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Biomedical subjects

M You

Publications and source records attributed to M You.

At least 55 records · Page 3Linked to original sources
PubMed1998

Modulation of methylnitrosourea-induced breast cancer in Sprague Dawley rats by dehydroepiandrosterone: dose-dependent inhibition, effects of limited exposure, effects on peroxisomal enzymes, and lack of effects on levels of Ha-Ras mutations.

Dehydroepiandrosterone (DHEA), the major steroid precursor of androgens and estrogens produced in peripheral tissues in primates, is an effective chemopreventive agent in the N-methyl-N-nitrosourea (MNU)-induced rat mammary tumor model. Dietary DHEA (5-600 ppm; 600 mg/kg diet) was administered beginning 1 week before MNU and administered continually throughout the duration of the experiment. The highest dose of DHEA (600 ppm) significantly decreased tumor incidence from 95 to 45% and increased tumor latency and decreased tumor multiplicity from 4.1 to 0.5 tumors/rat. Lower doses of DHEA (5, 24, and 120 ppm) were also effective, decreasing tumor multiplicity by 28, 40, and 55%, respectively, increasing tumor latency in a dose-dependent manner but only minimally affecting final tumor incidence. DHEA in the diet caused a dose-dependent increase in serum levels of DHEA. The 120-ppm dietary dose of DHEA resulted in serum levels of DHEA of approximately 42 pmol/ml levels, similar to those seen in young humans. When we examined whole mounts of mammary glands derived from rats exposed to higher levels of DHEA (600 ppm), we observed a striking increase in lobular development. The doses of DHEA used in these studies (< or =600 ppm) had minimal effects on the induction of fatty acid CoA synthetase, a peroxisome-associated enzyme. In contrast, a dose of 2000 ppm substantially increased levels of peroxisome-associated fatty acid CoA synthetase. The varied and striking efficacy of DHEA was achieved in the absence of any significant effect on body weight gain in the treated rats. Furthermore, tumors from rats treated with MNU alone or rats treated with MNU plus DHEA were examined for the presence of mutations in the Ha-Ras oncogene. There was a slight decrease in the percentage of tumors bearing Ha-Ras mutations in tumors derived from MNU-control rats as contrasted with tumors from MNU-DHEA (120 and 600 ppm)-treated rats. Based on the striking chemopreventive efficacy of continual exposure to DHEA, we examined the effects of more limited exposure to DHEA. Rats were treated with DHEA for a period of 7 weeks immediately before and after MNU injection. Rats were then placed on the control diet for the ensuing 15 weeks. Even this limited exposure to DHEA for a period of 7 weeks profoundly decreased final tumor incidence and multiplicity. Additionally, we examined the effects of intermittent dosing with DHEA. Rats were treated alternatively at 3-week intervals either with diet containing DHEA or with control diet. It was found that this intermittent dosing with DHEA also substantially inhibited the formation of mammary tumors.

Animals↗
PubMed1998

Identification of v-Rel oncogene-induced inhibitor of apoptosis by differential display.

The v-Rel oncoprotein is a member of the Rel/NF-kappaB family of transcription factors. v-Rel induces oncogenic transformation and inhibits apoptosis. To identify aberrantly expressed cellular genes in v-Rel transformed cells, gene expression patterns in normal and v-Rel transformed cells were compared by mRNA differential display. Northern blotting analysis with radiolabeled cDNAs from differential display confirmed the reproducible differential expression of 10 transcripts in v-Rel transformed cells. One of the identified genes, termed ch-IAP1, encodes a chicken homolog of the inhibitor-of-apoptosis protein (IAP) family. ch-IAP1 contains N-terminal baculovirus IAP repeats (BIR), the hallmark of IAPs, and has a C-terminal RING finger motif commonly present in the other IAPs. Like other IAPs, ch-IAP1 is expressed predominantly in the cytoplasm of cells. ch-IAP1 is highly expressed in v-Rel transformed fibroblasts, B- and T-cell lines, and spleen cell lines. In contrast, ch-IAP1 expression levels were low in chicken cell lines transformed by several other unrelated tumor viruses. Additionally, ch-IAP1 expression is downregulated in temperature-sensitive (ts) v-Rel transformed spleen cells at the nonpermissive temperature. Overexpression of the full-length ch-IAP1 suppresses mammalian cell apoptosis induced by the interleukin-1-converting enzyme (ICE), a member of the mammalian caspase family of cysteine proteases. Furthermore, expression of exogenous ch-IAP1 inhibits apoptosis of ts v-Rel transformed spleen cells at the nonpermissive temperature.

Animals↗
PubMed1998

An ergonomic approach to public squatting-type toilet design.

This paper reports a case study on public squatting-type toilet design, which was undertaken with a special emphasis on ergonomic considerations. A field survey on the use of public toilets in Taipei reveals that almost half of the subjects take a non-sitting posture while using the sitting-type public toilets and 86% of the subjects agreed that the squatting-type public toilets better satisfy sanitary requirements. An experiment was conducted to determine relevant anthropometric data for a redesign of squatting-type toilets. One of the variables studied was the effect of the footstep slope on squatting comfort. A total of 80 subjects as tested on four footstep slopes: 0 degrees, 15 degrees, 30 degrees and 45 degrees. Their heart rates were measured before and after the test, and their subjective evaluations of squatting comfort were also recorded. The 15 degrees slope was found to be preferred. These findings were then used in design development where mock-ups were presented to subjects for evaluation, then modifications were made and further tests conducted for verification. The result shows that the ergonomic approach is feasible recommended to be adopted in the process of product design of such facilities.

Adolescent↗
PubMed1998

Preclinical and clinical models of lung cancer chemoprevention.

In smokers, beta-carotene, retinol, and vitamins E and C appear to have little or a negative effect against human lung cancer development. Similarly, these chemicals have generally failed to inhibit lung tumorigenesis in rodents. The agents that have been shown to inhibit lung tumorigenesis in rodents, such as glucocorticoids, green tea, NSAIDs, and isothiocyanates, have not been tested yet in humans. These agents may be more effective in preventing human lung cancer in smokers than are the chemicals tested so far, especially if they are delivered by inhalation route.

Animals↗
PubMed1998

Effect of green tea on p53 mutation distribution in ultraviolet B radiation-induced mouse skin tumors.

In the present study, administration of green tea to SKH-1 mice, via the drinking fluid, was found to significantly reduce the incidence and volume of ultraviolet B (UVB) radiation-induced skin tumors. Thirty-six skin tumors induced by UVB and 32 skin tumors induced by UVB, in mice treated with green tea in their drinking water, were collected and examined for the presence of mutations in the p53 gene. Polymerase chain reaction products from p53 exons 5-8 were screened by single-strand conformation polymorphism and direct sequence analyses. Eight of 36 UVB-induced tumors contained nine p53 mutations, with four in exon 5 and five in exon 8. In contrast, nine of 32 UVB-induced tumors in mice treated with green tea contained 11 p53 mutations, with two in exon 5, five in exon 6 and four in exon 8. All of the p53 mutations occurred at dipyrimidine sequences. These results were further corroborated by p53 immunohistochemistry. The most frequent mutations were C-->T or T-->C transitions, which are consistent with the genetic alterations caused by UVB exposure. Interestingly, mutations found in exon 6 of the p53 gene occurred only in tumors from the UVB/green tea group. Thus, the tumors observed in UVB/green-tea-treated mice have a different exon distribution of p53 mutations than tumors obtained from mice treated with UVB alone.

Animals↗
PubMed1998

Chemopreventive effects of the aromatase inhibitor vorozole (R 83842) in the methylnitrosourea-induced mammary cancer model.

The chemopreventive activity of the highly specific nonsteroidal aromatase inhibitor, vorozole, was examined in the methylnitrosourea (MNU)-induced rat model of mammary carcinogenesis. Various doses of vorozole (0.08-1.25 mg/kg body wt/day) were administered daily (by gavage) to female Sprague-Dawley rats starting at 43 days of age. Seven days later, the rats were given a single i.v. dose of MNU (50 mg/kg body wt). Rats were continually treated with vorozole until the end of the experiment (120 days post-MNU). Vorozole caused a dose dependent inhibition of mammary cancer multiplicity. The highest dose of vorozole (1.25 mg/kg body wt/day) decreased cancer multiplicity by approximately 90%, and simultaneously decreased cancer incidence from 100 to 44%. The next two highest doses of vorozole (0.63 and 0.31 mg/kg body wt/day) inhibited MNU-induced mammary cancer multiplicity by 70-80%. Even the two lowest doses of vorozole (0.16 and 0.08 mg/kg body wt/ day) decreased cancer multiplicity -50%. Serum level determinations were performed on a variety of endpoints at either 4 or 24 h following the last dose of vorozole. Insulin-like growth factor (IGF)-1 levels were slightly, but significantly, increased by vorozole treatment. Vorozole induced striking increases in serum testosterone levels at 4 h at all the dose levels employed. Testosterone levels were significantly elevated over controls at 24 h in rats given the lower doses of vorozole (0.08-0.31 mg/kg body wt/day), but were significantly lower than in rats administered the higher doses of vorozole (0.63 or 1.25 mg/kg body wt/ day). This result presumably reflects the limited half-life of vorozole in rats. In a second series of experiments, the effects of limited duration of dosing with vorozole (2.5 mg/kg body wt/day) or intermittent dosing with vorozole were determined. Treatment of rats with vorozole for limited time periods, from 3 days post-MNU administration until 30 or 60 days post-MNU treatment, resulted in significant delays in the time to appearance of palpable cancers. However, these limited treatments did not greatly affect the overall incidence or multiplicity of mammary cancers when compared with the MNU controls at the end of the study (150 days post-MNU). Finally, the effects of intermittent dosing with vorozole (2.5 mg/kg body wt/day) were examined. Rats were administered cycles of vorozole daily for a period of 3 weeks followed by treatment with the vorozole vehicle for the next 3 weeks (total of four cycles). Although this intermittent treatment did inhibit the appearance of new tumors during each of the periods that vorozole was administered, it did not cause regression of palpable cancers.

Animals↗
PubMed1998

Decreased expression of the adenomatous polyposis coli (Apc) and mutated in colorectal cancer (Mcc) genes in mouse lung neoplasia.

A decrease in the intracellular concentrations of the transcripts for some tumor suppressor genes has been found during murine lung tumorigenesis; for p15INK4b and p16INK4a, this was due to homozygous deletions. We report here a decrease in the mRNA levels of the mutated in colorectal cancer (Mcc) and adenomatous polyposis coli (Apc) genes in mouse lung tumors and some neoplastic cell lines. This was assessed both by northern blotting and reverse transcriptase-polymerase chain reaction of RNA isolated from lung tumors that had been induced by urethane, N-nitrosodiethylamine, or 3-methylcholanthrene in (A/J x C57BL/6) F1 or A/J mice. A reduced amount of both Mcc and Apc messages was also seen when two neoplastic cell lines, a spontaneous transformant (E9) and a line derived from a chemically induced solid tumor (82-132), were compared with two independently derived nontumorigenic cell lines (E10 and C10); E9 was derived from E10, and all of these lines are probably of alveolar type 2 cell origin. A cell line derived from a chemically induced papillary lung tumor probably of bronchiolar Clara cell origin (LM2) had Mcc mRNA levels similar to those of C10 and E10 but reduced Apc mRNA levels. A line (p53-823) derived from a papillary tumor that arose in a mouse with a mutated p53 transgene had a reduced amount of the Mcc gene product only. These differential changes in the relative amounts of Apc and Mcc messages in LM2 and p53-823) cells may serve as useful models for studying the regulation of their expression. Both messages had half-lives of 6-9 h in normal E10 and neoplastic E9 cells, so decreased message stability does not account for these reductions. This is the first report of estimated degradation rates of these mRNAs. Apc and Mcc message content did not vary as a function of growth status of the cell lines. Single-strand conformation polymorphism analysis did not reveal mutations in Apc coding regions known to have a high mutation frequency in human colon tumors. Loss of heterozygosity of Apc and Mcc was not found in tumors that developed in the F1 mice, implying a lack of allelic deletions. These changes in tumor suppressor gene expression may contribute to the development and maintenance of neoplasia in lung epithelium.

Animals↗
PubMed1997

Positive effects of SH2 domain-containing tyrosine phosphatase SHP-1 on epidermal growth factor- and interferon-gamma-stimulated activation of STAT transcription factors in HeLa cells.

SHP-1 (also known as PTP1C, SHPTP-1, SHP, and HCP) is an SH2 domain-containing protein-tyrosine phosphatase. We have stably overexpressed the native form and a catalytically inactive cysteine to serine mutant of the enzyme, SHP-1-(Cys --> Ser), in human cervical carcinoma HeLa cells. Following stimulation of the cells with epidermal growth factor (EGF) and interferon-gamma (INF-gamma), signal transducers and activators of transcription (STAT) activity was analyzed by using two 32P-labeled DNA probes, namely hSIE which is derived from a high affinity mutant form of the serum-inducible element in the c-fos promotor and GAS which resembles the INF-gamma activation site. EGF induced hSIE binding activity only, and the activity was suppressed by approximately 70% when the inactive mutant form of SHP-1 was expressed but was essentially unaffected by expression of the native enzyme. INF-gamma treatment resulted in appearance of both hSIE and GAS binding activities. While expression of the inactive mutant reduced the activities by 30-50%, the native enzyme caused a 20-30% increase. Consistent with effects on STAT activation, altered SHP-1 expression also affected EGF-induced activation of the mitogen-activated protein kinase pathway; expression of SHP-1-(Cys --> Ser) inhibited activity of MEK by approximately 25%, whereas expression of SHP-1 resulted in a approximately 25% increase. Further studies revealed that overexpression of SHP-1 caused decreased tyrosine phosphorylation of the EGF receptor and that EGF induced phosphorylation and recruitment of SHP-1. Together, the data suggest that SHP-1 is positively involved in EGF- and INF-gamma-induced STAT activation in non-hematopoietic HeLa cells and that, in the EGF signaling system, SHP-1 functions at least partly by modulating tyrosine phosphorylation of EGF receptor.

Enzyme Activation↗
PubMed1997

Tissue-specific expression of the K-ras allele from the A/J parent in (A/J x TSG-p53) F1 mice.

Tissue-specific expression of parental K-ras allele(s) was investigated by single-strand conformation polymorphism analysis of the 3' untranslated region of the K-ras gene in normal lung, spleen, liver and kidney from (A/J x TSG-p53) F1 mice. The expression of A/J K-ras allele was equal to that of C57BL/6J allele in normal spleen, liver and kidney. However, transcripts from A/J K-ras allele were found to be 2-12-times greater than those from C57BL/6J allele in lung tissues harvested over a 20-week period. Similar to our previous observation with dimethylnitrosamine- and benzo[a] pyrene-induced lung tumors, K-ras mRNA transcribed from A/J allele was 10-40-times more abundant than those from C57BL/6J allele in all of 40 (A/J x TSG-p53) F1 mouse lung tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. In addition, K-ras mutations (G to A transitions at the second base of codon 12) were detected in 38 of 40 (95%) lung tumors and all of the mutations were found on the allele inherited from the A/J parent. These data demonstrate tissue-specific allele-specific transcription of the K-ras gene and provide further support to the thesis that K-ras allele itself is a primary mouse lung tumor susceptibility gene.

Alleles↗
PubMed1997

Cancer chemopreventive potential of sulforamate, a novel analogue of sulforaphane that induces phase 2 drug-metabolizing enzymes.

Chemoprevention involves the use of natural or synthetic substances to reduce the risk of developing cancer. Two dietary components capable of mediating chemopreventive activity in animal models by modulation of drug-metabolizing enzymes are sulforaphane, an aliphatic isothiocyanate, and brassinin, an indole-based dithiocarbamate, both found in cruciferous vegetables. We currently report the synthesis and activity of a novel cancer chemopreventive agent, (+/-)-4-methylsulfinyl-1-(S-methyldithiocarbamyl)-butane (trivial name, sulforamate), an aliphatic analogue of brassinin with structural similarities to sulforaphane. This compound was shown to be a monofunctional inducer of NAD(P)H:quinone oxidoreductase [quinone reductase (QR)], a Phase II enzyme, in murine Hepa 1c1c7 cell culture and two mutants thereof. Induction potential was comparable to that observed with sulforaphane (concentration required to double the specific activity of QR, approximately 0.2 microM), but cytotoxicity was reduced by about 3-fold (IC50 approximately 30 microm). In addition, sulforaphane, as well as the analogue, increased glutathione levels about 2-fold in cultured Hepa 1c1c7 cells. Induction of QR was regulated at the transcriptional level. Using Northern blotting techniques, time- and dose-dependent induction of QR mRNA levels were demonstrated in Hepa 1c1c7 cell culture. To further investigate the mechanism of induction, HepG2 human hepatoma cells were transiently transfected with QR-chloramphenicol acetyltransferase plasmid constructs containing various portions of the 5'-region of the QR gene. Sulforaphane and the analogue significantly induced (P < 0.0001) CAT activity at a concentration of 12.5 microM by interaction with the antioxidant responsive element (5-14-fold induction) without interacting with the xenobiotic responsive element. Moreover, both compounds significantly induced mouse mammary QR and glutathione S-transferase activity (feeding of 3 mg/mouse intragastric for 4 days), whereas the elevation of hepatic enzyme activities was less pronounced. Both sulforaphane and the analogue were identified as potent inhibitors of preneoplastic lesion formation in carcinogen-treated mouse mammary glands in organ culture (84 and 78% inhibition at 1 microm, respectively). On the basis of these results, the sulforaphane analogue can be regarded as a readily available promising new cancer chemopreventive agent.

Animals↗
PubMed1997

Chemopreventive effect of perillyl alcohol on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced tumorigenesis in (C3H/HeJ X A/J)F1 mouse lung.

This study was designed to test the chemopreventive potential of perillyl alcohol, an inhibitor of farnesyltransferase, in a mouse lung tumor bioassay. Perillyl alcohol is a naturally occurring monoterpene found in lavender, cherries, and mint. We have shown previously that the majority of lung tumors in this bioassay have an activating mutation in the K-ras gene, which occurs early in the development of mouse lung carcinogenesis. The Ras protein undergoes a series of post-translational modifications, the first of which is farnesylation at the cysteine of the C-terminal CAAX motif. These modifications lead to the anchoring of Ras p21 to the plasma membrane in its biologically active state. Activated Ras p21 couples growth regulatory signals from receptor tyrosine kinases to cytoplasmic second messengers. In a preliminary study, we determined the maximum tolerated dose of perillyl alcohol to be 75 mg/kg body weight. For the bioassay, 5-week-old male (C3H/HeJ X A/J) F1 hybrid mice were randomized into trial groups, and treated with perillyl alcohol three times per week i.p., starting 1 week prior to initiation with the carcinogen NNK, and continuing for 22 weeks after initiation. Our results show a 22% reduction in tumor incidence, and a 58% reduction in tumor multiplicity. Our study demonstrates that perillyl alcohol is an effective chemopreventive compound in the mouse lung tumor bioassay.

Animals↗
PubMed1997

Effect of early vs. late administration of 4-hydroxyphenylretinamide (4-HPR) on N-methyl-N-nitrosourea (MNU)-induced mammary tumorigenesis.

Mammary tumors were induced in 48-52-day-old female Sprague-Dawley rats in metestrus or diestrus with a single jugular injection of MNU (50 mg/kg). Control rats received the saline vehicle (Group 4 n = 9). Rats were fed 4% Teklad diet containing either 0 (Group 3, n = 20) or 782 mg 4-HPR/kg diet. 4-HPR supplementation was initiated either 1 week prior to (Group 1, n = 14) or 4 weeks following MNU administration (Group 2, n = 19). Neither body weight nor food intake differed significantly between treatment groups. Feeding of 4-HPR 1 week prior to tumor induction reduced the number of tumors (0.8 +/- .2) when compared to MNU control rats (2.1 +/- .4). Immunohistochemical staining of mammary tumor sections for PCNA was quantitated by microdensitometry and expressed as an HSCORE. No differences in HSCORE were observed between tumor groups although the percentage of nuclear area occupied by intermediate and darkly stained nuclei was reduced in the late 4-HPR group. GC-->AT transitions in codon 12 of the H-ras gene were detected in 50% (12/24) of MNU control tumors, 60% (6/10) of early 4-HPR tumors, and 38% (6/16) of late 4-HPR tumors. Mutation rates did not differ significantly between groups. 4-HPR appears to be a more effective chemopreventive when fed during the initiation period.

Animals↗
PubMed1997

Isometric muscle strength of Chinese young males in Taiwan.

This paper represents the results of an anthropometric measurement of the isometric muscle strength of Chinese young males in Taiwan aged from 16 to 20 years. The study uses a sample of 120 male students and measures four types of muscle strength: (1) right arm strength in exerting pull, push, adduction, abduction, lift, and press directions with five elbow angles (60, 90, 120, 150 and 180 degrees) in seated posture; (2) grip strength of both hands; (3) backlift strength: and (4) chest expanding strength. The obtained data are analysed and listed. Comparisons are made between the results of this study and those from domestic and foreign studies available in the literature. In general, their pattern is similar, but values obtained in this study are relatively smaller than those obtained in western countries.

Adolescent↗
PubMed1997

Smad4 (homolog of human DPC4) and Smad2 (homolog of human JV18-1): candidates for murine lung tumor resistance and suppressor genes.

In this study we investigated the mouse mad-related genes, Smad4/Dpc4 and Smad2 (homolog of JV18-1), as candidates for involvement in lung tumor resistance and suppression. These genes are located in a region of mouse chromosome 18 that is syntenic with human 18q21.1, where several genes that are mutated in various cancers have been mapped. A newly identified murine lung tumor resistance locus, Par2 has also been mapped to this region of chromosome 18. We found no mutations in the coding regions of either gene in 11 lung tumors from B6CF1 (C57BL/6 x BALB/c) mice by RT-PCR and SSCP/RFLP, suggesting that these genes are not mutated in lung carcinogenesis in this strain. Moreover, loss of heterozygosity in this region of chromosome 18 was not detected in 28 lung adenocarcinomas from B6CF1 mice, 17 lung adenocarcinomas from B6C3F1 mice or 18 lung adenocarcinomas from AB6F1 mice. These data provide evidence that a 'classical' tumor suppressor gene for mouse lung carcinogenesis in these strains does not reside in this region. In order to investigate Smad4/Dpc4 and Smad2 as candidates for the Par2 resistance locus mapped to this region, we also sequenced the coding regions of both genes in cDNA from normal lungs of A/J, BALB/c and C57BL/6 inbred strains of mice. No polymorphisms were detected in the coding region of Smad4. In Smad2, two sequence polymorphisms were identified that are not in the conserved regions of the gene. Northern blot analysis revealed no differential expression in normal lung tissue among the three strains for either gene. Thus, in this study we found no evidence that either Smad4 or Smad2 represents the Par2 lung tumor resistance locus or is a lung tumor suppressor gene in the B6CF1 mice.

Animals↗
PubMed1997

ch-IAP1, a member of the inhibitor-of-apoptosis protein family, is a mediator of the antiapoptotic activity of the v-Rel oncoprotein.

The oncoprotein v-Rel, a member of the Rel/NF-kappaB family of transcription factors, induces neoplasias and inhibits apoptosis. To identify differentially regulated cellular genes and to evaluate their relevance to transformation and apoptosis in v-Rel-transformed cells, mRNA differential display has been used. One of the recovered cDNAs corresponds to a gene that was highly expressed in v-Rel-transformed fibroblasts. Analysis of the isolated full-length cDNA of a chicken inhibitor-of-apoptosis protein (ch-IAP1) revealed that it encodes a 68-kDa protein that is highly homologous to members of the IAP family, such as human c-LAP1. Like other IAPs, ch-IAP1 contains the N-terminal baculovirus IAP repeats and C-terminal RING finger motifs. Northern blot analysis identified a 3.3-kb ch-IAP1 transcript expressed at relatively high levels in the spleen, thymus, bursa, intestine, and lungs. Expression of v-Rel in fibroblasts, a B-cell line, and spleen cells up-regulated the expression of ch-IAP1. In contrast, ch-IAP1 expression levels were low in chicken cell lines transformed by several other unrelated tumor viruses. ch-IAP1 was expressed predominantly in the cytoplasm of the v-Rel-transformed cells. ch-IAP1 suppressed mammalian cell apoptosis induced by the overexpression of the interleukin-1-converting enzyme. Expression of exogenous ch-IAP1 in temperature-sensitive v-Rel transformed spleen cells inhibited apoptosis of these cells at the nonpermissive temperature. Collectively, these results suggest that ch-IAP1 is induced during the v-Rel-mediated transformation process and functions as a suppressor of apoptosis in v-Rel-transformed cells.

Amino Acid Sequence↗
PubMed1997

Genetic alterations in mouse lung tumors: implications for cancer chemoprevention.

Specific genetic alterations affecting known tumor suppressor genes and proto-oncogenes occur during mouse lung tumorigenesis. These include mutational activation of the K-ras gene, commonly seen at a frequency of about 80% in both spontaneously occurring and chemically induced adenomas and adenocarcinomas of the lung, suggesting that it is an early event that persists into malignancy. Allelic loss of the p16 tumor suppressor gene also is a frequent event, occurring in about 50% of mouse lung adenocarcinomas, but rarely in lung adenomas, suggesting that it may play a role in malignant conversion or progression of lung tumors. Other genetic alterations detected in mouse lung tumors include reduced expression of Rb and p16, and increased c-myc expression. Alterations of these genes are also common in the genesis of human lung cancer. Genetic linkage analysis to identify human lung cancer susceptibility genes is difficult due to the genetic heterogeneity and exposure to environmental risk factors. The mouse lung tumor model has become a valuable alternative for identifying such genes. Recently, loci responsible for mouse lung tumor susceptibility have been mapped to chromosomes 6, 9, 17, and 19, while those linked to lung tumor resistance have been mapped to chromosomes 4, 11, 12, and 18. Known candidate susceptibility or resistance genes include the K-ras proto-oncogene on chromosome 6, and the p16 tumor suppressor gene on chromosome 4. With evidence of considerable overlap between the genetic alterations that underlie human and mouse lung tumorigenesis, the mouse lung tumor model has been expanded to include pre-clinical screening of chemopreventive agents against human lung cancer. Studies on the modulation of genetic defects in mouse lung tumors by known and potential chemopreventive agents should further the goal of developing an effective prevention and treatment of lung cancer.

Animals↗