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21.
22.
Dibenzo[a,l]pyrene-induced DNA adduction, tumorigenicity, and Ki-ras oncogene mutations in strain A/J mouse lung 总被引:1,自引:0,他引:1
Prahalad AK; Ross JA; Nelson GB; Roop BC; King LC; Nesnow S; Mass MJ 《Carcinogenesis》1997,18(10):1955-1963
Dibenzo[a,l]pyrene (DB[a,l]P), an environmental polycyclic aromatic
hydrocarbon, is the most potent carcinogen ever tested in mouse skin and
rat mammary gland. In this study, DB[a,l]P was examined for DNA adduction,
tumorigenicity, and induction of Ki-ras oncogene mutations in tumor DNA in
strain A/J mouse lung. Groups of mice received a single i.p. injection of
0.3, 1.5, 3.0, or 6.0 mg/kg DB[a,l]P in tricaprylin. Following treatment,
DNA adducts were measured at times between 1 and 28 days, while tumors were
counted at 250 days and analyzed for the occurrence of point mutations in
codons 12 and 61 of the Ki-ras oncogene. DB[a,l]P in strain A/J mouse lung
induced six major and four minor DNA adducts. Maximal levels of adduction
occurred between 5 and 10 days after injection followed by a gradual
decrease. DB[a,l]P-DNA adducts in lung tissue were derived from both anti-
and syn-11,12- dihydroxy-13,14-epoxy-
11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]PDE) and both
deoxyadenosine (dAdo) and deoxyguanosine (dGuo) residues in DNA as revealed
by cochromatography. The major adduct was identified as a product of the
reaction of an anti-DB[a,l]PDE with dAdo in DNA. DB[a,l]P induced
significant numbers of lung adenomas in a dose- dependent manner, with the
highest dose (6.0 mg/kg) yielding 16.1 adenomas/mouse. In
tricaprylin-treated control animals, there were 0.67 adenomas/mouse. Based
on the administered dose, DB[a,l]P was more active than other environmental
carcinogens including benzo[a]pyrene. As a function of time-integrated DNA
adduct levels, DB[a,l]P induced lung adenomas with about the same potency
as other PAHs, suggesting that the adducts formed by DB[a,l]P are similar
in carcinogenic potency to other PAHs in the strain A/J mouse lung model.
Analysis of the Ki- ras mutation spectrum in DB[a,l]P-induced lung tumors
revealed the predominant mutations to be G-->T transversions in the
first base of codon 12, A-->G transitions in the second base of codon
12, and A-->T transversions in the second or third base of codon 61,
concordant with the DNA adduct profile.
相似文献
23.
Nesnow S; Davis C; Nelson G; Ross JA; Allison J; Adams L; King LC 《Carcinogenesis》1997,18(10):1973-1978
C3H10T1/2CL8 (C3H10T1/2) mouse embryo fibroblasts were used to study the in
vitro carcinogenic activities of dibenzo[a,l]pyrene (DB[a,l]P) and
benzo[a]pyrene (B[a]P). The morphological transforming activities of these
rodent carcinogens were compared using replicate concentration- response
studies. In concentration ranges where both polycyclic aromatic
hydrocarbons (PAHs) were active, DB[a,l]P proved to be four to 12 times as
potent as B[a]P based on concentration. At lower concentrations DB[a,l]P
was active at 0.10 and 0.20 microM, concentrations where B[a]P was
inactive. This makes DB[a,l]P the most potent non-methylated PAH evaluated
to date in C3H10T1/2 cells. DNA adducts of DB[a,l]P in C3H10T1/2 cells were
analyzed by both TLC and TLC/HPLC 32P-postlabeling methods using
mononucleotide 3'-phosphate adduct standards derived from the reactions of
anti-DB[a,l]P-11,12-diol- 13,14-epoxide (anti-DB[a,l]PDE) and
syn-DB[a,l]P-11,12-diol-13,14- epoxide (syn-DB[a,l]PDE) with deoxyadenosine
3'-monophosphate and deoxyguanosine 3'-monophosphate. All of the DNA
adducts observed in C3H10T1/2 cells treated with DB[a,l]P were identified
as being derived from the metabolism of DB[a,l]P to its fjord region diol
epoxides through DB[a,l]P-11,12-diol. The predominant adduct was identified
as an anti-DB[a,l]PDE-deoxyadenosine adduct. Other major adducts were anti-
DB[a,l]PDE-deoxyguanosine and syn-DB[a,l]PDE-deoxyadenosine adducts with
minor amounts of syn-DB[a,l]PDE-deoxyguanosine adducts. These DNA adduct
data are consistent with similar findings of DB[a,l]PDE- deoxyadenosine
adducts in mouse skin studies and human mammary cells in culture.
相似文献
24.
Early stage nasopharyngeal carcinoma: radiotherapy dose and time factors in tumor control 总被引:1,自引:0,他引:1
Chang JT; See LC; Liao CT; Chen LH; Leung WM; Chen SW; Chen WC 《Japanese journal of clinical oncology》1998,28(3):207-213
OBJECTIVE: To evaluate radiotherapy dose and length of treatment in the
control of early stage nasopharyngeal carcinoma (NPC) treated with a
combination of external radiotherapy and brachytherapy, MATERIALS &
METHODS: We reviewed the records of 133 patients with early stage
nasopharyngeal carcinoma (stage I or II, AJC/UICC staging system) who
received definitive radiotherapy in Chang Gung Memorial Hospital from 1979
to 1991. The median follow-up time was 7.1 years with a minimum of 2 years.
All patients were treated with megavoltage external radiotherapy to the
nasopharynx area (63-72 Gy) followed by high dose rate intracavitary
brachytherapy (5-16.5 Gy in one to three fractions, spaced 1-2 weeks
apart). The median total dose and time of irradiation was 75 Gy (69.8-81.4
Gy) and 11.6 weeks (7.8-20 weeks) respectively. Survival analysis was used
to examine the effect of several variables on prognosis. RESULTS: The
5-year rates were 86.4% for local control, 84.7% for disease free survival,
88.5% for actuarial survival and 84.2% for overall survival. The treatment
group (combination of time and dose of irradiation) was the most important
prognostic factor according to Cox's proportional hazard model. Patients
receiving radiation at a total dose of < or = 75 Gy completed in < 12
weeks showed the best prognosis. CONCLUSION: Treatment time and total
treatment dose are both important factors in treating early stage NPC.
Decreasing the total radiation time to < 12 weeks and not exceeding a
radiation dose of 75 Gy gave the best results.
相似文献
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28.
S-phase-specific regulation by deletion mutants of the human thymidine kinase promoter. 总被引:10,自引:2,他引:10 下载免费PDF全文
K E Lipson S T Chen J Koniecki D H Ku R Baserga 《Proceedings of the National Academy of Sciences of the United States of America》1989,86(18):6848-6852
The levels of thymidine kinase (TK; EC 2.7.1.21) mRNA were determined in nine established cell lines derived from TK-ts13, a temperature-sensitive mutant cell line that arrests in late G1 phase of the cell cycle at the restrictive temperature. The derivative cell lines carried either a cDNA or a minigene of human TK under the control of TK promoters of different lengths. A tenth cell line carried a human TK cDNA under the control of a simian virus 40 promoter. Two different assays were used to determine the S-phase-specific regulation of human TK mRNA levels in quiescent cells stimulated to proliferate. Results from these two assays indicated that (i) the first two introns of the human TK gene had no effect on the S-phase-specific regulation of TK mRNA levels, although the presence of introns increased the amount of TK mRNA; (ii) similar amounts of TK mRNA were present in cells containing constructs with an 83-base-pair (bp) promoter as with other TK promoters comprising up to approximately 4000 bp of 5' flanking sequence; (iii) a 456-bp promoter was fully S-phase-regulated, whereas the 83-bp promoter was only partially regulated; (iv) a 63-bp promoter was much less regulated than an 83-bp promoter; and (v) the crucial element in the 20-bp fragment comprising bp -83 to -64 has been localized, by site-directed mutagenesis, to the CCAAT element at -70. 相似文献
29.
A humanised tissue‐engineered bone model allows species‐specific breast cancer‐related bone metastasis in vivo 下载免费PDF全文
VMC Quent AV Taubenberger JC Reichert LC Martine JA Clements DW Hutmacher D Loessner 《Journal of tissue engineering and regenerative medicine》2018,12(2):494-504
Bone metastases frequently occur in the advanced stages of breast cancer. At this stage, the disease is deemed incurable. To date, the mechanisms of breast cancer‐related metastasis to bone are poorly understood. This may be attributed to the lack of appropriate animal models to investigate the complex cancer cell–bone interactions. In this study, two established tissue‐engineered bone constructs (TEBCs) were applied to a breast cancer‐related metastasis model. A cylindrical medical‐grade polycaprolactone‐tricalcium phosphate scaffold produced by fused deposition modelling (scaffold 1) was compared with a tubular calcium phosphate‐coated polycaprolactone scaffold fabricated by solution electrospinning (scaffold 2) for their potential to generate ectopic humanised bone in NOD/SCID mice. While scaffold 1 was found not suitable to generate a sufficient amount of ectopic bone tissue due to poor ectopic integration, scaffold 2 showed excellent integration into the host tissue, leading to bone formation. To mimic breast cancer cell colonisation to the bone, MDA‐MB‐231, SUM1315, and MDA‐MB‐231BO breast cancer cells were cultured in polyethylene glycol‐based hydrogels and implanted adjacent to the TEBCs. Histological analysis indicated that the breast cancer cells induced an osteoclastic reaction in the TEBCs, demonstrating analogies to breast cancer‐related bone metastasis seen in patients. 相似文献
30.
Maggie Tabberer David A. Lomas Ruby Birk Noushin Brealey Chang-Qing Zhu Steve Pascoe Nicholas Locantore David A. Lipson 《Advances in therapy》2018,35(1):56-71