Biomedical subjects

P Koivisto

Publications and source records attributed to P Koivisto.

At least 19 recordsLinked to original sources

PubMed2001

N7-guanine adducts of the epoxy metabolites of 1,3-butadiene in mice lung.

Epoxy metabolites of 1,3-butadiene are electrophilic and can bind to nucleophilic sites in DNA forming DNA adducts. In this study, guanine N7 adducts of epoxy butene and guanine N7 adducts of epoxy butanediol were measured in lung tissues of mice inhalation exposed to various concentrations of 1,3-butadiene. 32P-postlabeling of DNA adducts were used to demonstrate that the DNA adducts derived from epoxybutene and epoxybutanediol were formed in a dose dependent manner. More than 98% of all adducts detected were formed from epoxybutanediol. Enantiomeric distribution of the adducts formed in vivo differs from that of in vitro experiments demonstrated before. In the case of epoxybutene most of the adducts were formed to the terminal carbon of the S-epoxybutene enantiomer. Most of the adducts derived from epoxybutanediol were formed from the 2S-3R enantiomer. The data demonstrates that enzymatic processes involved with activation and/or detoxification of the metabolites are enantiospecific and/or DNA repair machinery repairs the damage with stereochemical considerations. These are the crucial factors if interspecies differences in tumor sensitiveness is concerned.

Administration, Inhalation↗

PubMed2001

ANX7, a candidate tumor suppressor gene for prostate cancer.

The ANX7 gene is located on human chromosome 10q21, a site long hypothesized to harbor a tumor suppressor gene(s) (TSG) associated with prostate and other cancers. To test whether ANX7 might be a candidate TSG, we examined the ANX7-dependent suppression of human tumor cell growth, stage-specific ANX7 expression in 301 prostate specimens on a prostate tissue microarray, and loss of heterozygosity (LOH) of microsatellite markers at or near the ANX7 locus. Here we report that human tumor cell proliferation and colony formation are markedly reduced when the wild-type ANX7 gene is transfected into two prostate tumor cell lines, LNCaP and DU145. Consistently, analysis of ANX7 protein expression in human prostate tumor microarrays reveals a significantly higher rate of loss of ANX7 expression in metastatic and local recurrences of hormone refractory prostate cancer as compared with primary tumors (P = 0.0001). Using four microsatellite markers at or near the ANX7 locus, and laser capture microdissected tumor cells, 35% of the 20 primary prostate tumors show LOH. The microsatellite marker closest to the ANX7 locus showed the highest rate of LOH, including one homozygous deletion. We conclude that the ANX7 gene exhibits many biological and genetic properties expected of a TSG and may play a role in prostate cancer progression.

Annexin A7↗

PubMed2001

Amplification of EIF3S3 gene is associated with advanced stage in prostate cancer.

Gain of the long arm of chromosome 8 (8q) is one of the most common gains found in the advanced prostate cancer by comparative genomic hybridization. We have previously identified a putative target gene for the 8q gain, EIF3S3, that encodes a p40 subunit of eukaryotic translation initiation factor 3 (eIF3). Here, we studied the frequency of the EIF3S3 amplification in different stages of prostate cancer and co-amplification of EIF3S3 and oncogene MYC. In addition, prognostic utility of the EIF3S3 copy number alteration was evaluated. The analyses were done with fluorescence in situ hybridization and tissue microarray technology. High-level amplification of EIF3S3 was found in 11 of 125 (9%) of pT1/pT2 tumors, 12 of 44 (27%) of pT3/pT4 tumors, and 8 of 37 (22%) of lymph node metastases as well as in 26 of 78 (33%) and 15 of 30 (50%) of hormone refractory locally recurrent tumors and metastases, respectively. The amplification was associated with high Gleason score (P < 0.001). One of the 79 tumors with EIF3S3 amplification had only two copies of MYC, whereas all tumors with amplification of MYC had also amplification of EIF3S3 indicating common co-amplification of the genes. Gain of EIF3S3 was associated with poor cancer-specific survival in incidentally found prostate carcinomas (P = 0.023). In the analyses of prostatectomy-treated patients, the amplification was not statistically significantly associated with progression-free time. In conclusion, amplification of EIF3S3 gene is common in late-stage prostate cancer suggesting that it may be functionally involved in the progression of the disease.

Aged↗

PubMed2001

Relatives of prostate cancer patients have an increased risk of prostate and stomach cancers: a population-based, cancer registry study in Finland.

OBJECTIVE: Five to ten percent of prostate cancers may be caused by inherited genetic defects. In order to explore the nature of inherited cancer risks in the genetically homogeneous Finnish population, we investigated the incidence of prostate cancer and other cancers in first-degree relatives of prostate cancer patients by linking the population-based parish records on relatives with the Finnish Cancer Registry (FCR) data. METHODS: The study population was composed of first-degree relatives of two groups of prostate cancer patients diagnosed in Finland during 1988-1993: (1) all early-onset (<60 years) patients (n = 557) from the entire country, (2) a sample (n = 989) of prostate cancer patients diagnosed at an age of > 60 years. A total of 11,427 first-degree relatives were identified through parish records, and their cancer incidence was determined based on a total of 299,970 person-years. Standardized incidence ratios (SIR) were calculated based on expected cancer rates in the general population. RESULTS: The SIR of prostate cancer was increased in both Cohort 1 (2.5, 95% CI 1.9-3.2) and Cohort 2 (1.7, 95% CI 1.4 2.1). The risk of prostate cancer was high for relatives of patients diagnosed at an early age, and then leveled off for patients in the median age of prostate cancer diagnosis (70-79 years). However, the prostate cancer risk for relatives of patients diagnosed > or = 80 years was again statistically significantly elevated (SIR 1.8, 95% CI 1.3-2.6), suggesting a contribution of genetic factors to prostate cancer also at a late age of onset. Gastric cancer was the only other cancer type with a significantly elevated risk among the relatives. Increased risk of gastric cancer was seen only in male relatives of prostate cancer patients diagnosed at an early age, with the highest risk detected for the male relatives of prostate cancer patients diagnosed at an age of 55 years or less (SIR 5.0, 95% CI 2.8-8.2). CONCLUSIONS: Our population-based study indicates that hereditary factors may play an important role in the development of prostate cancer among the relatives of men diagnosed both at younger and older ages. This finding is relevant in the context of our observations that HPCX (hereditary prostate cancer susceptibility locus on Xq27-28) linkage in Finland is found exclusively among families with late age of onset. The association of gastric cancer with prostate cancer has not been reported previously, and may reflect the effects of a novel predisposition locus, which increases the risk to both of these common tumor types.

Adult↗

PubMed2000

Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression.

NKX3.1 is a prostate-specific homeobox gene located on chromosome 8p21. In the mouse, Nkx3.1 has growth-suppressive and differentiating effects on prostatic epithelium. Mutations of the coding region of NKX3.1 were not found in human prostate cancer, failing to support the notion that NKX3.1 was a tumor suppressor gene. To study the expression o NKX3.1 protein in human tissues and prostate cancer, we derived a rabbit antiserum against purified recombinant NKX3.1. Among normal human tissues, NKX3.1 expression was seen in testis, in rare pulmonary mucous glands, and in isolated regions of transitional epithelium of the ureter. NKX3.1 was uniformly expressed in nuclei of normal prostate epithelial cells in 61 histological sections from radical prostatectomy specimens. We analyzed 507 samples of neoplastic prostate epithelium, most of which were contained on a tissue microarray that contained samples from different stages of prostatic neoplasia. We observed complete loss of NKX3.1 expression in 5% of benign prostatic hyperplasias, 20% of high-grade prostatic intraepithelial neoplasias, 6% of T1a/b samples, 22% of T3/4 samples, 34% of hormone-refractory prostate cancers, and 78% of metastases. Our data show that NKX3.1 expression is highly, but not exclusively, specific for the prostate. Loss of NKX3.1 expression is strongly associated with hormone-refractory disease and advanced tumor stage in prostate cancer (P < 0.0001).

Animals↗

PubMed2000

Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus.

A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.

Aged↗

PubMed2000

Suxamethonium-induced rhabdomyolysis in a healthy middle-aged man.

A 43-year-old man developed rhabdomyolysis after uvulo- palatopharyngoplasty. After induction with thiopentone and suxamethonium the anesthesia was maintained with halothane. The patient responded to treatment and made an uneventful recovery. In earlier reports of rhabdomyolysis after general anaesthesia with halothane and suxamethonium almost all the patients had malignant hyperthermia (MH) or muscular dystrophy. About 50% of malignant hyperthermia patients carry a mutation in the RYR1 gene. Our patient did not have mutations in the four MH-associated genes tested, but the total amount of different mutations is by now about twenty. Therefore, despite these negative tests rhabdomyolysis may be a sign of subclinical malignant hyperthermia which cannot be ruled out by our investigations. This rare case of rhabdomyolysis in a healthy man suggests careful monitoring of the patient when-ever suxamethonium is used.

Adult↗

PubMed2000

Androgen receptor gene amplification at primary progression predicts response to combined androgen blockade as second line therapy for advanced prostate cancer.

PURPOSE: Amplification of the androgen receptor gene has been found in a third of hormone refractory prostate carcinomas. It is possible that amplification facilitates cell growth ability in low concentrations of androgens remaining in the serum after androgen deprivation therapy. We evaluate whether androgen receptor gene amplification at primary progression is associated with response to second line combined androgen blockade for prostate cancer. MATERIALS AND METHODS: A total of 77 patients with prostate cancer were treated initially with androgen deprivation monotherapy followed by combined androgen blockade after the first progression. After initiation of second line combined androgen blockade patients were followed every 3 months to evaluate treatment responses. Biopsies were taken from the prostate at the first progression under endocrine monotherapy. Androgen receptor gene copy number was determined by fluorescence in situ hybridization. RESULTS: Androgen receptor gene amplification was found in 10 of the 77 cases (13%) at the primary disease progression, and was associated with a favorable response to second line combined androgen blockade. Only 1 of 34 (3%) patients classified as nonresponders had androgen receptor gene amplification, whereas 9 of 41 (21%) classified as having either stable disease or response had amplification (p = 0.016). Patients with androgen receptor gene amplification also had a decrease in prostate specific antigen more often after combined androgen blockade than those with no amplification (p = 0.079). However, androgen receptor gene amplification was not associated with patient survival after the first progression. CONCLUSIONS: Androgen receptor gene amplification detected in tumors progressing during androgen deprivation monotherapy is associated with favorable treatment response to second line combined androgen blockade. This finding suggests that at least some androgen receptor amplified tumors retain a high degree of dependency on residual androgens remaining in serum after monotherapy.

Adult↗

PubMed2000

A genetic epidemiological study of hereditary prostate cancer (HPC) in Finland: frequent HPCX linkage in families with late-onset disease.

Several predisposition loci for hereditary prostate cancer (HPC) have been suggested, including HPC1 at 1q24-q25 (OMIM #601518) and HPCX at Xq27-q28 (OMIM #300147). Genetically homogeneous populations, such as that of Finland, and distinct subsets of families may help to minimize the genetic heterogeneity that complicates the genetic dissection of complex traits. Here, the role of the HPC1, and HPCX loci in a series of Finnish prostate cancer families was studied, especially in subgroups of families defined by age, number of affected cases, and the mode of disease transmission. DNA samples were collected from 57 Finnish HPC families with at least two living prostate cancer patients. Linkage analysis was carried out with 39 microsatellite markers for the HPC1 region and 22 markers for the HPCX region. The maximum two-point LOD score for the HPCX was 2.05 (marker DXS1205, at theta = 0.14), whereas HPC1 LOD scores were all negative. In HOMOG3R analyses, significant evidence of heterogeneity was observed. Subgroup analyses performed to explore the nature of this heterogeneity indicated that families with no male-to-male (NMM) transmission and a late age of diagnosis (>65 years) accounted for most of the HPCX-linked cases. The maximum HPCX LOD score in this subgroup was 3.12 (theta = 0.001). Nonparametric sibling pair analyses gave a peak LOD score of 3.04 (P < 0.000093) for the NMM transmission subgroup. No subgroup showed any positivity for HPC1. This study suggests that the HPCX-linked prostate cancer families represent a distinct subgroup characterized by NMM transmission of disease and late age of diagnosis.

Age of Onset↗

PubMed1999

Capillary solid-phase extraction-tandem mass spectrometry for fast quantification of free concentrations of tolterodine and two metabolites in ultrafiltered plasma samples.

A capillary solid-phase extraction (SPE) system has been coupled directly to electrospray tandem mass spectrometry for quantification of free tolterodine and metabolite concentrations in plasma. The unbound fraction of these compounds was obtained by ultrafiltration of plasma. The ultrafiltrate was directly injected onto the SPE capillary (4 mm x 200 microm, 5 microm C18). After desalting and clean-up of the sample, the analytes were eluted in backflush mode with methanol-1 mM triethylamine (70:30, v/v), providing considerable solute focusing. Elution from the SPE capillary was improved by inserting a short trapping capillary between the SPE capillary and the MS interface, by which analyte focusing was increased. The unresolved compounds eluted simultaneously with the remaining matrix compounds and were detected in a multiple-reaction monitoring (MRM) mode. No interference of the sample matrix on detection was observed, allowing aqueous standards to be used for calibration. Linear calibration curves were obtained between 0.05 and 1000 ng/ml (corresponding to 150 pM-3 microM) and the limit of detection was 50 pg/ml injecting 10 microl. Equilibration of the SPE capillary, sample loading, elution and detection took less then 6 min per sample.

Benzhydryl Compounds↗

PubMed1999

Hormone therapy failure in human prostate cancer: analysis by complementary DNA and tissue microarrays.

BACKGROUND: The molecular mechanisms underlying the progression of prostate cancer during hormonal therapy have remained poorly understood. In this study, we developed a new strategy for the identification of differentially expressed genes in hormone-refractory human prostate cancer by use of a combination of complementary DNA (cDNA) and tissue microarray technologies. METHODS: Differences in gene expression between hormone-refractory CWR22R prostate cancer xenografts (human prostate cancer transplanted into nude mice) and a xenograft of the parental, hormone-sensitive CWR22 strain were analyzed by use of cDNA microarray technology. To validate the data from cDNA microarrays on clinical prostate cancer specimens, a tissue microarray of specimens from 26 prostates with benign prostatic hyperplasia, 208 primary prostate cancers, and 30 hormone-refractory local recurrences was constructed and used for immunohistochemical detection of protein expression. RESULTS: Among 5184 genes surveyed with cDNA microarray technology, expression of 37 (0.7%) was increased more than twofold in the hormone-refractory CWR22R xenografts compared with the CWR22 xenograft; expression of 135 (2.6%) genes was reduced by more than 50%. The genes encoding insulin-like growth factor-binding protein 2 (IGFBP2) and 27-kd heat-shock protein (HSP27) were among the most consistently overexpressed genes in the CWR22R tumors. Immunohistochemical analysis of tissue microarrays demonstrated high expression of IGFBP2 protein in 100% of the hormone-refractory clinical tumors, in 36% of the primary tumors, and in 0% of the benign prostatic specimens (two-sided P =.0001). Overexpression of HSP27 protein was demonstrated in 31% of the hormone-refractory tumors, in 5% of the primary tumors, and in 0% of the benign prostatic specimens (two-sided P =.0001). CONCLUSIONS: The combination of cDNA and tissue microarray technologies enables rapid identification of genes associated with progression of prostate cancer to the hormone-refractory state and may facilitate analysis of the role of the encoded gene products in the pathogenesis of human prostate cancer.

Animals↗

PubMed1999

Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays.

Prostate cancer development and progression is driven by the accumulation of genetic changes, the nature of which remains incompletely understood To facilitate high-throughput analysis of molecular events taking place in primary, recurrent, and metastat prostate cancer, we constructed a tissue microarray containing small 0.6-mm cylindrical samples acquired from 371 formalin-fixed blocks, including benign prostatic hyperplasia (n = 32) and primary tumors (n = 223), as well as both locally recurrent tumors (n = 54) and metastases (n = 62) from patients with hormone-refractory disease. Fluorescence in situ hybridization (FISH) was applied to the analysis of consecutive tissue microarray sections with probes for five different genes. High-level (> or =3X) amplifications were very rare (<2%) in primary prostate cancers However, in metastases from patients with hormone-refractory disease, amplification of the androgen receptor gene was seen in 22%, MYC in 11%, and Cyclin-D1 in 5% of the cases. In specimens from locally recurrent tumors, the corresponding percentages were 23, 4, and 8%. ERBB2 and NMYC amplifications were never detected at any stage of prostate cancer progression. In conclusion, FISH to tissue microarray sections enables high-throughput analysis of genetic alterations contributing to cancer development and progression. Our results implicate a role for amplification of androgen receptor in hormonal therapy failure and that of MYC in the metastatic progression of human prostate cancer.

Cyclin D1↗

PubMed1999

Identification of the major tamoxifen-DNA adducts in rat liver by mass spectroscopy.

We present here the first mass spectroscopic (MS) identification of the main tamoxifen-induced DNA adducts in rat liver. The two main adducts were isolated by high-performance liquid chromatography (HPLC) and identified by MS, MS-MS and ultraviolet spectroscopy. Adduct 1 was the N-desmethyltamoxifen-deoxyguanosine adduct in which the alpha-position of the metabolite N-desmethyltamoxifen is linked covalently to the amino group of deoxyguanosine. Adduct 2 was confirmed to be the trans isomer of alpha-(N2-deoxyguanosinyl)tamoxifen, as previously suggested by co-chromatography.

Animals↗

PubMed1999

Butadiene diolepoxide- and diepoxybutane-derived DNA adducts at N7-guanine: a high occurrence of diolepoxide-derived adducts in mouse lung after 1,3-butadiene exposure.

Butadiene (BD) is a high production volume chemical and is known to be tumorigenic in rodents. BD is metabolized to butadiene monoepoxide (BMO), diepoxybutane (DEB) and butadiene diolepoxide (BDE). These epoxides are genotoxic and alkylate DNA both in vitro and in vivo, mainly at the N7 position of guanine. In this study, a 32P-post-labeling/thin-layer chromatography (TLC)/high-pressure liquid chromatography (HPLC) assay for BDE and DEB adducts at the N7 of guanine was developed and was used in determining the enantiomeric composition of the adducts and the organ dose of BD exposure in lung. Exposure of 2'-deoxyguanosine (dGuo), 2'-deoxyguanosine-5'-phosphate (5'-dGMP) and 2'-deoxyguanosine-3'-phosphate (3'-dGMP) to racemic BDE followed by neutral thermal hydrolysis gave two products (products 1 and 2) that were identified by MS and UV and NMR spectroscopy as a diastereomeric pair of N7-(2,3,4-trihydroxybutan-1-yl)-guanines. Exposure of dGuo nucleotides to RR/SS DEB (also referred to as dl DEB) followed by thermal depurination resulted in a single product coeluting with the BDE product 1. If the reaction mixture of BDE and 5'-dGMP was analyzed by HPLC before hydrolysis of the glycosidic bond, four major nucleotide alkylation products (A, B, C and D) with identical UV sepectra were detected. The products were isolated and hydrolyzed, after which A and C coeluted with product 1 and B and D coeluted with the product 2. The major adduct of DEB-exposed 5'-dGMP was N7-(2-hydroxy-3,4-epoxy-1-yl)-dGMP (product E). A 32P-post-labeling assay was used to detect BDE- and DEB-derived N7-dGMP adducts in DNA. Levels of adducts increased with a dose of BDE and DEB and exhibited a half life of 30 +/- 3 (r = 0.98) and 31 +/- 4 h (r = 0.95), respectively. Incubation of DEB-modified DNA at 37 degrees C at neutral pH for up to 142 h did not lead to an increase of N7-(2,3,4-trihydroxybutan-1-yl)-dGMP in the DNA. These observations led to the conclusion that the N7-(2,3, 4-trihydroxybutan-1-yl)-dGMP adducts in DNA can be used as a marker of BDE exposure and that N7-(2-hydroxy-3,4-epoxy-1-yl)-dGMP adducts are related to DEB exposure. Dose-related levels of BDE- and DEB-derived adducts were detected in lungs of mice inhaling butadiene. Most of the N7-dGMP adducts (73%; product D) were derived from the 2R-diol-3S-epoxide of 1,3-butadiene. The data presented in this paper indicate that in vivo, 98% of N7-dGMP alkylation after BD exposure is derived from BDE, and approximately 2% of the adducts were derived from DEB and BMO.

Animals↗

PubMed1999

PSA decline is an independent prognostic marker in hormonally treated prostate cancer.

OBJECTIVE: The aim of this study was to estimate the prevalence of primary hormone-refractory prostate cancer and to evaluate the prognostic value of decline of prostate-specific antigen (PSA) after primary hormonal therapy. MATERIAL AND METHODS: The material consisted of 236 consecutive, hormonally treated prostate cancer patients, whose clinicopathological findings, as well as serum PSA values, were retrieved from patient files. Multivariate analysis was performed based on the PSA decline at 12 months from the commencement of therapy and patients were thereafter categorised into four groups: complete response (CR), partial response (PR), stable disease (SD), and no response (NR) according to the biochemical response. RESULTS: Only 14 (5.9%) of the patients were included in the NR group, i.e. PSA declined less than 50%, suggesting that primary androgen-independent prostate cancer is uncommon. The PSA decline was significantly (p < 0.001) associated with cancer-specific survival. Patients with CR had a median survival of more than 6 years, whereas those with NR had a median survival of only 14 months. In multivariate analysis, PSA decline showed independent prognostic value together with M-stage and histological grade. CONCLUSIONS: Primary prostate cancer is probably even more sensitive to hormonal treatment than previously assumed, and PSA decline seems to be useful in predicting disease outcome after hormonal therapy.

Adenocarcinoma↗

PubMed1998

Column switching in capillary liquid chromatography-tandem mass spectrometry for the quantitation of pg/ml concentrations of the free basic drug tolterodine and its active 5-hydroxymethyl metabolite in microliter volumes of plasma.

A capillary column switching system was developed for the determination of low, unbound concentrations of the basic drug tolterodine and its active 5-hydroxymethyl (5-HM) metabolite in human plasma. Free concentrations of tolterodine and 5-HM at pM and nM (pg/ml and ng/ml) levels were obtained by ultrafiltration of 40-400 microliters plasma at 37 degrees C. The free fraction (%) was independent of the plasma concentrations of the analytes. Detection of the analytes was performed by sheathless electrospray tandem mass spectrometry in the multiple-reaction monitoring mode. The selectivity of the mass spectrometric detection and the additional clean-up on the pre-column allowed direct injection of the ultrafiltrated plasma samples. Tolterodine and 5-HM were pre-concentrated on a reversed-phase capillary pre-column (1 cm x 200 microns) and subsequently backflushed onto the separation column (25 cm x 200 microns). The stability of the chromatographic system was good; a large number of ultrafiltrated plasma samples could be injected and the relative standard deviation of the retention times was typically < or = 1% (within-day). The accuracy was between 86 and 105% and the precision was between 1 and 7% without the use of an internal standard. Linear calibration curves were obtained between 100 pM and 100 nM.

Benzhydryl Compounds↗

PubMed1998

DNA adducts in mouse testis and lung after inhalation exposure to 1,3-butadiene.

1,3-Butadiene is a widely used industrial chemical and also an environmental contaminant. Recent findings have shown that butadiene can also be a male germ cell mutagen. In this study, DNA adduct formation in testis and lung has been explored by using N7-alkylated guanines as a marker of biological effective dose. The adducts measured were the four structurally different guanine N7-adducts alkylated by butadienemonoepoxide, the main metabolite of 1,3-butadiene. This study demonstrates the dose-dependent adduct formation in lung and testis. At lower exposures (50 and 200 ppm) the adduct levels were about the same in the two organs, but at 500 ppm the adduct level was significantly (p < 0.03) higher in testis than in lung. The enantiomeric composition of the adducts detected was also different. In lung, all 4 possible adducts were present (S-C-1" dominating, 49%), but in testis only two out of four adducts were detected (S-C-2" being the most abundant adduct, 71%). These novel observations indicate that the DNA repair is different in these two organs studied and that heritable genetic effects observed may be mediated through the DNA adducts.

Alkylation↗

PubMed1998

Genetic alterations in hormone-refractory recurrent prostate carcinomas.

To study the genetic basis of tumor progression, we have screened 37 hormone-refractory prostate carcinomas for genetic changes by comparative genomic hybridization (CGH). All recurrent tumors showed genetic aberrations, with a mean total number of changes per tumor of 11.4 (range, 3 to 23). The most common genetic aberrations were losses of 8p (72.5%), 13q (50%), 1p (50%), 22 (45%), 19 (45%), 10q (42.5%), and 16q (42.5%) and gains of 8q (72.5%), 7q (40%), Xq (32.5%), and 18q (32.5%). The CGH results were further validated with fluorescence in situ hybridization (FISH) using probes for pericentromeric regions of chromosomes 7, 8, and 18 as well as probes for caveolin (7q31), c-myc (8q24), and bcl-2 (18q21.3). In addition, the samples had previously been analyzed for androgen receptor gene copy number. CGH and FISH results were concordant in 78% of cases. Seventeen of twenty-two tumors showed an increased copy number of c-myc by FISH. However, only 5 of 17 (29%) of the cases showed high-level (more than threefold) amplification. Both CGH and FISH findings suggested that in most of the cases 8q gain involves the whole q-arm of the chromosome. Four of seventeen (24%) cases showed increased copy number of bcl-2 by FISH; however, no high-level amplifications were found. To evaluate the clonal relationship of the primary and recurrent tumors, six primary-recurrent tumor pairs from the same patients were studied by CGH. In three of six cases (50%), the recurrent tumor had more than one-half of the aberrations found in the corresponding primary tumor, indicating a close clonal relationship. In the rest of the cases, such a linear clonal relationship was less evident. Altogether, these results suggest that recurrent prostate carcinomas are genetically unstable. The resulting heterogeneity may well underlie the poor responsiveness of hormone-refractory tumors to treatment.

Carcinoma↗