The Howard University Cancer Center: a quarter century of excellence in cancer care and research (1972 to 1997).
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Cancer Care Facilities↗
Biomedical subjects
N Brooks
Publications and source records attributed to N Brooks.
Synthesis, DNA binding, cytotoxicity and sequence specificity of a series of imidazole-containing analogs of the benzoic acid mustard distamycin derivative tallimustine containing an alkylating group at the C-terminus.
In an attempt to produce additional alkylation and crosslinking in the minor groove of DNA, imidazole-containing analogs of distamycin were synthesized with benzoic acid mustard (BAM) and methoxyaziridinyl moieties present at the N- and C-termini, respectively. Analogs 1a-c differed in the number of methylene units (2-4 respectively) between the C-terminal carbonyl group and the methoxyaziridinyl moiety. DNA binding affinity to several polynucleotides decreased with increasing linker length, whereas DNA interstrand crosslinking ability, as measured by a plasmid gel based assay, increased. The in vitro cytotoxicity in human chronic myeloid leukemia K562 cells and the panel of human tumor cell lines at the National Cancer Institute decreased with increasing number of methylene units, and no increase in cytotoxicity was observed over compound AR-1-122 which did not contain the methoxyaziridinyl moiety. 1a-c had the same sequence selectivity of alkylation as AR-1-122, showing alkylation only at 5'-TTTTGPu sequences. The relative binding to these sequences decreased with increasing number of methylene units. The addition of a methoxyaziridinyl moiety in this group of imidazole and BAM-containing compounds can, therefore, increase crosslinking ability to naked DNA but this does not result in an increase in cytotoxicity. In contrast the cytotoxicity was related to their ability to produce sequence specific alkylation at 5'-TTTTGPu sequences.
Alkylating Agents↗
Pre-clinical development of the anti-tumour agent CB 7646, bis N-(hydroxymethyl) trimethylmelamine, a stable analogue of trimelamol.
Formulation difficulties prevented the otherwise promising clinical development of the anti-tumour agent trimelamol (TM; tris-[hydroxymethyl]trimethylmelamine]). A synthetic analogue programme resulted in the identification of CB 7646 (bis N-[hydroxymethyl]trimethylmelamine) as a compound with improved stability and favourable formulation characteristics. The in vitro and in vivo activity of CB 7646 was shown to be very similar to that of TM. In addition, curative activities were shown in the PXN/65 human ovarian cancer xenograft and the MX-1 and T-61 human breast cancer xenograft models. The effectiveness of the N-(hydroxymethyl)melamines against platinum-refractory disease was noted in the phase I clinical trial of TM. In line with this finding, the present study confirmed the effective activity of both TM and CB 7646 against various forms of platinum resistance in in vitro models. Curative activity for TM and CB 7646 was seen in the HX110P human ovarian cancer xenograft with acquired carboplatin resistance. Animal studies indicated less neurotoxicity for CB 7646 than for TM. The pharmacokinetic profile of CB 7646 indicated a decreased plasma elimination, indicative of slower in vivo degradation than for TM. CB 7646, therefore, represents a promising candidate for clinical development, designed to supersede TM.
Animals↗
Effect of rapamycin on the expression of the IL-2 receptor (CD25).
The immunosuppressive macrolide rapamycin inhibits cytokine-driven proliferation of lymphocytes, acting at a later stage of T lymphocyte activation than the related compound FK506 or cyclosporin, which block IL-2 transcription. However, the effect of rapamycin on the expression of the IL-2 receptor alpha-chain (CD25) is less well documented. This study has investigated the effect of rapamycin on mRNA levels of CD25 and membrane expression of IL-2 receptor in human primary T lymphocytes activated by various stimuli. Rapamycin surprisingly inhibits CD25 upregulation subsequent to anti-CD3 or ionomycin stimulation. These effects are not secondary to an IL-2-mediated CD25 up-regulation, as rapamycin inhibits neither IL-2 synthesis nor IL-2-induced CD25 mRNA. Interestingly, sensitivity to rapamycin correlates with the requirement of de novo protein synthesis, as demonstrated by anisomycin inhibition of both ionomycin- and CD3-induced CD25 transcription. Thus, rapamycin inhibition of T cell activation may involve not only IL-2-driven proliferation, but also suppression of CD25 up-regulation.
Cells, Cultured↗
Substance P-(1-7) and substance P-(5-11) locally modulate dopamine release in rat striatum.
The effects of substance P, substance P-(1-7) and substance P-(5-11) on endogenous dopamine outflow in rat striatal slices were investigated. The dose-response curves (0.01 nM to 10 microM) were bell-shaped, with significant increases at 0.1 and 1 nM but with no effect at higher concentrations. The tachykinin NK1 receptor agonist, [Sar9,Met(O2)11]substance P, significantly increased dopamine outflow at 10 and 100 nM. The effects of substance P or substance P-(5-11) and 25 mM KCl were additive. A negative interaction was observed with substance P-(1-7) and K+. The increase in dopamine outflow elicited by 1 nM substance P and substance P-(5-11) was reversed by the tachykinin NK1 receptor antagonist WIN 51,708 (17 beta-hydroxy-17 alpha-ethynyl-5 alpha-androstano[3,2-b]pyrimido[1,2- alpha]benzimidazole) (25 and 250 nM), whereas only partial reversal was observed for the effect of substance P-(1-7). These results show that substance P fragments locally modulate striatal dopamine outflow and the mechanisms underlying this modulation may differ between N- and C-terminal fragments.
Androstanes↗
The role of the N-(hydroxymethyl)melamines as antitumour agents: mechanism of action studies.
The hexamethylmelamine analogue trimelamol (tris-hydroxymethyl[trimethyl]melamine) and its equicytotoxic stable analogues CB 7547, CB 7639 and CB 7669 have been used to clarify the mechanism of action for the N-(hydroxymethyl)melamines as antitumour agents. Two main mechanisms have been proposed and explored: (i) formation of a reactive iminium species forming covalent adducts with DNA; and (ii) local formaldehyde release leading to cytotoxic damage. 32P-postlabelling and thermal denaturation experiments showed these compounds to be interactive with cytosine and guanine. Trimelamol gave rise to DNA-interstrand crosslinks in naked plasmid DNA and in cultured cell lines, whereas the analogues failed to do so under a variety of experimental conditions. Along with our observations that cell lines with acquired resistance to the N-(hydroxymethyl)melamines showed no significant cross-resistance to classical bifunctional alkylating agents, DNA crosslinking may play only a minor role in their mechanism of action. In cultured cell lines treatment with formaldehyde, trimelamol and CB 7639 gave rise to high levels of DNA-protein crosslinks with a gradual disappearance over a 24 hr period. Along with our earlier observation that resistance to trimelamol coincides with cross-resistance to formaldehyde, we conclude that formaldehyde-release may be an important factor in their cytotoxicity. Further, the cytotoxicity of trimelamol or formaldehyde towards human ovarian cancer cells was not influenced by glutathione depletion. As the precise mechanism of action for the N-(hydroxymethyl)melamines is apparently not shared by many commonly used anticancer agents, this may confer their broad-spectrum activity versus heavily pretreated tumours.
Alkylating Agents↗
Post-traumatic morbidity in a civilian community of litigants: a follow-up at 3 years.
This paper examines post-traumatic morbidity in a community sample who had claimed compensation and been assessed 10-14 months after the Lockerbie Disaster. At 36 months 25 residents were reassessed by clinical interview and 35 by questionnaire. A chronic pattern of morbidity was found in 56% of this sample with the most frequent diagnoses being post traumatic stress disorder and depression, followed by other anxiety disorders. Only six cases were found to have "recovered" and there was only one case of delayed onset morbidity between 12 and 36 months. No unequivocal predictors of the presence of diagnosis or questionnaire scores were found.
Accidents, Aviation↗
Interleukin-2 receptor (CD25) upregulation on human T-lymphocytes: sensitivity to immunosuppressants is defined by the mode of T-lymphocyte activation.
We investigated the transcription and expression of the interleukin-2 receptor (IL-2R, CD25) in human T-lymphocytes after different modes of T-lymphocyte stimulation in the presence of the immunosuppressants cyclosporin (CsA) and tacrolimus (FK506) as well as the structurally related macrolide rapamycin. We demonstrate that CsA and FK506 inhibited IL-2R (CD25) gene transcription and protein expression after stimulation by anti-CD3 or ionomycin, but not by phorbol ester or IL-2. Rapamycin, which does not affect IL-2 transcription, surprisingly inhibited IL-2R upregulation after anti-CD3- or ionomycin-induced stimulation, but not by phorbol ester or IL-2. Interestingly, the protein synthesis inhibitor anisomycin inhibited anti-CD3- or ionomycin-, but not phorbol ester- and IL-2-induced CD25 gene transcription indicating the dependence on de novo protein synthesis of the former pathways. These data suggest that the pharmacological effect of the imunosuppressants tested on IL-2R gene expression may be predicted by the requirement of protein synthesis of a given activation pathway.
Cells, Cultured↗
Stable analogues of the antitumour agent trimelamol retain in vitro cytotoxicity in drug-sensitive and resistant rodent and human cell lines.
In spite of clinical activity in heavily-pretreated ovarian cancer, the antitumour s-triazine trimelamol [TM; tris(hydroxymethyl)-tris(methyl)melamine] had to be withdrawn from further clinical studies due to formulation difficulties related to instability. A synthetic programme has produced tris(hydroxymethyl) analogues containing electron-withdrawing groups in place of methyl-triscyanomethyl CB 7669, tristrifluoroethyl CB 7639, CB 7529 and trispropargyl CB 7547, all showing markedly superior stability to TM. Chemosensitivity testing of analogues (MTT assay, continuous exposure) using a panel of rodent and human cell lines showed activity close to that of TM, e.g. for the CH1 human ovarian cancer cell line. IC50 values were TM 23.4 microM, CB 7639 30.5 microM, CB 7529 29.5 microM, CB 7547 28.5 microM and CB 7669 27.3 microM. CB 7669 and CB 7639 required prolonged exposure (> 12 h) in order to exhibit equivalent cytotoxicity to a 2-h exposure to TM. Thus, rather than administration as a single daily dose, the stable analogues may be more suited to prolonged infusion, which was suggested as being a more beneficial regimen in clinical trials with TM. In line with clinical observations indicating the efficacy of TM in platinum-refractory ovarian cancer, we saw no significant cross-resistance to TM or CB 7529 in a range of platinum-sensitive and acquired-resistant cell line pairs or in an alkylating-agent resistant cell line, despite TM's ability to crosslink DNA. Data obtained using cell lines with acquired resistance to TM, CB 7669 and formaldehyde (released in the breakdown of TM) suggest a pivotal role for formaldehyde and a more minor role for alkylating activity in the mechanism of action of the N-(hydroxymethyl)melamines in vitro. Further clinical trials of these compounds are eagerly awaited, and their usefulness as second-line chemotherapy for heavily pretreated ovarian cancer deserves further investigation.
Animals↗
Anthracyclines and the heart.
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Antibiotics, Antineoplastic↗
Financing and payment reform for primary health care and substance abuse treatment.
One of the most controversial areas for health care reform concerns the treatment of alcohol and other drug problems, which account for some of the most rapidly rising costs in the health care sector. There is arguably no other set of conditions that show such variation in accessibility to treatment on the basis of insurance status, present the same degree of difficulty in providing comprehensive care, or challenge as many public and professional assumptions about behavioral, social and economic determinants. The purpose of this article is to discuss some of the financing and coverage barriers to comprehensive treatment for alcohol and other drug abuse; to discuss some innovative mechanisms for providing and financing comprehensive services; and to suggest some directions for public policy to support the development of new practice models that emphasize cost-effectiveness and efficiency of care.
Alcoholism↗
Pulmonary diffusion abnormalities in heart transplant recipients. Relationship to cytomegalovirus infection.
Lung function of patients with heart failure is characterized by a variety of changes proposed as being due to passive congestion, secondary pulmonary fibrosis, and/or recurrent pulmonary emboli. A diffusion impairment thought to be due to cyclosporine has also been noted in patients following heart transplantation. Similar changes of unclear origin have been observed in renal transplant recipients. The objective of this study was to determine the extent to which lung function changes are reversible by cardiac transplantation and relate changes to the status of the recipients lung in the presence of possible vascular, iatrogenic, immune, or infectious injury. We analyzed the data of 22 patients who underwent lung function testing before and after heart transplantation and correlated changes to hemodynamic change, episodes of rejection, concentration of cyclosporine, and cytomegalovirus infection. Despite excellent graft function, the carbon monoxide transfer factor deteriorated to a mean of 57 percent of predicted postoperatively. The fall in diffusion factor did not correlate with episodes of cardiac rejection, cyclosporine levels, or hemodynamic status. In those patients who had serologic evidence of cytomegalovirus infection, the reduction in transfer factor was greater compared to those without infection despite a normal chest radiograph. The effects of cardiopulmonary bypass were unlikely to have been responsible for the abnormalities as lung function was assessed at a mean of 14 months after surgery. In heart transplant recipients, a change in diffusion capacity may represent an additional marker for cytomegalovirus infection and reflect infectious/immune injury late following surgery.
Cyclosporine↗
Psychosocial assessment after traumatic brain injury.
Psychosocial outcome has been difficult to define, but nevertheless widely reported. More recent studies have demonstrated not only that the long term emotional costs of head injury are enormous for survivor and family members, but the functional consequences in terms of changes in family life, recreational and vocational activities, are great and prolonged. These consequences have more recently become the focus of rehabilitation, with studies demonstrating dramatic improvements in many aspects of productive living, and consequent lifetime cost savings of an enormous amount. The psychosocial deficits matter, they can be the focus of treatment, and the treatment can be successful and cost effective.
Activities of Daily Living↗
Adolescent health behaviour and similarity-attraction: friends share smoking habits (really), but much else besides.
Smoking habits and related attitudes were assessed in a sample of 4059 11- to 16-year-olds who also identified their best friends from among their fellow respondents. Subjects' responses were directly collated with those of their friends and indicated a clear covariation of smoking status (controlling for sex and age) as anticipated from previous research in which adolescents have been asked to report on the smoking habits of their friends. Such covariation, however, was not specific to smoking habits, but generalized to related measures of attitude and normative beliefs, alcohol use, health locus of control, school performance, spending habits and socio-economic status. Similarities on these other attributes were much the same, whether or not friends shared each others' smoking habits. It is concluded that these data argue against a simplistic view of unidirectional 'peer group influence' and invite an interpretation of friendship choice based on multiple dimensions of similarity.
Adolescent↗
The effects of muscle tension on cerebral circulation in blood-phobic and non-phobic subjects.
This study aimed to assess whether (1) a muscle tensing procedure which has been found to be useful in the treatment of blood-phobic patients produces an increase in heart rate and cerebral blood flow and (2) whether this increase is greater than that produced by mental effort alone. Subjects were 17 volunteers with a history of fainting in response to blood-injury stimuli, (12 were phobic) and 8 volunteers with no fainting history. They were required to (a) rest, (b) do mental arithmetic, and (c) repeatedly tense and release their arm and leg muscles. It was found that Ss, heart rate and cerebral blood flow velocity were significantly greater during the muscle tensing procedure than during mental arithmetic or resting conditions. The increased cerebral blood flow produced by muscle tensing may enable blood phobic patients to prevent fainting during exposure treatment.
Adolescent↗
New chronic schizophrenic patients: a comparison of daypatients and inpatients.
A group of 24 "new chronic" schizophrenic inpatients was compared with a group of 19 daypatients matched for duration of current care; both had spent between 1 and 6 years in continuous inpatient or daypatient care. The groups were compared on a variety of clinical, demographic, and social variables to identify specific variables that might distinguish the new chronic inpatient group. Despite a few nonsignificant trends in the data, the groups were found not to differ significantly on any variables. Both groups had long psychiatric histories with many previous hospital admissions, presented many negative symptoms of schizophrenia at interview, were quite disabled in terms of self-care and speech skills, had a low incidence of behavioural disturbance and had few contacts outside of the hospital. The majority of both groups expressed a clear preference for community care. The results therefore highlight the urgent need for more comprehensive and detailed assessment of patients in relation to decisions about retention in or discharge from inpatient hospital care and also the need to identify objective predictors of the success of such decisions.
Adult↗
Personality change after severe head injury.
Personality change is widely reported after head injury, but rarely investigated quantitatively. This Paper summarises recent quantitative studies concerned with the natural history of personality change after severe head injury; its nature; its prediction; and its consequences. Reports of personality change increase with increasing time after injury, and the changes reflect a variety of phenomena including changes in affect, behaviour, maturity, and responsibility. Although there is a relationship between injury severity and personality change, other features such as premorbid personality and lifestyle are important. A severe personality change has important functional consequences. Families become heavily burdened, and patients with severe personality change are very unlikely to return to work.
Brain Damage, Chronic↗
Expanding the benefits of the community project.
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Community Health Nursing↗