Biomedical subjects

Masahiro Takahashi

Publications and source records attributed to Masahiro Takahashi.

At least 19 recordsLinked to original sources

PubMed2007

Multidrug resistance-associated protein 7 expression is involved in cross-resistance to docetaxel in salivary gland adenocarcinoma cell lines.

The aim of the present study was to clarify whether ATP binding cassette transporters are refractory factors in head and neck cancers. For in vitro and in vivo chemotherapeutic studies, we used the following head and neck cancer cell lines: a mouse oral squamous cell carcinoma (SCC) cell line, Sq-1979; a human SCC cell line, SCCHA; a mouse salivary gland adenocarcinoma (SGA) cell line, NR-PG; and a human SGA cell line, HSY. We used a vinca alkaloid anticancer drug, vincristine (VCR), as a chemotherapeutic anticancer drug. To determine the cause of multidrug resistance, Western blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry of xenografted tumors in nude mice, drug efflux analysis, and drug efflux inhibitory assays were performed. VCR-treated cell lines, Sq-1979/VCR, SCCHA/VCR, NR-PG/VCR, and HSY/VCR, intensively expressed multidrug resistance (MDR) gene 1 mRNA and multidrug resistance associated protein (MRP) 1 mRNA. MRP7 mRNA and protein were expressed in NR-PG/VCR and HSY/VCR cells, but not in Sq-1979/VCR and SCCHA/VCR cells. In each cell clone of NR-PG/VCR and HSY/VCR, MRP7 mRNA was induced by VCR treatment, suggesting an acquired resistance to VCR in the context of MRP7 expression. In the in vivo chemotherapeutic nude mice model, VCR-treated xenografted SCCHA and HSY cells expressed MDR1 and MRP1. Moreover, MRP7 expression was immunohistochemically found in xenografted HSY cells of VCR-injected tumor-bearing mice, but not in SCCHA cells. Furthermore, doxorubicin accumulation was increased and drug cross-resistance to docetaxel decreased in HSY/VCR in the presence of a competitive MRP7 inhibitor, 17-beta-estradiol-(17-beta-D-glucuronide). These results indicate that MDR1 expression, MRP1 expression, and MRP7 expression are refractory factors in head and neck cancer chemotherapy and suggest that induction of MRP7 expression is involved in drug resistance to natural products, especially to docetaxel in SGA.

Adenocarcinoma↗

PubMed2006

Significance of extensive surgery including resection of the pancreas head for the treatment of gallbladder cancer--from the perspective of mode of lymph node involvement and surgical outcome.

The present study aimed to clarify the efficacy of extensive surgery, including pancreas head resection, for more complete lymphadenectomy in the treatment of gallbladder carcinoma. The study involved retrospective analyses of 65 consecutive patients with gallbladder carcinoma who underwent surgical resection between 1982 and 2003. Of these 65 patients, 41.5% displayed node-positive disease and among them 23.1% had positive para-aortic nodes. Of six node-positive 5-year survivors, five underwent pancreatoduodenectomy combined with S4aS5 hepatic subsegmentectomy. The 5-year survival rates were 76.2% for pN0, 30.0% for pN1, 45.8% for pN2, and 0% for pM1[lymph], respectively. Significant differences existed in survival rates. Postoperative recurrence was observed in 24.1% (13/54) of patients who underwent R0 resection. Of the four patients who displayed lymph node recurrence, two had pericholedocal and/or posterior pancreatoduodenal lymph node metastasis at the time of surgery and underwent pancreas-preserving regional lymphadenectomy. These results suggest that extensive resection, including resection of the pancreatic head, is effective in selected patients with up to pN2 lymph node metastasis, as long as complete removal of the cancer can be achieved. Pancreatoduodenectomy combined with S4aS5 hepatic subsegmentectomy should be considered when lymph node metastasis is obvious and the patient is in good condition.

Aged↗

PubMed2006

Effects of increasing concentrations of propofol on jugular venous bulb oxygen saturation in neurosurgical patients under normothermic and mildly hypothermic conditions.

BACKGROUND: Recent evidence suggested that propofol can deteriorate the cerebral oxygen balance compared with inhalational anesthetics. However, dose-related influences of propofol on cerebral oxygen balances were not clearly investigated. In the current study, the authors investigated the effects of increasing concentrations of propofol on jugular venous bulb oxygen saturation (Sj(O2)) in neurosurgical patients under normothermic and mildly hypothermic conditions. METHODS: After institutional approval and informed consent were obtained, 30 adult patients undergoing elective craniotomy were studied. Patients were randomly allocated to either normothermic or hypothermic group (n = 15 in each group). In the normothermic and hypothermic groups, tympanic membrane temperature was maintained at 36.5 degrees and 34.5 degrees C, respectively. Sj(O2) was measured at predicted propofol concentrations of 3, 5, and 7 microg/ml using a target-controlled infusion system in both groups. RESULTS: At a predicted propofol concentration of 3 microg/ml, there were no significant differences in Sj(O2) values between the normothermic and hypothermic groups, although the incidence of desaturation (Sj(O2) < 50%) was significantly higher in the normothermic group than in the hypothermic group (30% vs. 13%; P < 0.05). Sj(O2) values and the incidence of desaturation remained unchanged during the changes in predicted propofol concentration from 3 to 7 microg/ml both in the normothermic and hypothermic groups. CONCLUSION: The results indicated that the increasing concentrations of propofol did not affect Sj(O2) values in neurosurgical patients under normothermic and mildly hypothermic conditions.

Adult↗

PubMed2006

The effects of xenon on myogenic motor evoked potentials in rabbits: a comparison with propofol and isoflurane.

We compared the effects of xenon on myogenic motor evoked potentials (MEPs) with those of propofol and isoflurane in rabbits under ketamine/fentanyl anesthesia. Thirty animals were randomly allocated to one of 3 groups (n = 10 in each group). In the propofol group, propofol was administered at a rate of 0.4 mg x kg(-1) x min(-1) (small) and 0.8 mg x kg(-1) x min(-1) (large). In the isoflurane group, isoflurane was administered at 0.8% (small) and 1.6% (large). In the xenon group, xenon was administered at 35% (small) and 70% (large). Myogenic MEPs in response to stimulation with single pulse and a train of 5 pulses were recorded from the soleus muscle before, during (at small and large doses), and after the administration of each anesthetic. With single-pulse stimulation, MEPs were recorded in 90% and 50% of animals at small and large doses of xenon, respectively, and MEP amplitudes in the xenon and isoflurane groups were significantly lower compared with those in the propofol group. With train pulse stimulation, MEPs were recorded in 100% and 90% of animals at small and large doses of xenon, respectively, and a reduction in MEP amplitudes by xenon was more prominent than by propofol but less than isoflurane at large doses. These results suggest that MEP recording may be feasible under xenon anesthesia if multipulse stimulation is used, although xenon has suppressive effects on myogenic MEPs.

Anesthetics, Inhalation↗

PubMed2006

[A case of local recurrence of rectal cancer in long-term responding to combined therapy of low-dose CPT-11 and 5'-DFUR].

A 68-year-old man underwent Miles'operation for advanced rectal cancer. Local recurrence occurred 9 months following the operation. We started the combined therapy of low-dose CPT-11 and doxifluridine (5'-DFUR). CPT-11 was administered at 80 mg/body biweekly and 5'-DFUR was orally administered at 800 mg/day/body on day 3-7. We then reduced the CPT-11 dose to 60 mg/body because of neutropenia. Four months later,we obtained a decrease in the tumor marker (carcinoembryonic antigen: CEA) to the normal serum level, and stopped the medication. However, 3 months later the serum CEA level was increased, and we restarted the same therapy. Six months after restarting this therapy, the serum CEA level decreased to the normal level,and the local recurrence was decreased in size. We finished this combined therapy and changed to 5'-DFUR only. No tumor progression or recurrences in this patient are seen 2 years after completing this combined therapy.

Adenocarcinoma↗

PubMed2005

Personal factors involved in onset or progression of Ménière's disease and low-tone sensorineural hearing loss.

PURPOSE: To identify personal causative factors for Ménière's disease. PROCEDURES: Patterns of hearing loss progression were studied in patients with Ménière's disease and low-tone sensorineural hearing loss, and the involvement of stress and the relation of stressors to the onset or progression of the disease were analyzed. RESULTS: Low-tone loss recurred in 40% of patients even after hearing was restored, and low-tone loss progressed to high-tone loss after frequent repetitions of recovery and recurrence. High-tone loss tended to proceed to all-tone loss. Eighty percent of patients reported that stress was involved or deeply involved in the onset or progression of the disease. Common causative stressors were business-related pressure, insufficient sleep, and troubles at the workplace or at home. CONCLUSIONS: The present findings indicate that recovery and recurrence may be influenced by the strength and duration of stress that is produced when patients do not feel rewarded for engrossment in their work or for self-inhibiting behaviors.

Adolescent↗

PubMed2005

Postnatal developmental changes in immunohistochemical localization of alpha-smooth muscle actin (SMA) and vimentin in bovine testes.

The present study demonstrates the postnatal developmental changes in immunohistochemical localization of alpha-smooth muscle actin (SMA) and vimentin in the bovine testis. In the peritubular myoid cells of seminiferous tubules and the sub-epithelial and stromal cells of straight tubules and the rete testis, alpha-SMA starts appearing at around 4 months of age. Peritubular alpha-SMA attains the continuous mature pattern at around 5 months of age whereas sub-epithelial and stromal alpha-SMA increases with advancing age. Vimentin is localized in the perinuclear zone of Sertoli cells, peritubular and vascular wall cells, a few interstitial cells, and in the basal part of the epithelia of straight and rete tubules. Developmental changes are only evident in the Sertoli cell vimentin, which is basal and weak at birth and increases moderately until 4 months of age. From around 5 to 8 months of age when the Sertoli cells are under morphological transformation, vimentin intensity is considerably increased and the characteristic vimentin extensions connect the Sertoli nuclei to the basal membrane. These extensions get shorter at around 9 month of age as the Sertoli nuclei are positioned basally. The mature Sertoli cell perinuclear vimentin is strong and stable without infranuclear extension. In conclusion, the age of appearance of alpha-SMA coincides with the onset of postnatal division of spermatogonia, and vimentin may play a key role in stabilizing Sertoli cell nuclei during their transformation in bovine.

Actins↗

PubMed2005

Crystal structures of tyrosyl-tRNA synthetases from Archaea.

Tyrosyl-tRNA synthetase (TyrRS) catalyzes the tyrosylation of tRNA(Tyr) in a two-step reaction. TyrRS has the "HIGH" and "KMSKS" motifs, which play essential roles in the formation of the tyrosyl-adenylate from tyrosine and ATP. Here, we determined the crystal structures of Archaeoglobus fulgidus and Pyrococcus horikoshii TyrRSs in the l-tyrosine-bound form at 1.8A and 2.2A resolutions, respectively, and that of Aeropyrum pernix TyrRS in the substrate-free form at 2.2 A. The conformation of the KMSKS motif differs among the three TyrRSs. In the A.pernix TyrRS, the KMSKS loop conformation corresponds to the ATP-bound "closed" form. In contrast, the KMSKS loop of the P.horikoshii TyrRS forms a novel 3(10) helix, which appears to correspond to the "semi-closed" form. This conformation enlarges the entrance to the tyrosine-binding pocket, which facilitates the pyrophosphate ion release after the tyrosyl-adenylate formation, and probably is involved in the initial tRNA binding. The KMSSS loop of the A.fulgidus TyrRS is somewhat farther from the active site and is stabilized by hydrogen bonds. Based on the three structures, possible structural changes of the KMSKS motif during the tyrosine activation reaction are discussed. We suggest that the insertion sequence just before the KMSKS motif, which exists in some archaeal species, enhances the binding affinity of the TyrRS for its cognate tRNA. In addition, a non-proline cis peptide bond, which is involved in the tRNA binding, is conserved among the archaeal TyrRSs.

Adenosine Monophosphate↗

PubMed2005

Clinicopathological study of depth of subserosal invasion in patients with pT2 gallbladder carcinoma.

BACKGROUND: We examined whether depth of subserosal cancer invasion predicts lymph node involvement and survival in gallbladder carcinoma (GBC) patients with pathologicial subserosal invasion (pT2), to explore which patients benefit from radical second resection among patients with inapparent pT2 tumor. METHODS: Subjects comprised 31 patients with pT2 GBC. Thickness of the subserosal layer and vertical length of carcinoma invasion into the subserosa were measured under microscopy. Depth of subserosal invasion was divided subjectively into three categories: ss1, ss2, and ss3 (invasion of upper, middle, and lower thirds of the subserosal layer, respectively). Relationships between subserosal subclassification, histopathological factors, and prognosis were examined. RESULTS: Subserosal layers were significantly thicker (P < 0.001) in portions with cancer invasion (5.46 +/- 0.68 mm; range 1.0 approximately 13.75 mm) than those without cancer invasion (1.89 +/- 0.16 mm, range, 0.88 approximately 4.50 mm). Depth of carcinoma invasion into subserosa was 4.20 +/- 0.65 mm (range, 0.25 approximately 12.5 mm). Rate of lymphatic permeation, venous permeation, and lymph node involvement significantly increased with deeper subserosal invasion (P = 0.014, P = 0.027, P = 0.018, respectively). Among histopathological factors examined, only subserosal subclassification had a significant correlation with presence or absence of lymph node metastasis. Further, there was a significant correlation (P = 0.043) between the degree of subserosal invasion (ss1, ss2, and ss3) and involved nodal disease (pN0, pN1, and pM1 [lymph]). Although 5-year survival rates, according to the degree of subserosal invasion, tended to decrease with deeper invasion into the subserosal layer (ss1, 83.3%; ss2, 62.5%; ss3, 50.0%), no significant differences were noted. CONCLUSIONS: Pathological characteristics tend to become more aggressive with increasing depth of subserous carcinoma invasion in pT2 GBC. Depth of subserosal invasion is a predictor of presence and degree of lymph node metastasis in pT2 GBC. A sampling biopsy of the para-aortic nodes is recommended for inapparent pT2 GBC patients with subserosal invasion beyond one-thirds of the subserosal layer when they undergo radical second resection.

Carcinoma↗

PubMed2005

Orally administered crocetin and crocins are absorbed into blood plasma as crocetin and its glucuronide conjugates in mice.

A series of crocetin glycosides (crocins) are the main pigment of the stigmas of saffron (Crocussativus L.) and the fruits of gardenia (Gardenia jasminoides Ellis). Although numerous studies have demonstrated that crocetin and crocins have a variety of biological functions, the metabolism of dietary crocetin and crocins remains unknown. In the present study, we investigated the intestinal absorption of orally administered crocetin and crocins in mice. Orally administered crocetin was rapidly absorbed into the blood circulation and was present in plasma as an intact free form and as glucuronide conjugates (crocetin-monoglucuronide and -diglucuronide). Crocetin and its glucuronide conjugates were also found in crocins-administered mouse plasma, whereas intact crocins (glycoside forms) were not detected. These results indicate that orally administered crocins are hydrolyzed to crocetin before or during intestinal absorption, and absorbed crocetin is partly metabolized to mono- and diglucuronide conjugates.

Administration, Oral↗

PubMed2005

Muramyl dipeptide enhances osteoclast formation induced by lipopolysaccharide, IL-1 alpha, and TNF-alpha through nucleotide-binding oligomerization domain 2-mediated signaling in osteoblasts.

Muramyl dipeptide (MDP) is the minimal essential structural unit responsible for the immunoadjuvant activity of peptidoglycan. As well as bone-resorbing factors such as 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) and PGE2, LPS and IL-1alpha stimulate osteoclast formation in mouse cocultures of primary osteoblasts and hemopoietic cells. MDP alone could not induce osteoclast formation in the coculture, but enhanced osteoclast formation induced by LPS, IL-1alpha, or TNF-alpha but not 1alpha,25(OH)2D3 or PGE2. MDP failed to enhance osteoclast formation from osteoclast progenitors induced by receptor activator of NF-kappaB ligand (RANKL) or TNF-alpha. MDP up-regulated RANKL expression in osteoblasts treated with LPS or TNF-alpha but not 1alpha,25(OH)2D3. Osteoblasts expressed mRNA of nucleotide-binding oligomerization domain 2 (Nod2), an intracellular sensor of MDP, in response to LPS, IL-1alpha, or TNF-alpha but not 1alpha,25(OH)2D3. Induction of Nod2 mRNA expression by LPS but not by TNF-alpha in osteoblasts was dependent on TLR4 and MyD88. MDP also enhanced TNF-alpha-induced osteoclast formation in cocultures prepared from Toll/IL-1R domain-containing adapter protein (TIRAP)-deficient mice through the up-regulation of RANKL mRNA expression in osteoblasts, suggesting that TLR2 is not involved in the MDP-induced osteoclast formation. The depletion of intracellular Nod2 by small interfering RNA blocked MDP-induced up-regulation of RANKL mRNA in osteoblasts. LPS and RANKL stimulated the survival of osteoclasts, and this effect was not enhanced by MDP. These results suggest that MDP synergistically enhances osteoclast formation induced by LPS, IL-1alpha, and TNF-alpha through RANKL expression in osteoblasts, and that Nod2-mediated signals are involved in the MDP-induced RANKL expression in osteoblasts.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed2005

Inhibition of hydrogen peroxide-induced necrotic cell death with 3-amino-2-indolylmaleimide derivatives.

Novel analogs of indolylmaleimide derivatives (IM derivatives) were synthesized and tested for cell death-inhibitory activity. 2-(1H-Indol-3-yl)-3-pentylamino-maleimide IM-54 was the most effective cell death inhibitor among the compounds tested. IM-54 inhibited necrotic cell death induced by H2O2, but not apoptotic cell death induced by etoposide. These results indicated that this novel cell death inhibitor is distinct from the well-known caspase inhibitor, Z-VAD, which can block apoptotic cell death, but not necrotic cell death. IM-54 is expected to be a powerful bioprobe for clarifying the unique signaling pathway of necrotic cell death.

Antineoplastic Agents↗

PubMed2005

Comparative study of the daily lifestyle of patients with Meniere's disease and controls.

OBJECTIVES: This study was performed to investigate the possibility that daily lifestyle may have a causal relationship with Meniere's disease. METHODS: We conducted a questionnaire study of daily lifestyles among groups of patients with Meniere's disease and those with low-frequency hearing loss, and compared the results with those of control groups of local residents matched individually by gender and age. RESULTS: The Meniere's disease group diverged most widely from the control groups in their behavior patterns. Significant divergence was especially indicated in their engrossed, self-inhibiting, and time-constrained behaviors. Although the low-frequency hearing loss group also exhibited similar tendencies toward engrossment and in their feeling pressed for time, their self-inhibiting behavior was less pronounced. There was no major difference between the endolymphatic hydrops patient groups and the control groups on other items in the study such as daily lifestyle, environmental stress, and means of relaxation. CONCLUSIONS: The results of the present study strongly suggest that there may be a link between an individual's specific behavior patterns and the onset of Meniere's disease.

Adult↗

PubMed2005

Ultrasonographic monitoring of nuclear transferred fetal weight during the final stage of gestation in Holstein cows.

Dystocia or stillbirth accompanied by Large Offspring Syndrome (LOS) occurs rather frequently in Holstein nuclear transferred calves. In regard to prophylaxes, nuclear transferred Holstein fetuses were monitored with ultrasonography during the final stage of gestation. Fetal weight was estimated weekly based on the fetal metacarpal width using ultrasonography. Fourteen Holstein cows pregnant with Holstein nuclear transferred fetuses were the subjects of this experiment. The fetal weight was estimated by measuring the fetal metacarpal width during the last month of gestation according to the expected date of parturition. Measurements were performed on a weekly basis. The ultrasound-estimated metacarpal width and body weight of 13 of the fetuses in the last week of gestation (30.2+/-2.2 mm, 50.0+/-4.7 kg) were similar to the actual measurement immediately after birth (30.0+/-2.1 mm, 51.2+/-5.5 kg). These results indicate that ultrasonographic monitoring within a week of parturition to is accurate for estimating fetal weight. Prediction of LOS with ultrasonography contributes to reliable a diagnostic method that minimizes syndrome-related gyneco-obstetric complications at parturition with the aid of appropriate treatments.

Animals↗

PubMed2005

[Combined chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF), and radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN)].

We evaluated the recommend dose and efficacy of chemotherapy (CTx) and concurrent chemoradiotherapy (ConcCRTx) with docetaxel (DOC), cisplatin (CDDP) and 5-FU (TPF) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Patients underwent 2 cycles of chemotherapy with TPF. In ConcCRTx, radiation was targeted to begin on Day 1. We compared the efficacy of ConcCRTx and induction chemotherapy followed by radiation (CTx followed by RTx) with TPF. In CTx followed by RTx, radiation was targeted to begin 21 days after the end of CTx. The recommend dose of CTx with TPF was DOC 60 (Day 1), CDDP 70 (Day 4) and 5 FU 750 (Day 1-5) mg/ m2/ day and overall response rate of CTx with TPF was 95%. The recommended dose of ConcCRTx was DOC 50 (Day 1), CDDP 60 (Day 4) and 5-FU 600 (Day 1-5) mg/ m2/ day. Overall response rate of ConcCRTx and CTx followed by RTx with TPF were both 100%, and CR rate of them were 87% and 84% (p > 0.05). One-year survival rate of them were 69% and 95% (p < 0.05). More patients had distant metastasis in CTx followed by RTx than in ConcCRTx. Toxicity, such as mucositis, leukocytopenia and neutropenia, was higher in ConcCRTx than in CTx followed by RTx.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

[Promoter hypermethylation of tumor-associated genes in head and neck cancer].

An important pathway of gene transcriptional inactivation is hypermethylation at the CpG islands of promoter regions. Some tumor suppressor genes have been reported to harbor promoter hypermethylation in head and neck cancer. We studied DNA hypermethylation of 4 genes in 42 cases of primary head and neck cancer. We applied methylation specific PCR for p16, RAR-beta, RASSF1A, and Fhit genes. Hypermethylation was detected at p16 in 43%, at RAR-beta in 40%, at RASSF1A in 12%, and at Fhit in none of the cases. Hypermethylation of at least one gene was detected in 26 (62%) of the 42 cases. No significant correlation was seen between methylation status and clinicopathological findings or prognosis. Hypermethylation of several tumor-associated genes plays an important role in tumorigenesis of head and neck cancer. We discuss clinical implications and their application.

Acid Anhydride Hydrolases↗

PubMed2005

[Endoscopic radiofrequency ablation for liver metastasis of colorectal cancer].

The application of radiofrequency ablation (RFA) for liver metastasis of colorectal cancer has not yet acquired an established status in clinical cancer therapy research. Removing as much tumor tissue as possible is desirable, but some cases do not allow optimal surgical ablation due to general condition of the patient and tumor status. We introduced endoscopic RFA for liver cancer in 2003, and have applied the procedure to 6 cases with H1 or H2 liver metastases of colorectal cancer to which surgical ablation could not be applied due to the poor general health of patients. Mean tumor diameter was 22.9 mm, and mean number of tumors per patient was 1.2. Tumor location was: S4, n = 2; S5, n = 1; S4, n = 1; S7, n = 2; and S8, n = 1. Mean frequency of session was 3.0. No complications occurred in any cases, and no reoperations were required. Although no recurrence of tumors in the vicinity of ablation was observed, 2 cases of each lung metastasis and intrahepatic recurrence were identified. Intrahepatic recurrence underwent hepatic arterial infusion (HAI) chemotherapy for simultaneous metastatic hepatic tumors (H2) prior to RFA, and relapses occurred in the metastatic focus where the efficacy of HAI was observed. At this point, 2 deaths were reported, 1 each from cancer and other diseases, and mean duration of survival after the procedure was 451.2 days. These results indicate that endoscopic RFA with good local control should be an available treatment for cases involving colorectal cancer with metastasis to the liver in which surgical ablation is difficult to apply.

Adult↗

PubMed2004

Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout mice.

INTRODUCTION: Ataxia-telangiectasia is an autosomal-recessive disease that affects neuro-immunological functions, associated with increased susceptibility to malignancy, chromosomal instability and hypersensitivity to ionizing radiation. Although ataxia-telangiectasia mutated (ATM) heterozygous deficiency has been proposed to increase susceptibility to breast cancer, some studies have not found excess risk. In experimental animals, increased susceptibility to breast cancer is not observed in the Atm heterozygous deficient mice (Atm+/-) carrying a knockout null allele. In order to determine the effect of Atm heterozygous deficiency on mammary tumourigenesis, we generated a series of Atm+/- mice on the p53+/- background with a certain predisposition to spontaneous development of mammary carcinomas, and we examined the development of the tumours after X-irradiation. METHODS: BALB/cHeA-p53+/- mice were crossed with MSM/Ms-Atm+/- mice, and females of the F1 progeny ([BALB/cHeA x MSM/Ms]F1) with four genotypes were used in the experiments. The mice were exposed to X-rays (5 Gy; 0.5 Gy/min) at age 5 weeks. RESULTS: We tested the effect of haploinsufficiency of the Atm gene on mammary tumourigenesis after X-irradiation in the p53+/- mice of the BALB/cHeA x MSM/Ms background. The singly heterozygous p53+/- mice subjected to X-irradiation developed mammary carcinomas at around 25 weeks of age, and the final incidence of mammary carcinomas at 39 weeks was 31% (19 out of 61). The introduction of the heterozygous Atm knockout alleles into the background of the p53+/- genotype significantly increased the incidence of mammary carcinoma to 58% (32 out of 55) and increased the average number of mammary carcinomas per mouse. However, introduction of Atm alleles did not change the latency of development of mammary carcinoma. CONCLUSION: Our results indicate a strong enhancement in mammary carcinogenesis by Atm heterozygous deficiency in p53+/- mice. Thus, doubly heterozygous mice represent a useful model system with which to analyze the interaction of heterozygous genotypes for p53, Atm and other genes, and their effects on mammary carcinogenesis.

Animals↗