PubMed Health⌕ Search

Biomedical subjects

J Dell

Publications and source records attributed to J Dell.

At least 19 recordsLinked to original sources
PubMed1999

Effects of SCH 59228, an orally bioavailable farnesyl protein transferase inhibitor, on the growth of oncogene-transformed fibroblasts and a human colon carcinoma xenograft in nude mice.

The products of the Ha-, Ki-, and N-ras proto-oncogenes comprise a family of 21 kDa guanine nucleotide-binding proteins which play a crucial role in growth factor signal transduction and in the control of cellular proliferation and differentiation. Activating mutations in the ras oncogenes occur in a wide variety of human tumors. Ras proteins undergo a series of posttranslational processing events. The first modification is addition of the 15-carbon isoprene, farnesyl, to a Cys residue near the carboxy-terminus of Ras. Prenylation allows the Ras oncoprotein to localize to the plasma membrane where it can initiate downstream signalling events leading to cellular transformation. Inhibitors of the enzyme which catalyzes this step, farnesyl protein transferase (FPT), are a potential class of novel anticancer drugs which interfere with Ras function. SCH 59228 is a tricyclic FPT inhibitor which inhibits the farnesylation of purified Ha-Ras with an IC50 of 95 nM and blocks the processing of Ha-Ras in Cos cells with an IC50 of 0.6 microM. SCH 59228 has favorable pharmacokinetic properties upon oral dosing in nude mice. The in vivo efficacy of SCH 59228 was evaluated using a panel of tumor models grown in nude mice. These included several rodent fibroblast lines expressing mutationally-activated (val12) forms of the Ha-Ras oncogene. In some cases, these proteins contain their native C-terminal sequence (CVLS) which directs farnesylation. In one model, the C-terminal sequence was altered to CVLL, making the expressed protein a substrate for a distinct prenyl transferase, geranylgeranyl protein transferase-1. When dosed orally at 10 and 50 mg/kg (four times a day, 7 days a week) SCH 59228 significantly inhibited tumor growth of cells expressing farnesylated Ha-Ras in a dose-dependent manner; over 90% growth inhibition was observed at the 50 mg/kg dose. Tumor growth of cells expressing the geranylgeranylated form of Ha-Ras was less potently inhibited. Growth of tumors derived from a rodent fibroblast line expressing activated Ki-Ras containing its native C-terminal sequence (CVIM), which preferentially directs farnesylation, was also inhibited by SCH 59228. Inhibition in the Ki-Ras model was less than that observed in the Ha-Ras model. In contrast, tumors derived from cells transformed with the mos oncogene were not significantly inhibited even at the highest dose level. SCH 59228 also significantly and dose-dependently inhibited the growth of human colon adenocarcinoma DLD-1 xenografts (which express activated Ki-ras). These results indicate that SCH 59228 possesses in vivo antitumor activity upon oral dosing in tumor models expressing activated ras oncogenes. This is the first report of oral antitumor activity with an FPT inhibitor. These results are discussed in light of recent observations on alternative prenylation of some Ras isoforms.

Alkyl and Aryl Transferases↗
PubMed1999

Adenovirus-mediated p53 gene therapy has greater efficacy when combined with chemotherapy against human head and neck, ovarian, prostate, and breast cancer.

PURPOSE: Adenovirus-mediated p53 gene therapy for cancer is currently undergoing phase I/II clinical trials. The drug used in our clinical trials (p53 Ad; ACN53; SCH58500) consists of a replication-deficient, type 5 adenovirus vector expressing human wildtype p53 tumor suppressor under the control of the cytomegalovirus promoter. In preclinical models, p53 Ad has therapeutic efficacy against a wide range of human tumor types containing nonfunctional p53, both in vitro and in vivo. Results from early clinical trials using p53 gene therapy by itself support optimism for the future of this therapeutic approach. However, it is likely that many phase II/III trials will incorporate an arm comparing traditional chemotherapy against chemotherapy combined with p53 gene therapy. Therefore, it is important to study possible interactions between p53 Ad and chemotherapeutic drugs in preclinical models before starting the clinical trials. METHODS: Proliferation of tumor cells was quantitated after incubation with various combinations of p53 Ad and chemotherapeutic drugs. Human tumor xenografts in scid mice were dosed with intraperitoneal or intratumoral p53 Ad with or without chemotherapeutic drugs and the tumor burden after therapy monitored. RESULTS: p53 Ad combined with cisplatin, doxorubicin, 5-fluorouracil, methotrexate, or etoposide inhibited cell proliferation more effectively than chemotherapy alone in SCC-9 head and neck, SCC-15 head and neck, SCC-25 head and neck, SK-OV-3 ovarian, DU-145 prostate, MDA-MB-468 breast, and MDA-MB-231 breast tumor cells. No obvious dependence on dosing schedule was observed. Greater anticancer efficacy was also demonstrated in four human tumor xenograft models in vivo. Of particular significance, there was enhanced efficacy using the three drug combination of p53 Ad, cisplatin, and paclitaxel in an ovarian cancer model. CONCLUSION: These results support the combination of p53 gene therapy with chemotherapy in clinical trials.

Adenoviridae↗
PubMed1998

Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice.

We have been developing a series of nonpeptidic, small molecule farnesyl protein transferase inhibitors that share a common tricyclic nucleus and compete with peptide/protein substrates for binding to farnesyl protein transferase. Here, we report on pharmacological and in vivo studies with SCH 66336, a lead compound in this structural class. SCH 66336 potently inhibits Ha-Ras processing in whole cells and blocks the transformed growth properties of fibroblasts and human tumor cell lines expressing activated Ki-Ras proteins. The anchorage-independent growth of many human tumor lines that lack an activated ras oncogene is also blocked by treatment with SCH 66336. In mouse, rat, and monkey systems, SCH 66336 has excellent oral bioavailability and pharmacokinetic properties. In the nude mouse, SCH 66336 demonstrated potent oral activity in a wide array of human tumor xenograft models including tumors of colon, lung, pancreas, prostate, and urinary bladder origin. Enhanced in vivo efficacy was observed when SCH 66336 was combined with various cytotoxic agents (cyclophosphamide, 5-fluorouracil, and vincristine). In a Ha-Ras transgenic mouse model, prophylactic treatment with SCH 66336 delayed tumor onset, reduced the average number of tumors/mouse, and reduced the average tumor weight/animal. In a therapeutic mode in which gavage treatment was initiated after the transgenic mice had developed palpable tumors, significant tumor regression was induced by SCH 66336 in a dose-dependent fashion. This was associated with increased apoptosis and decreased DNA synthesis in tumors of animals treated with SCH 66336. Enhanced efficacy was also observed in this model when SCH 66336 was combined with cyclophosphamide. SCH 66336 is presently being evaluated in Phase I clinical trials.

3T3 Cells↗
PubMed1998

Recombinant E1-deleted adenovirus-mediated gene therapy for cancer: efficacy studies with p53 tumor suppressor gene and liver histology in tumor xenograft models.

Type 5 adenoviral (Ad) vectors have been the "vector-of-choice" for preclinical studies on p53 tumor suppressor gene therapy of cancer. Previous studies have examined the in vivo efficacy of p53 Ad when given intratumorally. However published information does little to guide clinicians in the design of intraperitoneal (i.p.) dosing trials for i.p. tumors, e.g., ovarian, or clinical trials using regional organ perfusion, e.g., for lung tumors. Therefore, we examined several parameters with special significance for these routes of administration. Lung metastases from p53mut MDA-MB-231 mammary xenografts were treated with therapeutic levels of intravenous buffer, beta-galactosidase (beta-Gal) Ad, or p53 Ad. Treatment with intravenous p53 Ad significantly reduced the number of metastases per lung and there was a dramatic reduction in the surface area occupied by these tumors as compared to control groups. Two types of i.p. tumor xenografts were used for preclinical modeling of i.p. gene therapy, the p53null SK-OV-3 ovarian and the p53mut DU-145 prostate human cancers. In a study examining the effect of different vehicle volumes on the efficacy of a constant drug dose, all mice treated with p53 Ad had reduced tumor burden compared to controls. Dosing volumes between 0.2 and 1 ml were equally effective and all were more effective than a dosing volume of 0.1 ml. However, reduced efficacy was observed when a volume of 1.5 ml was used. When the effect of dosing frequency on antitumor efficacy was examined, fractionated doses of p53 Ad had somewhat greater efficacy than fewer, bolus injections. One of the significant elements in the emerging toxicology associated with recombinant adenoviruses is the hepatocyte pathology caused by high systemic concentrations of adenovirus. For recombinant Ad used in this study, there was a pronounced dose-dependence for the liver response, with very high, repeated doses causing significant hepatocellular insult. Expression of cytoplasmic beta-Gal protein coincided with areas of greatest damage in mice treated with high doses of beta-Gal Ad. Ultrastructural examination of hepatocyte intranuclear inclusions revealed moderately electron-dense, tightly packed granular material interspersed with more electron-dense nuclear material. Human tumor xenografts, but not mouse tissues, expressed viral hexon protein. In summary, hepatic toxicity caused by high concentrations of recombinant adenovirus was observed in murine cancer models. However, therapeutic levels of p53 Ad could be achieved which had dramatic efficacy without significant pathology.

Adenoviridae↗
PubMed1998

Inhibitors of farnesyl protein transferase. 4-Amido, 4-carbamoyl, and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]- cyclohepta[1,2-b]pyridin-11-yl)piperazine and 1-(3-bromo-8-chloro-6,11- dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperazine.

The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl) piperazine to explore the SAR of this series of FPT inhibitors is described. This resulted in the synthesis of the 4- and 3-pyridylacetyl analogues 45a and 50a, respectively, both of which were orally active but were found to be rapidly metabolized in vivo. Identification of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interesting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. Novel replacements for the pyridylacetyl moiety were also sought, and this resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopiperidinylacetyl derivatives 135a and 160a, respectively. All of these derivatives exhibited greatly improved pharmacokinetics. The synthesis of the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b (+/-) and 85b [11S(-)] and the 4-carboxamidopiperidinylacetamido derivative 160b (+/-), all of which exhibited potent FPT inhibition in vitro. All three showed excellent oral bioavailability in vivo in nude mice and cynomolgus monkeys and exhibited excellent antitumor efficacy against a series of tumor cell lines when dosed orally in nude mice.

3T3 Cells↗
PubMed1998

Adenovirus-mediated p53 gene therapy and paclitaxel have synergistic efficacy in models of human head and neck, ovarian, prostate, and breast cancer.

Synergy (or antagonism) between two chemical agents is an in vitro empirical phenomenon, in which the observed effect of the combination is more (or less) than what would be predicted from the effects of each agent working alone. Although mathematical synergy is not directly provable in the clinical setting, it does predict a favorable outcome when the two therapeutics are combined in vivo and strongly suggests the presence of in vivo synergy. In contrast, overt antagonism warns of future problems. Sophisticated three-dimensional statistical modeling was used to evaluate the presence of synergistic, additive, or antagonistic efficacy between adenovirus (Ad)-mediated p53 gene therapy (p53 Ad) and paclitaxel (Taxol) in a panel of human tumor cell lines. Cells were either pretreated with paclitaxel 24 h before p53 Ad or treated with both agents simultaneously. Cell proliferation was measured 3 days later. Paclitaxel had synergistic or additive efficacy with p53 gene therapy. In no case was the interaction antagonistic. Cell cycle analysis demonstrated that p53 Ad arrested cells in G0/G1 prior to apoptotic cell death, whereas paclitaxel arrested cells in G2-M prior to apoptotic cell death. When combined, the relative concentration of each agent determined the dominant cellular response. These results are consistent with the previously reported cell cycle effects of p53 or paclitaxel, respectively; however, these data fail to explain the observed drug synergy. We found that low concentrations of paclitaxel (1-14 nM) increased the number of cells transduced by recombinant Ad 3-35% in a dose-dependent manner, which is one possible mechanism for the observed synergy. Of particular note, the concentrations of paclitaxel responsible for increased Ad transduction were lower than the concentrations required for microtubule condensation. The efficacy of combination therapy was also evaluated in vivo. In the p53null SK-OV-3 xenograft model of ovarian cancer, a dosing schedule of p53 Ad that, by itself, had a relatively minimal effect on tumor burden (16%) caused a much greater decrease in tumor burden (55%) when combined with paclitaxel. Greater combined efficacy was also observed in the p53mut DU-145 prostate, p53mut MDA-MB-468 breast, and p53mut MDA-MB-231 breast cancer xenograft models in vivo. In summary, p53 Ad for cancer shows enhanced efficacy when combined with paclitaxel. This combination is recommended for clinical cancer trials.

Adenoviridae↗
PubMed1997

Structure-activity relationship of 3-substituted N-(pyridinylacetyl)-4- (8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene )- piperidine inhibitors of farnesyl-protein transferase: design and synthesis of in vivo active antitumor compounds.

Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure-activity relationship (SAR) study of compounds arising from substitution at the 3-position of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.

3T3 Cells↗
PubMed1996

Fetal startle response observed under ultrasonography: a good predictor of a reassuring biophysical profile.

OBJECTIVE: To correlate the vibroacoustic stimulus-evoked fetal startle response observed under ultrasonography with the subsequent biophysical profile (BPP) score. METHODS: Vibroacoustic stimulation was applied under ultrasound observation to gravidas who had a nonreactive fetal heart rate in the first 10 minutes of monitoring. Fetal startle response was defined as a sudden movement of fetal extremities in the 2 seconds following stimulus. Subsequently, nonstress testing was completed and a BPP performed on all women who required vibroacoustic stimulation. The presence or absence of a fetal startle response was compared with the observed BPP score. RESULTS: Two hundred tests were performed at 35.3 +/- 3.7 weeks. After the vibroacoustic stimulation, 70% of the nonreactive tracings became reactive. Mothers perceived the fetal startle response after vibroacoustic stimulus in 93% of cases. All cases with a fetal startle response after a vibroacoustic stimulation had a subsequent BPP score of 8 or more (negative predictive value of 100%). In addition, all patients with a nonreassuring BPP score were in the group of patients with absent fetal startle response. However, the positive predictive value of an absent fetal startle response for a subsequent BPP score of 6 or less was only 10%. CONCLUSION: This preliminary study suggests that the fetal startle response predicts a BPP score equal to or greater than 8. After the availability of larger studies supporting these findings, this test could be used as a rapid antepartum test to predict fetal well-being.

Acoustic Stimulation↗
PubMed1994

Adolescent onset psychosis. A clinical and outcome study.

58 psychotic adolescents between the ages of 12 and 17 diagnosed according to RDC criteria were matched with psychiatric comparisons and followed-up using a two stage design. Information upon the group as a whole was obtained using death records, criminal records and data from the Oxford Record Linkage System. A sub-sample of 21 matched pairs were interviewed using the Schedule for Affective Disorders and Schizophrenia--Life time version (SADS-L) and the Adult Personality Functioning Assessment (APFA). The outcome of adolescent schizophrenia was poor with 78% continuously ill and socially handicapped. Outcome was better for bipolar disorders and schizo-affective disorders and similar to psychiatric comparisons.

Adolescent↗
PubMed1993

Do chart reviews and interviews provide the same information about breast and cervical cancer screening?

The National Cancer Institute of the United States has set a goal for the year 2000 that 80-90% of eligible women should have a Pap smear every 3 years and that 80% of women aged 50-70 should receive an annual breast examination and mammogram. Very few studies have examined how we might best measure our progress towards this goal. Specifically, should we employ interview data or data derived from medical records? To respond to this question, data were gathered at two different public health clinics in poor areas of Chicago using both techniques. The interviews estimated significantly higher proportions of women receiving Pap smears, breast examinations, and mammograms in the previous 12-month interval than were estimated from randomly selected medical records. A review of the literature suggests the same pattern exists when other studies using these two data gathering processes are compared. We are thus left with a serious problem, one that must be resolved before we will be able to fully assess our progress in increasing breast and cervical cancer screening.

Aged↗
PubMed1991

Patterns of breast and cervical cancer screening at three public health centers in an inner-city urban area.

In an effort to examine breast and cervical cancer screening patterns among poor African-American urban women, medical records were abstracted at three public health centers located in the inner city of Chicago. The proportions of eligible women at these three centers who received Pap smears, breast examinations, and mammograms were computed. These proportions were notably low and differed significantly among the three centers. Because the literature is now suggesting that an appropriate sequence best defines adequate screening, sequences of screenings were also determined and were found to be lacking. All of these screening histories fall far below the screening objectives set by the National Cancer Institute for the year 2000. This information suggests that interventions are needed that will help health centers serving poor women to deliver more frequent cancer screening.

Black or African American↗
PubMed1988

The neurological, psychosocial and demographic correlates of hypergraphia in patients with epilepsy.

The multiaetiological determinants and correlates of interictal hypergraphia in patients with epilepsy were studied. A variety of neurological, psychosocial and demographic variables were examined in order to determine their relationship to experimental and clinically derived measures of hypergraphia in a sample of 50 patients with epilepsy. The results indicate that hypergraphia is of multifactorial origin in general, with especially strong relationships with measures of psychopathology. These results are related to the larger literature concerned with interictal behavioural change in patients with epilepsy.

Adult↗
PubMed1983

Seizures in relation to head injury.

Seizures have a two-fold relationship with head injury: they can cause a head injury, or they can be the result of a head injury. We compare these two groups in terms of cause, severity, likelihood of sequelae, outcome, radiological investigation, and surgical intervention. Of 702 patients admitted with a head injury to Cook County Hospital (CCH), 25 patients (3.6%) had seizures causing a head injury (Group 1). Another 29 patients (4.1%) experienced a head injury which caused a seizure (Group 2). The remaining 648 patients (Group 3) had no seizure involvement in relation to their injury. Group 1 and Group 3 were similar in terms of severity and sequelae. Group 2, in which a statistically significant increase in both was noted, was dramatically different. It thus appears that seizures indicate increased severity and sequelae in a head injury only when they result from that injury, and not when they cause it. The emergency physician must thus be prepared to distinguish these two situations, for patients in Group 2 have an increased need for neuroradiologic procedures and neurosurgical intervention.

Craniocerebral Trauma↗
PubMed1983

Seizures and civilian head injuries.

Although several studies have reported on the risk of "early seizures" (seizures occurring within 7 days following a head injury), the reported proportions of patients experiencing these seizures vary from 1.4 to 15%. This wide divergence may be due to problems with methodology such as case selection and definitions of head injury and early seizures. In a series of 702 patients admitted with a head injury to Cook County Hospital (CCH), Chicago, Illinois, 29 (4.1%) had early seizures. This proportion is twice as high as one previously reported in a comparable series. This may reflect an actual difference between the two series or a case selection bias serving to elevate the proportion of patients with early seizures at CCH.

Adolescent↗
PubMed1983

Urban head injury: a clinical series.

Consecutive head-injured patients admitted to Cook County Hospital in Chicago, Illinois, over a 12-month period were examined upon admission and discharge. Information was collected about the nature of the injury, symptoms, signs, and sequelae for 702 patients. Detailed descriptions of the causes of these injuries, and their correlates, were also obtained.Approximately 80 percent of the patients had localized pain, loss of consciousness and/or posttraumatic amnesia, and associated injuries; 16 percent had a skull fracture, 7.0 percent had an intracranial hematoma, 4.1 percent had early seizures, and 2.4 percent died.Skull x-ray examinations were performed on 93.4 percent of the patients (16.9 percent were positive) and radiographic examination of the cervical spine was performed on 67.2 percent (1.7 percent were positive). Utilization of EEGs, computerized tomography scans, and arteriograms was also assessed.Falls were the leading cause of injury (45.8 percent) for patients under 16 years of age and interpersonal injuries accounted for the majority (55.7 percent) of the injuries to adults. About 15 percent of the adults sustained severe or fatal injuries, compared with only 7 percent of the children.It is concluded that although this set of data suggests new considerations for the prevention of head injuries, the lack of comparative data about the medical correlates of these injuries inhibits similar observations about medical care.

Adolescent↗