Biomedical subjects

H Ide

Publications and source records attributed to H Ide.

At least 127 records · Page 7Linked to original sources

PubMed1997

Growth regulation of human prostate cancer cells by bone morphogenetic protein-2.

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-beta (TGF-beta) family and have been identified as factors that stimulate bone formation in vivo. They turned out to be multifunctional molecules regulating the growth, differentiation, and apoptosis in various target cells. Some BMPs and their receptors (BMPRs) are expressed on prostate cancer cells. We have reported previously that BMPR-IB mRNA expression is highest in the prostate, a characteristic that is not shared by the other BMPRs, BMPR-IA and BMPR-II. However, the amounts of BMPR-IB mRNA were significantly low in prostate tissues after androgen withdrawal therapy. They were also low in prostate cancer cell lines. Semiquantitative RT-PCR showed that BMPR-IB mRNA was induced by androgen in the androgen-sensitive human prostatic cancer cell line LNCaP, whereas the expression of BMPR-IA and BMPR-II mRNAs was not affected by androgen. When the recombinant human BMP-2 was added to the LNCaP cells in the presence of androgen, cell growth was inhibited. In contrast, the growth rate was increased by the addition of the same ligand when the cells were cultured in the absence of androgen; under this condition, the amounts of BMPR-IB mRNA were decreased significantly. These observations showed that the amounts of BMPR-IB, but not those of BMPR-IA, were regulated by androgen and further suggest that BMPR-IA and BMPR-IB differentially modulate prostate cancer cell growth in response to BMP under different hormonal conditions; BMPR-IA elicits growth stimulation, and BMPR-IB conveys a negative regulatory signal in response to BMP-2.

Bone Morphogenetic Protein 2↗

PubMed1997

Retinoic acid changes the proximodistal developmental competence and affinity of distal cells in the developing chick limb bud.

In the developing chick limb bud, retinoic acid (RA) has a striking effect on anteroposterior axis formation, resulting in a duplicated pattern of digits. There is no evidence, however, that RA affects proximodistal axis formation in the developing chick limb bud, although RA induces proximodistal duplication in regenerating amphibian limbs. We describe a series of investigations on the effect of RA on the proximodistal axis in the chick limb bud. A RA-containing bead applied to the anterior margin of the chick limb bud at stage 20 induces the anteroposterior duplication of autopodial structures at the wrist level. We found that the RA-treated tissue has the ability to form more proximal structures. When a tissue graft from the RA-treated anterior region was implanted into a stage 17 wing bud (in which the stylopod is developing in the progress zone), the graft produced a humerus, radius-ulna, and digits. When the graft was implanted into a stage 19 wing bud (in which the zeugopod is developing in the progress zone), a zeugopod and digits were formed. These results were associated with changes in the expression of Hox-A genes in the RA-treated grafts, whose domains were reorganized to be similar to those in host tissues 24 h after grafting. When a small graft of RA-treated tissue was implanted into the apex of a stage 19 wing bud, the cells were found in the zeugopod and autopod, whereas cells of control fragments were found only in the autopod region. In vitro, distal cells from different stage limb buds are known to segregate from each other. However, RA-treated stage 24 distal cells did not sort out from stage 20 distal cells and mixed homogeneously. These results suggest that RA induces distal cells to adopt "younger" properties which render them susceptible to forming more proximal patterns under the direction of host signals. The effects of RA on proximodistal patterns in developing chick limb buds appear to differ from its effects on proximodistal patterns in regenerating urodele limbs because RA can induce the proximodistal duplication in situ in the regenerating limbs.

Animals↗

PubMed1997

Deglycosylation susceptibility and base-pairing stability of 2'-deoxyoxanosine in oligodeoxynucleotide.

We have demonstrated recently that nitrous acid or nitric oxide converts 2'-deoxyguanosine (dGuo) into 2'-deoxyoxanosine (dOxo) [Suzuki, T., Yamaoka, R., Nishi, M., Ide, H., & Makino, K. (1996) J. Am. Chem. Soc. 118, 2515-2516]. In the present study, we have measured susceptibility of the N-glycosidic bond of dOxo to spontaneous hydrolysis and its base-pairing stability to evaluate the biological significance of dOxo as a new lesion in DNA. When oligodeoxynucleotide d(T5OT6) (O = dOxo), isolated from nitrous acid-treated d(T5GT6), was incubated at pH 4.0 and 70 degrees C, hydrolysis of the N-glycosidic bond of dOxo occurred with a first-order rate constant. Comparison of the rate constants with those of dGuo and dXao indicates that the N-glycosidic bond of dOxo was as stable as that of dGuo in d(T5GT6) and hydrolyzed 44-fold more slowly than that of 2'-deoxyxanthosine (dXao), a simultaneously generated damage by nitrous acid and nitric oxide. For the estimation of the base-pairing stability, UV melting curves were measured for the duplexes of d(T5OT6).d(A6NA5) (N = A, G, C, and T) at neutral pH. The Tm values obtained were 15.3, 14.1, 19.3, and 16. 3 degrees C for N = A, G, C, and T, respectively, which are much lower than that of the intact duplex containing a G.C pair at the same position [d(T5GT6).d(A6CA5), Tm = 32.8 degrees C] but comparable with those of d(T5XT6).d(A6NA5) (X = dXao, Tm = 14.8-22.3 degrees C). CD spectra of the four duplexes containing dOxo showed preservation of the structure of the intact duplex at low temperature. UV and NMR pH-titration studies indicated the pKa for the ring-opening and -closing equilibrium to be 9.4, implying that dOxo is in the ring-closed form at physiological pH. This structure appears to be not suitable geometrically for the hydrogen bond formation with a specific counter base, thus causing equally low Tm values for all the counter bases. Consequently, these results imply that dOxo, a novel DNA lesion, may have an important and unique role in mutagenic events in cells.

Acid-Base Equilibrium↗

PubMed1997

Gene therapy for peritoneal dissemination of pancreatic cancer by liposome-mediated transfer of herpes simplex virus thymidine kinase gene.

Peritoneal dissemination is one of the most common complications of the malignancies of the digestive system, such as gastric or pancreatic cancers. Yet, no effective therapy has been established so far to alleviate this devastating and often fatal end-stage condition. Here we describe a novel approach of intraperitoneal (i.p.) lipofection of a suicidal gene to the pancreatic cancer cells in a mouse peritoneal dissemination model. A human pancreatic cancer cell line, PSN-1, was inoculated into the peritoneal cavity of nude mice. Eight days later, a herpes simplex virus thymidine kinase (HSV-TK) gene expression plasmid under a potent hybrid promoter CAG was injected as a DNA-lipopolyamine complex. Ganciclovir (GCV) was then administered for 8 days, and the mice were examined for tumor development at the 24th day after the tumor inoculation. Although all 24 control mice showed macroscopic peritoneal dissemination and solid tumors on the pancreas, 8 of the 14 mice treated with HSV-TK and GCV were free of tumors, and only a few small tumors were observed in the remaining 6 mice. Treatment-related toxicity was not observed. The semiquantitative reverse transcription polymerase chain reaction (RT-PCR) analysis suggested that the HSV-TK transgene was expressed in about 10% of tumor cells but not in the normal pancreas or in the small intestine. When the lacZ gene was transduced in place of the HSV-TK gene, the blue-stained cells were identified only in tumor nodules and not in normal organs. This preclinical study suggests the therapeutic feasibility of the i.p. lipofection-based suicidal gene/prodrug strategy for peritoneal dissemination of pancreatic cancer.

Animals↗

PubMed1997

Substrate and mispairing properties of 5-formyl-2'-deoxyuridine 5'-triphosphate assessed by in vitro DNA polymerase reactions.

5-Formyluracil (fU) is one of the thymine lesions produced by reactive oxygen radicals in DNA and its constituents. In this work, 5-formyl-2'-deoxyuridine 5'-triphosphate (fdUTP) was chemically synthesized and extensively purified by HPLC. The electron withdrawing 5-formyl group facilitated ionization of fU. Thus, p K a of the base unit of fdUTP was 8.6, significantly lower than that of parent thymine (p K a = 10.0 as dTMP). fdUTP efficiently replaced dTTP during DNA replication catalyzed by Escherichia coli DNA polymerase I (Klenow fragment), T7 DNA polymerase (3'-5'exonuclease free) and Taq DNA polymerase. fU-specific cleavage of the replication products by piperidine revealed that when incorporated as T, incorporation of fU was virtually uniform, suggesting minor sequence context effects on the incorporation frequency of fdUTP. fdUTP also replaced dCTP, but with much lower efficiency than that for dTTP. The substitution efficiency for dCTP increased with increasing pH from 7.2 to 9.0. The parallel correlation between ionization of the base unit of fdUTP (p K a = 8.6) and the substitution efficiency for dCTP strongly suggests that the base-ionized form of fdUTP is involved in mispairing with template G. These data indicate that fU can be specifically introduced into DNA as unique lesions by in vitro DNA polymerase reactions. In addition, fU is potentially mutagenic since this lesion is much more prone to form mispairing with G than parent thymine.

Base Composition↗

PubMed1997

Cloning of human bone morphogenetic protein type IB receptor (BMPR-IB) and its expression in prostate cancer in comparison with other BMPRs.

Bone metastasis is a common event in prostate cancer, and it is known that some of the bone morphogenetic proteins (BMPs) are expressed in prostate cancer cells, while no study on the expression of their receptors, BMPRs, has been reported. Here we report cloning and sequence analysis of the human BMPR-IB cDNA. We also analysed the expression of transcripts of three types of the BMPR genes in human tissues and prostate cancer cell lines. The BMPR-IB mRNA was present in various organs, but the highest level was found in the prostate. Moreover, the amount of BMPR-IB mRNA was significantly low in prostate cancer tissues after androgen withdrawal and was also low in prostate cancer cell lines. RT-PCR analysis showed that the BMPR-IB message was upregulated by androgen stimulation in the LNCaP cell line which expresses the androgen receptor. By contrast, the mRNA levels of BMPR-IA and BMPR-II were not significantly different among non-cancerous and cancerous prostate tissues. It was also suggested that human BMPR-IA and BMPR-IB might have different biological functions in the prostate, although their sequences were 85.3% identical in the serine-threonine kinase domain.

Amino Acid Sequence↗

PubMed1997

Induction of additional limb at the dorsal-ventral boundary of a chick embryo.

In the early chick embryo, an apical ectodermal ridge (AER) is formed from the overlying ectoderm of the presumptive limb bud region at the dorsal-ventral (DV) boundary. We report here that the ectopic DV boundary formed in the presumptive wing, flank, and leg fields induces an ectopic AER structure. Dorsal tissue (ectoderm and mesoderm) from the presumptive wing field of stage 10 to 17 embryos was inserted into a slit in the somatopleure of the future ventral side of host embryos. The same method was used to implant ventral tissue into the future dorsal side of host embryos. After the implantation, ectopic AER was induced and an additional limb or limb-like structure developed. In related experiments, ectoderm-free presumptive wing tissue was implanted, which resulted in a considerably decreased frequency of ectopic AER formation. Further analysis of chick and quail chimeras suggests that the ectopic AER was formed from the ectodermal cells overlying the boundary of host and graft mesodermal cells. These results indicate that the DV boundary organizes the AER structure in the limb bud field of early-stage chick embryos and that the ectoderm of the grafted tissues plays an important role in this process.

Animals↗

PubMed1997

Replication bypass and mutagenic effect of alpha-deoxyadenosine site-specifically incorporated into single-stranded vectors.

alpha-2'-Deoxyadenosine (alpha) is a major adenine lesion produced by gamma-ray irradiation of DNA under anoxic conditions. In this study, single-stranded recombinant M13 vectors containing alpha were constructed and transfected into Escherichia coli to assess lethal and mutagenic effects of this lesion. The data for alpha were further compared with those obtained with M13 vectors containing normal A or a model abasic site (F) at the same site. The transfection assay revealed that alpha constituted a moderate block to DNA replication. The in vivo replication capacity to pass through alpha was approximately 20% relative to normal A, but 20-fold higher than that of F constituting an almost absolute replication block. Similar data were obtained by in vitro replication of oligonucleotide templates containing alpha or F by E.coli DNA polymerase I. The mutagenic consequence of replicating M13 DNA containing alpha was analyzed by direct DNA sequencing of progeny phage. Mutagenesis was totally targeted at the site of alpha introduced into the vector. Mutation was exclusively a single nucleotide deletion and no base substitutions were detected. The deletion frequency associated alpha was dependent on the 3'-nearest neighbor base: with the 3'-nearest neighbor base T mutation (deletion) frequency was 26%, whereas 1% with the 3'-nearest neighbor base G. A possible mechanism of the single nucleotide deletion associated with alpha is discussed on the basis of the misinsertion-strand slippage model.

Bacteriophage M13↗

PubMed1997

Ascidian tyrosinase gene: its unique structure and expression in the developing brain.

Tadpole larvae of ascidians have two sensory pigment cells in the brain. One is the otolith cell that functions as a gravity receptor, the other pigment cell is part of a primitive photosensory structure termed the ocellus. These sensory cells, like vertebrate pigment cells, contain membrane-bounded melanin granules and are considered to reflect a crucial position in the evolutionary process of this cell type. To investigate the molecular changes accompanying the evolution of pigment cells, we have isolated from Halocynthia roretzi a gene encoding tyrosinase, a key enzyme in melanin biosynthesis. The cDNA has an open reading frame (ORF) of 596 amino acids, which is 36-39% identical in amino acid sequence to vertebrate tyrosinases. In addition, the sequence analysis of both cDNA and genomic clones reveals an unusual organization of the tyrosinase gene, an extraordinary 3' untranslated region of the transcripts with significant homology to the coding sequence, and a single short intron in the sequence encoding a cytoplasmic domain. Expression of the gene is detected first in two pigment precursor cells positioned in the neural plate of early neurulae, and later in two melanin-containing pigment cells within the brain of late tailbud embryos. Its expression pattern correlates well with the appearance of tyrosinase enzyme activity in the developing brain. These results provide the first description of pigment cell differentiation at the molecular level in the ascidian embryo, and also will contribute to a better understanding of the evolution of chordate pigment cells.

Amino Acid Sequence↗

PubMed1997

Shh expression in developing and regenerating limb buds of Xenopus laevis.

The zone of polarizing activity (ZPA) is a specialized region involved in the antero-posterior (A-P) axis formation in chick and mouse limb buds. The existence of ZPA in the posterior margin is suggested in Xenopus hindlimb buds because 180 degree rotation of the distal limb tip induces the supernumerary limb. In this study, we investigated the expression of Sonic hedgehog (shh), a molecular marker for ZPA, in Xenopus developing limb buds and regenerating blastemas by whole-mount in situ hybridization. Although shh was expressed in the posterior margin of the limb bud like in chicks, its expression domain did not correspond to the ZPA map of Xenopus hindlimb buds. shh expression was distant from the ZPA at stage 53 in particular. To clarify the difference between the shh expression domain and ZPA, we examined shh expression in 180 degree rotated limb buds. As a result, ectopic shh expression was newly induced in the proximal region to its original expression domain. These results suggest that ZPA is accompanied by shh expression as in chick limb buds. Furthermore we examined shh expression in regenerating blastemas. shh was reexpressed in the posterior margin of the blastema. This result supports the possibility that ZPA also exists in the regenerating blastema.

Animals↗

PubMed1997

A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group Study.

OBJECTIVE: To determine whether postoperative adjuvant chemotherapy confers a survival benefit on patients with esophageal squamous cell carcinoma undergoing radical surgery, we undertook a cooperative, prospective randomized controlled trial. METHODS: A total of 205 patients underwent transthoracic esophagectomy with lymphadenectomy at eleven institutions between December 1988 and July 1991. These patients were prospectively randomized into two groups (100 patients underwent surgery alone and 105 patients had additional two courses of combination chemotherapy with cisplatin (70 mg/m2) and vindesine (3 mg/m2). The two groups did not differ with respect to sex, age, location of tumor, and distributions of pT, pN, pM, or p stage. RESULTS: The 5-year survival was 44.9% in the surgery alone group and 48.1% in the surgery plus chemotherapy group. The relative risk was estimated to be 0.89 (95% confidence interval, 0.61 to 1.31) in the surgery plus chemotherapy group compared with the surgery alone group. No significant differences in survival were detected between the two groups, even with lymph node stratification. CONCLUSION: Postoperative adjuvant chemotherapy with cisplatin and vindesine has no additive effect on survival in patients with esophageal cancer compared with surgery alone.

Adult↗

PubMed1997

Antibodies to oxidative DNA damage: characterization of antibodies to 8-oxopurines.

The 8-oxo-7,8-dihydropurines (8-oxopurines) are important cellular premutagenic lesions produced in DNA by free radicals. Specific antibodies were prepared to detect these lesions. For antigens, 8-oxo-7,8-dihydroadenosine (8-oxoAdo) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) were synthesized from the bromonucleosides, and the immunogens were produced by conjugating these to either bovine serum albumin or rabbit serum albumin by the periodate method. Polyclonal antibodies specific for the haptens were elicited from rabbits immunized with the BSA conjugates. The antibodies to 8-oxoAdo (anti-8-oxoAdo) and 8-oxoGuo (anti-8-oxoGuo) precipitated the homologous antigens in an Ouchterlony gel diffusion assay and no cross-reactivity was observed toward the normal nucleosides or to the heterologous 8-oxopurine. Specificity was also examined by hapten inhibition of antibody reactivity with the homologous conjugates using ELISA. For anti-8-oxoAdo, the IC50 for 8-oxoAdo was 8 mumol/L and 8-bromoadenosine, guanosine, and inosine did not inhibit, even at concentrations of 1.25 mmol/L. Similarly, the IC50 for anti-8-oxoGuo for 8-oxoGuo was 0.1 mumol/L. 8-Methoxyguanosine also inhibited the reaction but was about 500-fold less effective than the eliciting hapten. Other nucleosides tested did not inhibit at concentrations up to 100 mumol/L. Both antibodies could easily detect the corresponding damage in x-irradiated f1 DNA at a dose of 7.5 Gy and both antibodies recognized the corresponding lesion in duplex DNA; however, with anti-8-oxoGuo the signal was reduced about 50% compared to single-stranded DNA. In order to determine the exact amount of each lesion produced in irradiated DNA, and to standardize the ELISA signal, both products were measured after alkaline phosphatase digestion of x-irradiated calf thymus DNA using high-pressure liquid chromatography (HPLC) coupled to an electrochemical detector. Anti-8-oxoGuo could detect ten 8-oxoG residues and anti-8-oxoAdo could detect two 8-oxoA residues per 10,000 nucleotides. Thus, these antibodies should be useful for the detection and measurement of 8-oxopurines in cellular DNA.

Adenosine↗

PubMed1997

Msx1 expressing mesoderm is important for the apical ectodermal ridge (AER)-signal transfer in chick limb development.

The apical ectodermal ridge (AER) is a specialized thickening of the distal limb ectoderm, and its signals are known to support limb morphogenesis. The expression of a homeobox gene, Msx1, in the distal limb mesoderm depends on signals from the AER. In the present paper it is reported that Msx1 expression in the distal mesoderm is necessary for the transfer of AER signals in chick limb buds. Interruption of AER-mesoderm interaction by insertion of a thick filter led to the inhibition of pattern specification in the mesoderm just under the filter. In such cases, the expression of Msx1 disappeared in the mesoderm under the filter, suggesting that AER is able to signal over short ranges. In advanced limb buds, Msx1 is also expressed in the proximal mesoderm under the anterior ectoderm. However, it was found that a grafted antero-proximal mesoderm shows no inhibitory effects on pattern specification of the host mesoderm, as is the case with the distal mesoderm. On the other hand, grafted mesoderms without potent Msx1 re-expression, even underneath AER, disturbed normal limb development. In such cases, the expression of Msx1 disappeared in the mesoderm under the grafts, whereas Fgf-8 expression was maintained in the AER above the graft. These results indicate that the expression of Msx1 in the mesoderm is important for the transfer of AER signals.

Animals↗

PubMed1997

16S rRNA gene sequence of Rubrobacter radiotolerans and its phylogenetic alignment with members of the genus Arthrobacter, gram-positive bacteria, and members of the family Deinococcaceae.

The nearly complete sequence of the 16S rRNA gene of an extremely highly radiotolerant bacterium, Rubrobacter radiotolerans (reclassified from Arthrobacter radiotolerans based on chemical characteristics), was determined by PCR amplification of the genomic DNA followed by cloning of the amplified gene and sequencing by the dideoxynucleotide method. The sequence was aligned with the sequences of members of the genus Arthrobacter and also with the sequences of representatives of the gram-positive bacteria having high G + C contents and the family Deinococcaceae (radioresistant micrococci and their relatives). The results of our phylogenetic analysis confirmed that R. radiotolerans is not a member of the Arthrobacter group and thus supported the previous reclassification. Moreover, although it is radioresistant and has a high G+C content, R. radiotolerans is more closely related to the gram-positive bacteria with high G+C contents than to the radioresistant members of the Deinococcaceae.

Arthrobacter↗

PubMed1997

Effects of 60Co gamma-rays, ultraviolet light, and mitomycin C on Halobacterium salinarium and Thiobacillus intermedius.

Lethal effects of 60Co gamma-rays, UV light, and mitomycin C on two kinds of bacteria, Halobacterium salinarium which grows in highly concentrated salt media and Thiobacillus intermedius which requires reduced sulfur compounds, were studied and compared with those on Escherichia coli B/r. D37 values for H. salinarium, T. intermedius and E. coli B/r were 393, 150, and 92 Gy, respectively, by exposure to 60Co gamma-rays. They were 212, 38, and 10 J/m2, respectively, by exposure to UV light and 2.36, 0.25, and 0.53 microgram/ml/h, respectively, by exposure to mitomycin C. Against these agents, H. salinarium was much more resistant than T. intermedius and E. coli B/r.

Cobalt Radioisotopes↗

PubMed1997

Apical ectodermal ridge-dependent expression of the chick 67 kDa laminin binding protein gene (cLbp) in developing limb bud.

Apical ectodermal ridge (AER)-mesoderm interaction is important for morphogenesis in the developing chick limb bud. Genes whose expression is dependent upon the presence of AER, are likely to play important roles in the AER-mesoderm interaction. We report here the gene expression pattern of the chick homolog of the 67 kDa laminin binding protein (LBP), which is a non-integrin laminin receptor whose function relates to cell attachment, spreading, and polarization. Northern analysis showed that a single 1.4 kb transcript exists in stage 20 limb buds and which is dramatically reduced 24 hr after removal of AER. In situ hybridization analysis revealed that the chick 67 kDa laminin binding protein gene (cLbp) was expressed in the mesodermal region overlapping the Msx1-expressing domain and in the AER in early stage limb buds. Expression in the mesoderm was gradually restricted to the distal region underneath the AER as development proceeds. The expression in the limb mesoderm could be induced by local application of FGF-2 which could thus mimic the AER functions. These results indicated that the expression of cLbp depends on AER signals and that the 67 kDa non-integrin receptor binding to laminin plays a role in the AER-mesoderm interaction.

Animals↗

PubMed1997

[Ki-1-positive anaplastic large-cell lymphoma with mediastinal involvement].

A 30-year-old woman was admitted to our hospital because of an abnormal mass shadow in the right side of the mediastinum on a a chest X-ray film. The chest X-ray film and computed tomogram revealed a mass approximately 4.8 cm in diameter in the right side of the mediastinum. The mass had invaded the right supraclavicular fossa. Lymph-node biopsy was done. Microscopical examination of an HE-stained specimen of a supraclavicular lymph nodes showed prediferation of large atypical lymphocytes. These atypical lymphocytes were stained immunohistochemically with anti-Ki-1 antibody. No T cell or B cell markers were found on these cells. No other tumors were detected by radiological examination. Therefore, our diagnosis was anaplastic large-cell lymphoma, which is identical to Ki-1 lymphoma of the mediastinum.

Adult↗

PubMed1997

Suppression of Ki-ras p21 levels leading to growth inhibition of pancreatic cancer cell lines with Ki-ras mutation but not those without Ki-ras mutation.

Ki-ras point mutation characteristically occurs frequently in human pancreatic cancer. To clarify the effect of antisense Ki-ras RNA on various pancreatic cancer cell lines, a plasmid expressing an antisense Ki-ras gene fragment (AS-K-ras-LNSX) was transduced into seven human pancreatic cancer cell lines (AsPC-1, MIA PaCa-2, PANC-1, PSN-1, BxPC-3, Hs 700T, and Hs 766T) by liposome-mediated transfection. Western blot analysis showed that transfection of AS-K-ras-LNSX led to a significant reduction in the amounts of Ki-ras p21 protein in all the pancreatic cancer cell lines except BxPC-3. The growth of pancreatic cancer cell lines having Ki-ras point mutations (AsPC-1, MIA PaCa-2, PANC-1, and PSN-1) was suppressed after transduction of AS-K-ras-LNSX, whereas the effect of the antisense construct on the growth was not significant in cell lines with a wild-type Ki-ras gene (BxPC-3, Hs 700T, and Hs 766T). These results suggest that the pancreatic cancer cells with activated Ki-ras depend heavily on a Ki-ras p21-mediated growth signal pathway for their growth because they were far more susceptible to the suppression of the Ki-ras p21 protein than the cells with wild-type Ki-ras. The remarkably increased dependence of the cancer-cell growth circuitry on one or a few crucial regulatory molecules may thus be a common feature of the cancer cells and implies a novel rationale for the targeting of cancer therapy.

Cell Division↗