriate use of CSFs in accordance with ASCO guideline recommendations occurred from 1994 to 1997, but there remain many opportunities to reduce CSF use with no clinical harm. Many oncologists continue to support the use of CSFs in scenarios and with scheduling criteria that the guidelines and evidence do not support. ASCO's evidence-based guidelines should be linked with formal continuous quality improvement initiatives to substantially improve the quality of supportive oncology care.

Hematopoietic Stem Cells↗
PubMed1999

American Society of Clinical Oncology 1998 update of recommended breast cancer surveillance guidelines.

OBJECTIVE: To determine an effective, evidence-based, postoperative surveillance strategy for the detection and treatment of recurrent breast cancer. Tests are recommended only if they have an impact on the outcomes specified by American Society of Clinical Oncology (ASCO) for clinical practice guidelines. POTENTIAL INTERVENTION: All tests described in the literature for postoperative monitoring were considered. In addition, the data were critically evaluated to determine the optimal frequency of monitoring. OUTCOME: Outcomes of interest include overall and disease-free survival, quality of life, toxicity reduction, and secondarily cost-effectiveness. EVIDENCE: A search was performed to determine all relevant articles published over the past 20 years on the efficacy of surveillance testing for breast cancer recurrence. These publications comprised both retrospective and prospective studies. VALUES: Levels of evidence and guideline grades were rated by a standard process. More weight was given to studies that tested a hypothesis directly relating testing to one of the primary outcomes in a randomized design. BENEFITS, HARMS, AND COSTS: The possible consequences of false-positive and -negative tests were considered in evaluating a preference for one of two tests providing similar information. Cost alone was not a determining factor. RECOMMENDATIONS: The attached guidelines and text summarize the updated recommendations of the ASCO breast cancer expert panel. Data are sufficient to recommend monthly breast self-examination, annual mammography of the preserved and contralateral breast, and a careful history and physical examination every 3 to 6 months for 3 years, then every 6 to 12 months for 2 years, then annually. Data are not sufficient to recommend routine bone scans, chest radiographs, hematologic blood counts, tumor markers (carcinoembryonic antigen, cancer antigen [CA] 15-5, and CA 27.29), liver ultrasonograms, or computed tomography scans. VALIDATION: The recommendations of the breast cancer expert panel were evaluated and supported by the ASCO Health Services Research Committee reviewers and the ASCO Board of Directors.

Breast Neoplasms↗
PubMed1999

Recommended colorectal cancer surveillance guidelines by the American Society of Clinical Oncology.

OBJECTIVE: To determine the most effective, evidence-based, postoperative surveillance strategy for the detection of recurrent colon and rectal cancer. Tests are to be recommended only if they have an impact on the outcomes listed below. POTENTIAL INTERVENTION: All tests described in the literature for postoperative monitoring were considered. In addition, the data were critically evaluated to determine the optimal frequency of monitoring. OUTCOMES: Outcomes of interest included overall and disease-free survival, quality of life, toxicity reduction, and cost-effectiveness. The American Society of Clinical Oncology (ASCO) Colorectal Cancer Surveillance Expert Panel was guided by the principle of cost minimization, ie, when two strategies were believed to be equally effective, the least expensive test was recommended. EVIDENCE: A complete MEDLINE search was performed of the past 20 years of the medical literature. Keywords included colorectal cancer, follow-up, and carcinoembryonic antigen, as well as the names of the specific tests. The search was broadened by articles from the tumor marker ASCO panel literature search, as well as from bibliographies of selected articles. VALUES: Levels of evidence and guideline grades were rated by a standard process. More weight was given to studies that tested a hypothesis directly relating testing to one of the primary outcomes in a randomized design. BENEFITS/HARMS/COSTS: The possible consequences of false-positive and false-negative tests were considered in evaluating a preference for one of two tests that provide similar information. Cost alone was not a determining factor. RECOMMENDATIONS: The expert panel's recommended postoperative monitoring schema is discussed in this article. VALIDATION: Five outside reviewers, the ASCO Health Services Research Committee, and the ASCO Board of Directors examined this document. SPONSOR: American Society of Clinical Oncology.

Colorectal Neoplasms↗
PubMed1999

HMC-1 mast cells activate human orbital fibroblasts in coculture: evidence for up-regulation of prostaglandin E2 and hyaluronan synthesis.

The purpose of this study was to determine the effects of mast cell coculture on human orbital fibroblasts. Thyroid-associated ophthalmopathy is characterized by infiltration of lymphocytes and mast cells and connective tissue activation in the orbit, leading to a disordered accumulation of hyaluronan and intense inflammation. Here, we report that HMC-1, an established human mast cell line, can activate human orbital fibroblasts to produce increased levels of prostaglandin E2 (PGE2) and hyaluronan when cocultured. HMC-1 cells up-regulate, in these fibroblasts, the expression of PG endoperoxide H synthase-2 (EC 1.14.99.1, PGHS-2), the inflammatory cyclooxygenase. This induction, at a pretranslational level, underlies the increase in PGE2 synthesis. The up-regulation can be attenuated with dexamethasone (10 nM), and the increase in PGE2 production can be inhibited by SC 58125, a specific PGHS-2 inhibitor. Moreover, anti-interleukin-4 receptor antibodies can block prostanoid production in the fibroblasts elicited by HMC-1 cells, suggesting that this cytokine might represent a molecular conduit for mast cell/fibroblast cross-talk. HMC-1 cells also increased hyaluronan synthesis, as was evidenced by a 2-fold increase in [3H]glucosamine incorporation into the macromolecule. To our knowledge, these findings are the first demonstrating the ability of mast cells to activate orbital fibroblasts, and the findings suggest a potential role for these cell-cell interactions in the pathogenesis of thyroid-associated ophthalmopathy.

Cell Line↗
PubMed1999

Expression of hyaluronan synthase messenger ribonucleic acids and their induction by interleukin-1beta in human orbital fibroblasts: potential insight into the molecular pathogenesis of thyroid-associated ophthalmopathy.

The disordered accumulation of hyaluronan, a nonsulfated glycosaminoglycan, is a hallmark feature of the tissue remodeling observed in thyroid-associated ophthalmopathy (TAO). Orbital fibroblasts have been shown to exhibit substantial up-regulation of hyaluronan synthesis when activated with proinflammatory cytokines such as interleukin-1beta (IL-1beta). Recently, three members of the hyaluronan synthase (HAS) gene family were cloned. Here we report that IL-1beta can dramatically and consistently induce in orbital fibroblasts the expression of HAS2 in the five orbital strains examined. HAS3 messenger ribonucleic acid (mRNA) was also detectable in all these strains by RT-PCR under both control and IL-1beta-treated conditions. In contrast, HAS1 mRNA was detected by Northern blot analysis in only one of the strains treated with IL-1beta, but in three of five strains examined by RT-PCR. These HAS inductions by the cytokine were time dependent and could be attenuated with dexamethasone and cycloheximide. They were accompanied by an increased incorporation of [3H]glucosamine into hyaluronan, and dexamethasone could attenuate induction of macromolecular synthesis as well. Our observations suggest that the cytokine-dependent induction of the HAS genes in orbital fibroblasts may be the molecular basis at least in part for the increased accumulation of hyaluronan, driven by immunocompetent cells, in orbital connective tissue and the extraocular muscles in TAO.

Blotting, Northern↗
PubMed1999

A sociodemographic and economic comparison of breast reconstruction, mastectomy, and conservative surgery.

BACKGROUND: There are a variety of surgical choices for women with early-stage breast cancer, including breast-conserving surgery, mastectomy, or mastectomy plus reconstructive surgery. This report examines some of the factors that affect these choices and the costs of the various treatment options. METHODS: Data from the Virginia Cancer Registry were linked to insurance claims from the Trigon Blue Cross and Blue Shield Company for women with local and regional staged breast cancer from 1989 to 1991 in Virginia. Multivariate analyses and cost studies were performed. RESULTS: There were 592 women who underwent breast-conserving surgery (BCS, 26%), mastectomy (58%), or mastectomy plus reconstruction (16%). Increasing age reduced the use of reconstruction. The choice of reconstruction was not affected by tumor size, nodal status, or race. Sixty percent of women had immediate breast reconstruction at the time of mastectomy; the majority had the implant procedure. The cost of BCS ($21,582) was higher than that of mastectomy ($16,122, P < .01). The costs for BCS and mastectomy were significantly lower than for mastectomy plus reconstruction ($31,047, P < .05). The 2-year cost for immediate reconstruction was $8200 less than for delayed procedures and was similar to the cost of BCS. CONCLUSIONS: Age was the driving force in reconstruction decisions. Clinical factors such as tumor size and nodal status were more important for the choice between BCS and mastectomy. There are significant cost differences between the various procedures. For a similar cosmetic outcome, BCS is less expensive than breast reconstruction. When reconstruction is required, a simultaneous procedure is less expensive.

Blue Cross Blue Shield Insurance Plans↗
PubMed1999

Transformation of an acetaminophen toxicity nomogram to an artificial neural network.

A computerized artificial neural network was built based on the Rumack-Matthew nomogram for treatment of acetaminophen toxicity. NeuralWorks Predict 1.0 was used to build the network. The training set consisted of two input parameters, plasma concentration (microg/ml) and time of ingestion, and an output. The output was a binary unit representing the recommended use of N-acetylcysteine for the prevention of acetaminophen hepatotoxicity. The predictions made by the neural network correlated well with the expected values (95%). Since these networks can be modified with additional data, the present network may be useful for optimizing the use of N-acetylcysteine for the prevention of acetaminophen hepatotoxicity.

Acetaminophen↗
PubMed1998

Assessment of rapid morphological changes associated with elevated cAMP levels in human orbital fibroblasts.

Orbital fibroblasts exhibit a phenotype distinct from that of other types of fibroblasts. Addition of prostaglandin E2 (PGE2) to culture medium elicits a dramatic change in orbital fibroblast morphology. That response is mediated through the generation of cAMP. Orbital fibroblasts can generate high levels of PGE2 through induction by proinflammatory cytokines of prostaglandin endoperoxide H synthase-2 (PGHS-2). Here we compare the influence on fibroblast morphology of exogenous PGE2, forskolin, and 8-br-cAMP to that mediated through PGHS-2 induction by a lymphocyte-derived cytokine. Within a few hours, orbital fibroblasts treated with any of these test compounds appear under phase-contrast microscopy to exhibit a stellate morphology. When these changes were assessed quantitatively by electric cell-substrate impedance sensing (ECIS), it became evident that 8-br-cAMP, forskolin, and PGE2 initiated shape changes within 30 min of addition to the culture medium, while effects of the cytokine were first evident after approximately 3.5 h. Dermal fibroblasts failed to respond to any of these compounds with regard to changes in cellular morphology. Analysis of micromotion, manifested as small impedance fluctuations, revealed that orbital fibroblasts treated with 8-br-cAMP exhibit less motion than did untreated cells. These results suggest that orbital fibroblast shape can be altered by several compounds known to alter intracellular cAMP levels. They demonstrate the utility of ECIS in the assessment of very rapid and dynamic cellular events associated with changes in cell morphology.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1998

Activation of human orbital fibroblasts through CD40 engagement results in a dramatic induction of hyaluronan synthesis and prostaglandin endoperoxide H synthase-2 expression. Insights into potential pathogenic mechanisms of thyroid-associated ophthalmopathy.

Human orbital fibroblasts play a putative role in the pathogenesis of thyroid-associated ophthalmopathy (TAO). We hypothesize that the hyaluronan accumulation and inflammation in TAO derive from enhanced biosynthetic activities of orbital fibroblasts. CD40, a member of the tumor necrosis factor-alpha receptor superfamily, is a critical signaling molecule expressed by B lymphocytes. Engagement of CD40 with CD154 or CD40 ligand results in the activation of target genes. Orbital fibroblasts also display CD40. Here we report that CD40 engagement leads to substantial increases in hyaluronan synthesis in orbital fibroblasts. The increase is approximately 5-fold above control values, is comparable to the induction elicited by IL-1beta and could be attenuated with dexamethasone but not by SC 58125, a prostaglandin endoperoxide H synthase-2 (PGHS-2)-selective inhibitor. PGHS-2 is also induced by CD40 engagement in a time-dependent manner, and this is mediated through increases in levels of steady-state mRNA. The induction of PGHS-2 leads to a dramatically enhanced prostaglandin E2 production that can be blocked by SC 58125 and dexamethasone. CD40 ligand up-regulates the synthesis of IL-1alpha, and blocking this cytokine with exogenous IL-1 receptor antagonist (IL-1ra) or with IL-1alpha neutralizing antibodies partially attenuates the induction of PGHS-2. In contrast, CD40 ligand up-regulation of hyaluronan synthesis is unaffected by IL-1ra. CD40 cross-linking enhances mitogen-activated protein kinase activation, and interrupting this pathway attenuates the PGHS-2 induction. Thus the CD40/CD40 ligand bridge represents a potentially important activational pathway for orbital fibroblasts that may underlie the cross-talk between these cells and leukocytes. These findings may be relevant to the pathogenesis of TAO and provide insights into previously unrecognized, potential therapeutic targets.

CD40 Antigens↗
PubMed1998

A comparison of patterns of care of nonsmall cell lung carcinoma patients in a younger and Medigap commercially insured cohort.

BACKGROUND: The objective of this study was to examine and compare lifetime treatment patterns and hospitalization of incident nonsmall cell lung carcinoma (NSCLC) between pre-Medicare eligible (age < 65 years) and supplemental Medigap (age > or = 65 years) enrollees in a commercially insured cohort using insurance claims. METHODS: Claims from Virginia Blue Cross and Blue Shield beneficiaries with NSCLC submitted between 1989-1991 were merged with records from the Virginia Cancer Registry (VCR). Data from the VCR identified incident cases, disease stage, and type of tumor. Initial treatment categories were stratified using Physicians' Current Procedural Terminology codes. RESULTS: There were 1706 incident NSCLC patients; 349 were age < or = 64 years ("younger") and 1212 were age > or = 65 years ("elderly"). Having commercial insurance was not associated with any survival advantage compared with national averages at 2 years. In comparison with elderly patients, younger patients more often were treated with surgery for local disease (80.2% vs. 54.8%) and surgery alone or in combination with radiation for regional disease (51.9% vs. 32.0%). Radiation was used more often in elderly patients compared with younger patients with local disease (30.5% vs. 14.0%) but less often in patients with distant disease (76.2% vs. 54.9%). Compared with elderly patients, younger patients presenting with distant disease received more chemotherapy (18.8% vs. 5.1%; P <0.001); late palliative use of chemotherapy or radiation occurred in only 4-8% of younger patients. Compared with elderly patients, younger patients with regional or distant disease spent more days in the hospital (compared with national averages at 2 years: regional disease, 30.0 vs. 23.9 days; distant disease, 33.0 vs. 21.4 days; P <0.0001). CONCLUSIONS: The results of this study show that more comprehensive health insurance is not associated with better outcomes in patients with NSCLC. Age specific trends for greater use of surgery, radiation, and total hospitalization in younger patients is consistent with other reports. Commercial health care claims supplemented by clinical staging from cancer registries can address long term practice patterns in patients with cancer.

Aged↗
PubMed1998

Molecular cloning and characterization of the human and mouse UDP-glucose dehydrogenase genes.

The enzyme UDP-glucose dehydrogenase (Udpgdh) (EC 1.1.1.22) converts UDP-glucose to UDP-glucuronate, a critical component of the glycosaminoglycans, hyaluronan, chondroitin sulfate, and heparan sulfate. Although Udpgdh is a comparatively well characterized enzyme, no vertebrate genes encoding this enzyme have been reported to date. We report the cloning and characterization of the human and mouse UDP-glucose dehydrogenase genes. Mouse and human cDNAs predicted proteins of 493 and 494 amino acids, 24-25 residues longer at their carboxyl termini than the previously reported bovine Udpgdh sequence. The mouse Ugdh gene is composed of 10 exons, spanning 15 kilobases. Northern analyses indicated widespread expression of the gene in embryo and adult. Through interspecific backcross analyses, we localized the Ugdh gene to mouse chromosome 5 at approximately 39 centimorgans, suggesting that the human UGDH gene is localized to chromosome 4p13-15. Results from Southern analyses strongly suggest that Udpgdh is encoded by a single gene in the mouse. Transfection of mouse Ugdh expression vectors led to an increase in detectable Udpgdh activity in mammalian cells. Preliminary expression studies indicated that proinflammatory cytokines, such as interleukin 1beta, can substantially increase the expression of human UGDH in cultured human fibroblasts, suggesting that glycosaminoglycan biosynthesis may be partly regulated by the availability of activated UDP-glucuronate, as determined by relative Udpgdh expression levels.

Amino Acid Sequence↗
PubMed1998

Combined chemoradiotherapy vs. radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of the Eastern Cooperative Oncology Group.

Squamous carcinoma of the thoracic esophagus has an extremely poor prognosis. This study, EST-1282, was undertaken by the Eastern Cooperative Oncology Group (ECOG) to determine whether the combined use of 5-fluorouracil (5-FU), mitomycin C, and radiation therapy improved the disease-free survival and overall survival of patients with carcinoma of the esophagus, compared to those who received radiation therapy alone. Two- and 5-year survivals were 12% and 7% in the radiation alone arm and 27% and 9% in the chemoradiation arm. Patients treated with chemoradiation had a longer median survival (14.8 months), compared to patients receiving radiation therapy alone (9.2 months). This difference was statistically significant. The same pattern of survival was noted in almost all subgroups independent of whether surgical resection was performed.

Analysis of Variance↗
PubMed1998

Amino acids and peptides. XXXIII. A bifunctional poly(ethylene glycol) hybrid of laminin-related peptides.

A novel amino acid type poly(ethylene glycol) (aaPEG) was prepared and its application as a drug-carrier was examined. The peptides, Pro-Asp-Ser-Gly-Arg (PDSGR) and Tyr-Ile-Gly-Ser-Arg (YIGSR) which are active fragments of Laminin (a cell adhesion protein), were previously reported to be inhibitors of experimental metastasis. Both peptides were conjugated with aaPEG (average molecular weight, 3,000) to prepare a bifunctional peptide-PEG hybrid. The hybrid, PDSGR-aaPEG-YIGSR, was manually prepared by the solid-phase fluorenylmethyloxycarbonyl (Fmoc) strategy. The antimetastatic activity of the peptides in mice was not lost when conjugated to form a larger aaPEG molecule. YIGSR(375 nmol) and PDSGR (375 nmol and 750 nmol) did not demonstrate antimetastatic activity, but a mixture of PDSGR (187 nnmol) and YIGSR (187 nmol) exhibited an inhibitory effect. The inhibitory effect of the hybrid (187 nmol) was more potent than that of the mixture (PDSGR and YIGSR), indicating that the inhibitory effect of the peptides was potentiated by hybrid formation with aaPEG.

Animals↗