Biomedical subjects

S Amin

Publications and source records attributed to S Amin.

At least 55 records · Page 3Linked to original sources

PubMed2000

Unrepaired fjord region polycyclic aromatic hydrocarbon-DNA adducts in ras codon 61 mutational hot spots.

The fjord region diol-epoxide metabolites of polycyclic aromatic hydrocarbons display stronger tumorigenic activities in rodent studies than comparable bay region diol-epoxides, but the molecular basis for this difference between fjord and bay region derivatives is not understood. Here we tested whether the variable effects of these genotoxic metabolites of polycyclic aromatic hydrocarbons may result from different DNA repair reactions. In particular, we compared the repairability of DNA adducts formed by bay region benzo[a]pyrene (B[a]P) diol-epoxides and the structurally similar but significantly more tumorigenic fjord region diol-epoxide metabolites of benzo[c]phenanthrene (B[c]Ph). For that purpose, we incorporated both types of polycyclic aromatic hydrocarbon adducts into known hot spot sites for carcinogen-induced proto-oncogene activation. Synthetic DNA substrates were assembled using a portion of human N-ras or H-ras that includes codon 61, and stereospecific B[a]P or B[c]Ph adducts were synthesized on adenine N6 at the second position of these two ras codon 61 sequences. DNA repair was determined by incubating the site-directed substrates in human cell extracts, followed by electrophoretic visualization of radiolabeled oligonucleotide excision products. These cell-free assays showed that all tested bay region B[a]P-N6-dA adducts are removed by the human nucleotide excision repair system, although excision efficiency varied with the particular stereochemical configuration of each B[a]P residue. In contrast, all fjord region B[c]Ph-N6-dA adducts located in the identical sequence context and with exactly the same stereochemical properties as the corresponding B[a]P lesions were refractory to the nucleotide excision repair process. These findings indicate that the exceptional tumorigenic potency of B[c]Ph or related fjord region diol-epoxides may be attributed, at least in part, to slow repair of the stable base adducts deriving from the reaction of these compounds with DNA.

Adenine↗

PubMed2000

Synthesis of anti-1,2-dihydroxy-3,4-epoxy-1,2,3, 4-tetrahydro-6-nitrochrysene and its reaction with 2'-deoxyguanosine- 5'-monophosphate, 2'-deoxyadenosine-5'-monophosphate, and calf thymus DNA in vitro.

The remarkable carcinogenic activity of 6-nitrochrysene (6-NC) in several animal models, and its environmental presence, suggest its potential importance with regard to human cancer development. Depending on the bioassay model, 6-NC can be activated by simple nitro reduction, ring oxidation, or by a combination of ring oxidation and nitro reduction. Only the first pathway has been clearly established. Thus, this study purports to unequivocally define the other pathways. Toward this end, we report for the first time the synthesis of anti-1,2-dihydroxy-3,4-epoxy-1,2,3, 4-tetrahydro-6-nitrochrysene (6-NCDE), a likely ultimate carcinogenic metabolite of 6-NC. Also, we describe our initial investigation of its binding with calf thymus DNA, 2'-deoxyguanosine-5'-monophosphate (2'-dGuo), and 2'-deoxyadenosine-5'-monophosphate (2'-dAdo) in vitro. These adduct markers were then employed for comparison with those obtained in the rat after in vivo treatment with 6-NC. On the basis of the results, it appears that the major adduct formed in the liver of rats treated with 6-NC is not derived from 6-NCDE.

Animals↗

PubMed2000

The BCSH guideline on addressograph labels: experience at a cardiothoracic unit and findings of a telephone survey.

In 1998 we implemented a BCSH recommendation that addressograph labels should not be used on blood transfusion specimen tubes. Over a 12-month period before the ban was introduced our laboratory received 5964 red cell transfusion requests, 182 (3.1%) of which contained an error in the identification details (ID) supplied on the request form and/or specimen. Three of these errors were of the 'wrong patient' type, i.e. the sample belonged to a different patient from the one whose ID appeared on the specimen tube and request form. Over the 12 months after the ban was introduced 511 (8. 1%) of 6326 requests contained a labelling error, an increase in error rate of 165%; no wrong-patient errors were identified, however. In a survey, seven (29.2%) of 24 transfusion laboratories in the UK accepted specimens labelled with addressograph stickers; in four of these cases a local blood transfusion committee had agreed that the BCSH guideline should not be followed. We believe the BCSH guideline is valid; its implementation, however, has major financial and workload implications, which probably explains why many hospitals apparently do not comply with it.

Blood Banks↗

PubMed2000

Three-year outcome of first-episode psychoses in an established community psychiatric service.

BACKGROUND: Changes in service provision, secular trends in substance misuse and changing social structures might affect outcome in psychosis. AIMS: To assess the three-year outcome of an inception cohort of first-episode psychoses treated in a modern, community-oriented service; to compare outcomes with an earlier cohort treated in hospital-based care; and to examine the predictive validity of ICD-10 diagnostic criteria. METHOD: Three-year follow-up (1995-1997) of an inception cohort of first-episode psychoses and comparison with two-year follow-up (1980-1982) of the Determinants of Outcome of Severe Mental Disorders (DOSMED) Nottingham cohort. RESULTS: On most outcome measures, non-affective psychoses had a worse outcome than affective psychoses. Affective psychoses had better outcome than previously reported. Substance-related psychoses had very poor occupational outcome. Similar proportions of the current and DOSMED cohort were in remission but the former were rated as having greater disability. CONCLUSIONS: In a modern community service, 30-60% of patients with first-episode psychoses experience a good three-year outcome. The ICD-10 criteria have good predictive validity.

Activities of Daily Living↗

PubMed2000

Modulation of growth of human prostate cancer cells by the N-acetylcysteine conjugate of phenethyl isothiocyanate.

There is growing evidence that thiol conjugates of isothiocyanates present in cruciferous vegetables are effective cancer chemopreventive and potentially active therapeutic agents. The effects of the N-acetylcysteine conjugate of phenethyl isothiocyanate (PEITC-NAC) on tumor cell growth were analyzed in human prostate cancer cell lines LNCaP, androgen-dependent, and DU-145, androgen-independent. Exposure of the cells to PEITC-NAC at high concentrations caused cytolysis, while at lower concentrations PEITC-NAC mediated a dose-dependent growth modulation, with reduction of DNA synthesis and growth rate, inhibition of clonogenicity and induction of apoptosis in both types of prostate cancer cells. PEITC-NAC decreased cells in S and G2M phases of cell cycle, blocking cells entering replicating phases. In parallel, a significant enhancement of cells expressing the cell cycle regulator p21 as well as its intensity was determined using a fluorescent antibody technique. The action of PEITC-NAC was time-dependent, with the magnitude of inhibition increasing to 50-65% after PEITC-NAC exposure for several days. Interaction of tumor cells with dissociation products of PEITC-NAC, PEITC and NAC, are proposed as the mechanism of growth regulation.

Anticarcinogenic Agents↗

PubMed2000

A neoadjuvant clinical trial in colorectal cancer patients of the human anti-idiotypic antibody 105AD7, which mimics CD55.

Thirty-five patients received 105AD7 human anti-idiotype vaccination prior to surgery for colorectal carcinoma. Patients were immunized before and also received one to two immunizations after surgical resection of their colorectal cancer. The vaccine was well tolerated with no associated toxicity. Lymphocytic infiltration within the resected tumors was quantified by immunohistochemistry and image analysis. Enhanced infiltration of helper T cells (CD4) and natural killer (NK) cells (CD56) were observed in the tumors from immunized patients when compared with tumors from stage, grade, site, age, and sex matched unimmunized patients. NK activity was increased in the blood, peaking 7-10 days post immunization and then dropping rapidly and correlating with NK extravasation within the tumor. Comparison of the amino acid sequences of 105AD7 anti-idiotype and the antigen it mimics, CD55, has predicted that patients with HLA-DR1, HLA-DR3, and HLA-DR7 haplotypes should show helper T cell responses following 105AD7 vaccination. Eighty-three percent of patients expressing these haplotypes responded to 105AD7, whereas 88% of patients who failed to express these haplotypes were nonresponders. With a median follow-up of 4 years (range, 2.5-6 years) 65% of patients remained disease free. This trial shows that 105AD7 stimulates antitumor inflammatory responses allowing extravasation within tumor deposits of both helper T cells and NK cells. This represents a way of evaluating immune responses in patients both within the blood and at the tumor site. The study confirms that immunization with a human anti-idiotypic antibody results in immune responses in 83% of patients with a permissive haplotype.

Antibodies, Anti-Idiotypic↗

PubMed2000

Analgesic principle from Abutilon indicum.

Bioactivity guided isolation of Abutilon indicum yielded eugenol [4-allyl-2-methoxyphenol], which was found to possess significant analgesic activity. At doses of 10, 30, and 50 mg/kg body weight, eugenol exhibited 21.30 (p < 0.05), 42.25 (p < 0.01) and 92.96% (p < 0.001) inhibition of acetic acid induced writhing in mice. At a dose of 50 mg/kg body weight, eugenol showed 33.40% (p < 0.05) prolongation of tail flicking time determined by the radiant heat method.

Acetates↗

PubMed1999

Metabolic fate of glutathione conjugate of benzo[a]pyrene-(7R,8S)-diol (9S,10R)-epoxide in human liver.

Benzo[a]pyrene-(7R,8S)-diol (9S,10R)-epoxide [(+)-anti-BPDE] is believed to be the activated form of the widely spread environmental pollutant benzo[a]pyrene. Glutathione (GSH) S-transferase (GST)-catalyzed conjugation of (+)-anti-BPDE with GSH is an important mechanism in its cellular detoxification. Here, we report that the GSH conjugate of (+)-anti-BPDE [(-)-anti-BPD-SG] is a potent inhibitor (K(i) 15 microM) of class Mu human GST isoenzyme, which, among human liver GSTs, is a highly efficient detoxifier of (+)-anti-BPDE. Thus, the inhibition of GST activity by (-)-anti-BPD-SG may hinder GSH conjugation of (+)-anti-BPDE, unless the conjugate is metabolized and/or eliminated. The results of the present study show that gamma-glutamyltranspeptidase (gamma-GT) can metabolize (-)-anti-BPD-SG at a rate of about 0.29 nmol/min/mg protein. Our studies also show that (-)-anti-BPD-SG is transported across the human canalicular liver plasma membrane (cLPM) in an ATP-dependent manner at a rate of about 0.33 nmol/min/mg protein. The ATP-dependent transport of (-)-anti-[(3)H]BPD-SG across human cLPM follows Michaelis-Menten kinetics (K(m) 84 microM; V(max) 0.33 nmol/min/mg). In conclusion, the results of the present study suggest that both gamma-GT-mediated metabolism and ATP-dependent canalicular transport may be important steps in overall detoxification of (+)-anti-BPDE in the human liver.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed1999

Solution conformation of the (+)-trans-anti-benzo[g]chrysene-dA adduct opposite dT in a DNA duplex.

The solution structure of the adduct derived from the covalent bonding of the fjord region (+)-(11S, 12R, 13R, 14S) stereoisomer of anti -11,12-dihydroxy-13,14-epoxy-11,12,13, 14-tetrahydrobenzo[g]chrysene, (+)- anti -B[g]CDE, to the exocyclic N(6)amino group of the adenine residue dA6, (designated (+)- trans-anti -(B[g]C)dA6), positioned opposite a thymine residue dT17 in the DNA sequence context d(C1-T2-C3-T4-C5-(B[g]C)A6-C7-T8-T9-C10-C11). d(G12-G13-A14-A15-G16-T17-G18-A19-G20++ +-A21-G22) (designated (B[g]C)dA. dT 11-mer duplex), has been studied using structural information derived from NMR data in combination with molecular dynamics (MD) calculations. The solution structure of the (+)- trans-anti -(B[g]C)dA.dT 11-mer duplex has been determined using an MD protocol where both interproton distance and dihedral angle restraints deduced from NOESY and COSY spectra are used during the refinement process, followed by additional relaxation matrix refinement to the observed NOESY intensities to account for spin diffusion effects. The results established that the covalently attached benzo[g]chrysene ring intercalates into the DNA helix directed towards the 5'-side of the modified strand and stacks predominantly with dT17 when intercalated between dC5.dG18 and (B[g]C)dA6.dT17 base-pairs. All base-pairs, including the modified (B[g]C)dA6.dT17 base-pair, are aligned through Watson-Crick pairing as in normal B -DNA. In addition, the potential strain associated with the highly sterically hindered fjord region of the aromatic portion of the benzo[g]chrysenyl ring is relieved through the adoption of a non-planar, propeller-like geometry within the chrysenyl ring system. This conformation shares common structural features with the related (+)- trans-anti -(B[c]Ph)dA adduct in the identical base sequence context, derived from the fjord region (+)-(1S,2R,3R,4S)-3, 4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene stereoisomer, in which intercalation is also observed towards the 5'-side of the modified dA6.dT17 base-pair.

Binding Sites↗

PubMed1999

Primer length dependence of binding of DNA polymerase I Klenow fragment to template-primer complexes containing site-specific bulky lesions.

The binding of the benzo[a]pyrene metabolite anti-BPDE (r7, t8-dihydroxy-t9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene) to the N(2) group of 2'-deoxyguanosine residues (dG) is known to adversely affect the Michaelis-Menten primer extension kinetics catalyzed by DNA Pol I and other polymerases. In this work, the impact of site-specific, anti-BPDE-modified DNA template strands on the formation of Pol I (Klenow fragment, KF)/template-primer complexes has been investigated. The 23-mer template strand 5'-d(AAC GC-(1) T(-)(2) ACC ATC CGA ATT CGC CC), I (dG = (+)-trans- and (-)-trans-anti-BPDE-N(2)-dG), was annealed with primer strands 18, 19, or 20 bases long. Complex formation of these template-primer strands with KF(-) (exonuclease-free) at different enzyme concentrations was determined using polyacrylamide gel mobility shift assays in the absence of dNTPs. The lesion dG causes an increase in the dissociation constants, K(d), of the monomeric, 1:1 KF(-)/DNA template-primer complexes by factors of 10-15 when the 3'-end base of the primer strand is positioned either opposite dG, or opposite dC(-)(1) in I, and the shapes of the binding isotherms are sigmoidal. The sigmoidal shapes are attributed to the formation of dimeric 2:1 KF(-)/DNA template-primer complexes. In contrast, when the 3'-end of the primer strand extends only to dT(-)(2) in I, the K(d) of 1:1 complexes is increased by factors of only 2-3, the shapes of the binding isotherms are hyperbolic and nonsigmoidal and are similar to those observed with the unmodified control, and monomeric KF(-)/DNA complexes are dominant. The impact of bulky lesions on polymerase/DNA complex formation in polymerase-catalyzed primer extension reactions needs to be taken into account in interpreting the site-specific Michaelis-Menten kinetics of these reactions.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed1999

Solution structure of the (+)-cis-anti-benzo[a]pyrene-dA ([BP]dA) adduct opposite dT in a DNA duplex.

Minor adducts, derived from the covalent binding of anti-benzo[a]pyrene-7,8-dihydroxy-9,10-epoxide to cellular DNA, may play an important role in generating mutations and initiating cancer. We have applied a combined NMR-computational approach including intensity based refinement to determine the solution structure of the minor (+)-cis-anti-[BP]dA adduct positioned opposite dT in the d(C1-T2-C3-T4-C5-[BP]A6-C7-T8-T9-C10-C11). (d(G12-G13-A14-A15-G16-T17-G18-A19-G20+ ++-A21-G22) 11-mer duplex. The BP ring system is intercalated toward the 5'-side of the [BP]dA6 lesion site without disrupting the flanking Watson-Crick dC5.dG18 and [BP]dA6.dT17 base pairs. This structure of the (+)-cis-anti-[BP]dA.dT 11-mer duplex, containing a bay region benzo[a]pyrenyl [BP]dA adduct, is compared with the corresponding structure of the (+)-trans-anti-[BPh]dA.dT 11-mer duplex (Cosman et al., Biochemistry 32, 12488-12497, 1993), which contains a fjord region benzo[c]phenanthrenyl [BPh]dA adduct with the same R stereochemistry at the linkage site. The carcinogen intercalates toward the 5'-direction of the modified strand in both duplexes (the adduct is embedded within the same sequence context) with the buckling of the Watson-Crick [BP]dA6.dT17 base pair more pronounced in the (+)-cis-anti-[BP]dA.dT 11-mer duplex compared to its Watson-Crick [BPh]dA.dT17 base pair in the (+)-trans-anti-[BPh]dA.dT 11-mer duplex. The available structural studies of covalent polycyclic aromatic hydrocarbon (PAH) carcinogen-DNA adducts point toward the emergence of a general theme where distinct alignments are adopted by PAH adducts covalently linked to the N(6) of adenine when compared to the N(2) of guanine in DNA duplexes. The [BPh]dA and [BP]dA N(6)-adenine adducts intercalate their polycyclic aromatic rings into the helix without disruption of their modified base pairs. This may reflect the potential flexibility associated with the positioning of the covalent tether and the benzylic ring of the carcinogen in the sterically spacious major groove. By contrast, such an intercalation without modified base pair disruption option appears not to be available to [BP]dG N(2)-guanine adducts where the covalent tether and the benzylic ring are positioned in the more sterically crowded minor groove. In the case of [BP]dG adducts, the benzopyrenyl ring is either positioned in the minor groove without base pair disruption, or if intercalated into the helix, requires disruption of the modified base pair and displacement of the bases out of the helix.

Adenine↗

PubMed1999

Increased expression of cyclooxygenase-2 in rat lung tumors induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone: the impact of a high-fat diet.

Aberrant or excessive expression of cyclooxygenase (COX)-2 has been implicated in the pathogenesis of many disease processes, including carcinogenesis. COX-2 expression was immunohistochemically examined in archival samples (D. Hoffmann et al., Cancer Res., 53: 2758-2761, 1993) of lung neoplasms (adenomas, adenocarcinomas, and adenosquamous carcinomas) induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in male F344 rats that had been fed either a semipurified AIN-76A diet with high-fat (HF; 23.5% corn oil) or low-fat (LF; 5% corn oil) content. The intensity and extent of COX-2 positivity was graded from 0 (undetectable or negligible expression) to grades 1 (<30% expression), 2 (30-60% expression), 3 (60-90% expression), and 4 (>90% expression). The scoring criteria were similar to those used with specimens from human lung cancers (T. Hida et al., Cancer Res., 58: 3761-3764, 1998). In group 1 (NNK plus HF diet), adenomas, adenocarcinomas, and adenosquamous carcinomas were of mean grades 2, 3, and 4, respectively; in group 2 (NNK plus LF diet), the corresponding mean grades were 1, 1, and 3. Although control rats, given HF (group 3) or LF (group 4) diets but no NNK, developed spontaneous lung tumors, the expression of COX-2 was either negligible (one adenoma of grade 0 in group 3) or of a very low grade (one adenocarcinoma of grade 1 in group 4). In addition, the latency of the tumors in the peripheral lung in assays with NNK is significantly shorter in rats maintained on the HF diet than in those on LF diet. COX-2 expression was not evident in normal lung tissues. We report here for the first time that NNK induces increasingly higher levels of COX-2 expression with progressive stages of lung tumorigenesis when rats are fed the HF diet. The increase in COX-2 expression may be associated with the development of lung tumors induced by NNK. This well-defined animal model is valuable for studying modulation of COX-2 expression in lung carcinogenesis by various factors, including dietary components.

Animals↗

PubMed1999

Retinoic acid increases tyrosine phosphorylation of focal adhesion kinase and paxillin in MCF-7 human breast cancer cells.

Treatment of estrogen receptor (ER)-positive MCF-7 human breast cancer cells with retinoic acid (RA) inhibited cell growth and increased cell adhesion to fibronectin. In contrast, ER- MDA-MB-231 cells failed to respond. Western blot analysis showed that tyrosine phosphorylation of two major bands at Mr 125,000 and Mr 68,000 was induced by RA in ER+ MCF-7 human breast carcinoma cells. However, this induction was a late phenomenon detectable at 12 and 24 h, but not within 3 h. A similar increase of tyrosine phosphorylation by RA was observed in ER+ human breast cancer cell lines T-47D and ZR-75-1, but not in the ER- cell lines MDA-MB-231, MDA-MB-453, and MDA-MB-468. Focal adhesion kinase and paxillin, which localize in focal adhesion plaques and may play important roles in the integrin signaling pathway, were identified as the major proteins showing RA-induced tyrosine phosphorylation. The retinoid X receptor-selective compound SR11237 failed to induce tyrosine phosphorylation, indicating that retinoid X receptor activation is not involved in this phenomenon. In contrast, stable overexpression of a truncated RA receptor (RAR) alpha cDNA, RARalpha403, with strong RAR dominant negative activity prevented the increase in tyrosine phosphate, suggesting that RAR signaling is involved in RA-induced tyrosine phosphorylation. Tyrosine phosphorylation was induced the most by the RAR-alpha (193836), followed by RAR-gamma (194433), but was not significantly induced by RAR-gamma (193174)-selective retinoids. This study demonstrates a coordinated albeit relatively late effect of RA on cell adhesion and tyrosine phosphorylation in ER+ human breast cancer cells and suggests RAR-alpha as the major responsible retinoid receptor.

Antineoplastic Agents↗

PubMed1999

The role of vitamin D in corticosteroid-induced osteoporosis: a meta-analytic approach.

OBJECTIVE: To determine if vitamin D is more effective than no therapy or calcium alone in the management of corticosteroid-induced osteoporosis, and to determine how vitamin D compares with other osteoporosis therapies, e.g., bisphosphonates, calcitonin, or fluoride, for this condition. METHODS: We evaluated all formulations of vitamin D, including its active metabolites and analogs. A systematic search for published and unpublished studies was conducted using MEDLINE (1966-December 1997), bibliographic references, abstracts from proceedings of recent national meetings, and contact with pharmaceutical companies and content experts. We included all randomized controlled trials lasting at least 6 months (and reporting extractable results), of patients receiving oral corticosteroids, that compared vitamin D with either 1) no therapy or calcium alone, or 2) bisphosphonates, calcitonin, or fluoride. The primary outcome measure of interest was change in lumbar spine bone mineral density. RESULTS: We found a moderate beneficial effect of vitamin D plus calcium versus no therapy or calcium alone (9 trials) (effect size 0.60; 95% confidence interval [95% CI] 0.34, 0.85; P < 0.0001). In comparisons of vitamin D with other osteoporosis therapies, bisphosphonates were more effective than vitamin D (6 trials) (effect size 0.57; 95% CI 0.09, 1.05). Calcitonin was similar in efficacy to vitamin D (4 trials) (effect size 0.03; 95% CI -0.39, 0.45). Fluoride was more effective than vitamin D, but there were only 2 trials. CONCLUSION: Vitamin D plus calcium is superior to no therapy or calcium alone in the management of corticosteroid-induced osteoporosis. Vitamin D is less effective than some osteoporosis therapies. Therefore, treatment with vitamin D plus calcium, as a minimum, should be recommended to patients receiving long-term corticosteroids.

Adrenal Cortex Hormones↗

PubMed1999

Fibrin glue reduces the severity of intra-abdominal adhesions in a rat model.

BACKGROUND: The purpose of this study was to determine whether fibrin glue inhibits intra-abdominal adhesions. METHODS: Twenty rats underwent midline laparotomy. To maximize adhesions, bilateral peritoneal muscular defects were created and covered with polypropylene mesh sewn with a braided suture. The bowel was abraded with dry gauze. Rats were randomized to either fibrin glue (FG) sprayed over the mesh or to control (no further treatment) groups. At 1 week, the adhesion density (graded 0 to 3), the percentage of the patch covered by adhesion (0% to 100%), and adhesion type were recorded. RESULTS: The mean adhesion density was 1.45+/-0.33 for FG versus 2.8+/-0.11 for controls (P = 0.001). The mean percentage of adhesions was 36+/-9.9 for the FG group and 94+/-3.7 for controls (P = 0.0002). Bowel or solid organs were adherent to the patch in 6 of 20 (30%) in the FG group versus 12 of 20 (70%) in controls (P = 0.057). CONCLUSIONS: Topical fibrin glue reduces the density and severity of intra-abdominal adhesions in a rat model.

Animals↗

PubMed1999

Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients.

BACKGROUND: Although a number of studies have documented the long-term survival of patients with cutaneous T-cell lymphoma (CTCL), none have provided data as to the relative survival of all 4 skin stages. OBJECTIVE: We document survival of CTCL patients by T stage relative to that of an age-, sex-, and race-matched population. METHODS: The survival of 489 patients with CTCL registered since 1957 was compared with that of a California control population. RESULTS: For stage T1 (< 10% skin involved) there was no significant difference between the observed and expected survivals. For the other 3 stages the observed survival was significantly inferior to that of the expected survival (P = .002). At 10 years the relative survivals were: T2 (10% or more skin involved) 67.4%, T3 (tumor stage) 39.2%, T4 (generalized erythroderma) 41.0%. T2 plaque stage patients had an inferior relative survival (P = .001), whereas T2 patch stage patients did not. Lymphadenopathy had an unfavorable impact on prognosis. There was a strong trend toward diagnosing CTCL at an earlier stage in more recent years. We estimate that from 15% to 20% of our patients died of CTCL or related complications. CONCLUSION: The relative survival of CTCL patients worsens with increasing skin stage, although stages T3 and T4 had closely similar survivals. The great majority of patients with CTCL do not die of their disease.

Adolescent↗

PubMed1999

Synthesis of anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydro-11-methylbenzo[a]pyrene and its reaction with DNA.

Substitution of a methyl group in the bay region can enhance the tumorigenicity of polycyclic aromatic hydrocarbons such as chrysene, benz[a]anthracene, and others. This phenomenon has been related to facile DNA adduct formation of bay region diol epoxides with a methyl group and epoxide ring in the same bay. While anti-7, 8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and its DNA adduct formation have been studied extensively, it is not known whether a methyl substituent in the bay region alters the reactivity of DNA in this system. This is of interest because 11-methylbenzo[a]pyrene, which has a bay region methyl group, is more tumorigenic than benzo[a]pyrene. To examine the question, we have devised and employed an efficient synthesis based on photochemical cyclization, and prepared anti-7,8-dihydroxy-9, 10-epoxy-7,8,9,10-tetrahydro-11-methylbenzo[a]pyrene, the likely ultimate carcinogen of 11-methylbenzo[a]pyrene. We have then reacted anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydro-11-methylbenzo[a]pyrene with calf thymus DNA and found that it gives three major adducts. These were identified as having resulted from cis- and trans-ring opening of the (S,R,R, S)-enantiomer and from trans-ring opening of the (R,S,S, R)-enantiomer. The standard deoxyguanosine adduct markers were prepared, and their structures were tentatively assigned on the basis of their CD and 1H NMR spectra. The adduct distribution of anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydro-11-methylbenzo[a]pyrene is quite different from that observed in the reaction of DNA with the corresponding diol epoxides of benzo[a]pyrene or with 5-methylchrysene. The heterogeneity of adducts obtained with anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydro-11-methylbenzo[a]pyrene thus may be related to the enhanced tumorigenicity of 11-methylbenzo[a]pyrene.

Benzopyrans↗

PubMed1999

Reactions of dihydrodiol epoxides of 5-methylchrysene and 5, 6-dimethylchrysene with DNA and deoxyribonucleotides.

Both syn and anti dihydrodiol epoxides from 5-methylchrysene (5-MCDE) and 5,6-dimethylchrysene (5,6-DMCDE) were reacted under the same conditions with native DNA, denatured DNA, and purine deoxyribonucleotides, and the products were quantified. The extents of reaction with the deoxyribonucleotides were consistently greater for 5,6-DMCDE than for 5-MCDE. The yield of adducts in the reaction with DNA ranged from being a few-fold to 50-fold greater than those found in the corresponding deoxyribonucleotide reactions for both 5-MCDE and 5,6-DMCDE. The DNA-dependent enhancement of product yield was greater for 5-MCDE than for 5,6-DMCDE with a few exceptions among cis and trans deoxyadenosine adducts. The most substantial differences in DNA-dependent enhancement were found for deoxyguanosine adducts; thus, steric hindrance between the 6-methyl group in the 5,6-DMCDE and the minor groove in the DNA double helix may account for the greater DNA-dependent enhancement found in the 5-MCDE reactions.

Carcinogens↗