Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Altered and deregulated cyclin-dependent kinase (cdk) activity is now believed to play a major role in the pathogenesis of head and neck squamous cell carcinomas (HNSCC), thus providing a suitable cellular target for therapeutic intervention. UCN-01 (7-hydroxy-staurosporine), a known protein kinase C and cdk modulator, demonstrates antiproliferative and antitumor properties in many experimental tumor models and may represent a potential candidate to test in HNSCC. In this study, UCN-01 displayed potent antiproliferative properties (IC50 of approximately 17-80 nM) in HNSCC cells. Cell cycle analysis revealed that UCN-01 treatment of HNSCC cells for 24 h leads to a G1 block with a concomitant loss of cells in S and G2-M and the emerging sub-G1 cell population, confirmed to be apoptotic by terminal deoxynucleotidyl transferase-mediated nick end labeling analysis. Additional in vitro studies demonstrated a G1 arrest that was preceded by depletion in cyclin D3, elevation of p21(WAF1) and p27(KIP1) leading to a loss in activity of G1 cdks (cdk2, cdk4), and reduction in pRb phosphorylation. Antitumor properties of UCN-01 were also assessed in vivo by treating HN12 xenografts (7.5 mg/kg/i.p./daily) with UCN-01 for 5 consecutive days. Total sustained abolition of tumor growth (P < 0.00001) was obtained with only one cycle of UCN-01 treatment. Terminal deoxynucleotidyl transferase-mediated nick end labeling staining of xenograft samples revealed a higher incidence of apoptosis in treated tissues when compared with control. Additional tissue analysis demonstrated that elevated p27(KIP1) with minimal increase in p21(WAF1) and reduced cyclin D3 levels were readily detected in those animals treated with UCN-01, similar to those observed in HNSCC cells. Thus, UCN-01 exhibits both in vitro and in vivo antitumor properties in HNSCC models, and these effects are associated with a decrease in cyclin D3 and an increase in p27(KIP1) protein levels, thus providing appropriate surrogate markers to follow treatment efficacy in vivo and, therefore, a suitable drug candidate for treating HNSCC patients.
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PMID:Antitumor activity of UCN-01 in carcinomas of the head and neck is associated with altered expression of cyclin D3 and p27(KIP1). 1242 46

Under some conditions, p21(Waf1/Cip1) plays an assembly factor role for the cyclins and cyclin-dependent kinases, and recent reports demonstrate that p21 can act as an anti-apoptotic protein. Thus, it is logical to exploit this function of p21 as an anti-cancer target. We have performed a pilot study showing that daily subcutaneous injection of a phosphorothioate antisense p21 oligodeoxynucleotide, which we have previously shown to attenuate p21 levels in vitro, into nude mice who have been implanted with highly metastatic breast cancer cells results in inhibition of tumor growth and angiogenesis. Inhibition of in vitro endothelial capillary formation confirms that these oligodeoxynucleotides have a direct effect upon tumor angiogenesis. The attractiveness of our novel approach to breast cancer therapy, which capitalizes on the anti-apoptotic function of p21, derives from the ease of transfection of antisense oligodeoxynucleotides as well as the observations that p21(-/-) mice do not develop spontaneous tumors, making techniques exploiting the assembly factor and anti-apoptotic role of p21 worthy of further study against breast cancer.
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PMID:Suppression of breast cancer growth and angiogenesis by an antisense oligodeoxynucleotide to p21(Waf1/Cip1). 1244 76

Events that contribute to tumor formation include mutations in the ras gene and loss or inactivation of cell cycle inhibitors such as p21(Cip1) and p27(Kip1). In our previous publication, we showed that mice expressing the MMTV/v-Ha-ras transgene developed tumors earlier and at higher multiplicities in the absence than in the presence of p21(Cip1). To further evaluate the combinatorial role of genetic alterations and loss of cell cycle inhibitors in tumorigenesis, we performed two companion studies. In the first study, wild type and p21(Cip1)-null mice were exposed to the chemical carcinogen, urethane. Similar to its effects in v-Ha-ras mice, loss of p21(Cip1) accelerated tumor onset and increased tumor multiplicity in urethane-treated mice. Lung tumors were the predominant tumor type in urethane-treated mice regardless of p21(Cip1) status. In the second study, tumor formation was monitored in v-Ha-ras mice expressing or lacking p27(Kip1). Unlike p21(Cip1), the absence of p27(Kip1) had no effect on the timing or multiplicity of tumor formation, which was largely restricted to mammary and salivary glands. However, once tumors appeared, they grew faster in p27(Kip1)-null mice than in p27(Kip1)-wild type mice. Increases in growth rate were particularly striking for salivary tumors in ras/p27(-/-) mice. Loss of p21(Cip1), on the other hand, had no effect on tumor growth rate in v-Ha-ras mice. Collectively, our data suggest that p21(Cip1) suppresses tumor formation elicited by multiple agents and that p21(Cip1) and p27(Kip1) suppress tumor formation in different ways.
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PMID:Loss of the cell cycle inhibitors p21(Cip1) and p27(Kip1) enhances tumorigenesis in knockout mouse models. 1246 68

Cancer develops when the balance between cell proliferation and cell death is disrupted, and the ensuing aberrant proliferation leads to tumor growth. The cyclin-dependent kinase inhibitor p21 is induced by both p53-dependent and -independent mechanisms following stress, and induction of p21 may cause cell cycle arrest. As a proliferation inhibitor, p21 is poised to play an important role in preventing tumor development. This notion is supported by data indicating that p21-null mice are more prone to spontaneous and induced tumorigenesis, and p21 synergizes with other tumor suppressors to protect against tumor progression in mice. However, a number of recent studies have pointed out that in addition to being an inhibitor of cell proliferation, p21 acts as an inhibitor of apoptosis in a number of systems, and this may counteract its tumor-suppressive functions as a growth inhibitor. In the current review, we discuss the role of p21 in regulating cell death and the potential relevance of its expression in cancer.
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PMID:The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. 1247 24

The tumor-suppressor p53 is a multifunctional protein mainly responsible for maintaining genomic integrity. p53 induces its tumor-suppressor activity by either causing cell-cycle arrest (G(1)/S or G(2)/M) or inducing cells to undergo apoptosis. This function of wild-type p53 as "guardian of the genome" is presumably achieved by forming molecular complexes with different DNA targets as well as by interacting with a number of cellular proteins, e.g., Mdm2, Gadd45, p21, 14-3-3sigma, Bax and Apaf-1. Upon activation, p53 activates p21, which in turn controls the cell cycle by regulating G(1) or G(2) checkpoints. Here, we report SMAR1 as one such p53-interacting protein that is involved in delaying tumor progression in vivo as well as in regulating the cell cycle. SMAR1 is a newly identified MARBP involved in chromatin-mediated gene regulation. The SMAR1 gene encodes at least 2 alternatively spliced variants: SMAR1(L) (the full-length form) and SMAR1(S) (the shorter form). We report that expression of SMAR1(S), but not of SMAR1(L), mRNA was decreased in most of the human cell lines examined, suggesting selective silencing of SMAR1(S). Overexpression of SMAR1(S) in mouse melanoma cells (B16F1) and their subsequent injection in C57BL/6 mice delays tumor growth. Exogenous SMAR1(S) causes significant retardation of B16F1 cells in the G(2)/M phase of the cell cycle compared to SMAR1(L). SMAR1(S) activates p53-mediated reporter gene expression in mouse melanoma cells, breast cancer cells (MCF-7) and p53 null cells (K562), followed by activation of its downstream effector, p21. We further demonstrate that SMAR1 physically interacts and colocalizes with p53. These data together suggest that SMAR1 is the only known MARBP that delays tumor progression via direct activation and interaction with tumor-suppressor p53.
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PMID:Direct interaction with and activation of p53 by SMAR1 retards cell-cycle progression at G2/M phase and delays tumor growth in mice. 1249 67

Recent studies indicate that cyclooxygenase-2 (COX-2) is overexpressed in pancreatic adenocarcinoma and may play a critical role in this rapidly progressing form of cancer. A human pancreatic adenocarcinoma cell line, Mia PaCa-2, was incubated for 18 hours with 5 micromol/L of rofecoxib (Vioxx), a selective COX-2 inhibitor. Total RNA was isolated and gene expression analyzed by DNA microarray chips. In a separate experiment, athymic mice were orthotopically injected with 7.5 x 10(5) Mia PaCa-2 cells through a minilaparotomy. After 1 month, laparotomy was repeated to measure tumor size, and mice were randomized to receive reformulated rodent chow containing either 12.5 mg/kg/day of rofecoxib or no drug for 21 days. Tumor growth was assessed by comparing volume before and after treatment. In vitro, rofecoxib decreased gene expression of cyclin D1/PRAD1, a key component of cell cycle progression, while increasing expression of several cell cycle arrest genes, including p21/WAF1, p33/ING, GADD34, and GADD45 (P < 0.05). In vivo, tumor growth was significantly reduced in treated vs. control mice (P < 0.05). No systemic toxicity was observed in mice receiving rofecoxib. These data suggest that rofecoxib slows the growth of human pancreatic cancer through changes in gene expression that favor cell cycle arrest.
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PMID:Selective cyclooxygenase-2 inhibitor rofecoxib (Vioxx) induces expression of cell cycle arrest genes and slows tumor growth in human pancreatic cancer. 1250 22

Diadenosine oligophosphates (Ap(n)A) have been proposed to function as intracellular and extracellular signaling molecules in animal cells. Here, we have examined the cellular and molecular mechanisms underlying the induction of apoptosis by diadenosine 5',5"'-P(1),P(4)-tetraphosphate (Ap(4)A). We have shown a dose-dependent apoptotic response in cells treated with Ap(4)A. Flow cytometric analysis indicated an involvement of Ap(4)A at an early stage of G1/S arrest. No difference in the amount of p21(waf1) was observed in HL60 cells treated with Ap(4)A compared to control cells. The level of retinoblastoma protein (pRb) dropped dramatically when apoptosis was extensive. The cleavage of pRb was abrogated if Ap(4)A-treated cells were incubated with general caspase inhibitor zVAD-fmk. Ap(4)A also induced a profound decrease in the level of the Bcl-2 protein. The lack of effect of Ap(4)A on CDK1 activity indicated that Ap(4)A is not involved in "aberrant mitosis". We suggest that in vivo Ap(4)A may play a significant role in tumor growth suppression by inducing apoptosis.
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PMID:The involvement of diadenosine 5',5"'-P1,P4-tetraphosphate in cell cycle arrest and regulation of apoptosis. 1250 98

Chemotherapy resistance is a significant obstacle in lung cancer therapy, and has been found to frequently correlate with amplification and overexpression of the c-myc oncogene. Earlier studies have shown that c-Myc inhibition alone is not always effective in cancer models. The purpose of this study was to test different dosing regimen, which included commonly used chemotherapeutic drugs in combination with c-Myc inhibition in a Lewis lung syngeneic drug-resistant murine tumor model. Inhibition of c-myc was specifically achieved by using phosphorodiamidate Morpholino oligomer (PMOs), a novel, non-toxic antisense DNA chemistry for inhibition of gene expression by an RNase H-independent mechanism. When administration of cisplatin overlapped with c-myc PMO (AVI-4126) treatment there was no additional effect on tumor growth inhibition compared to cisplatin alone. In contrast, using a dosing regimen in which cisplatin or taxol treatment preceded AVI-4126, a dramatic decrease in tumor growth rate was observed with tumor areas less then 0.5 cm2 in 60% of the animals at the end of the study. This effect was specific to c-Myc inhibition as other antisense PMOs against p21 or Rad51 showed no such effect in combination with chemotherapy. Immunoblot and HPLC-based analysis of tumor lysates at the end of the study confirmed c-Myc inhibition and detection of intact AVI-4126, respectively. In conclusion, AVI-4126 potentiates the efficacy of chemotherapeutic drugs in a manner that is schedule dependent.
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PMID:Resistance to chemotherapeutic drugs overcome by c-Myc inhibition in a Lewis lung carcinoma murine model. 1254 57

p21-Ras, the protein product of the proto-oncogene Ras is overactivated in malignant astrocytomas despite the absence of mutation. It is known that p21-Ras participates in signaling events from membrane tyrosine kinase receptors and a variety of intracellular biochemical pathways to downstream targets. Signal transduction inhibition by targeting against Ras is now thought to be a promising therapeutic strategy for malignant astrocytomas. This study demonstrates that Ras pathway inactivation by a farnesyltransferase inhibitor, B1620, effectively inhibits in vitro and in vivo growth of human astrocytoma cells, although normal human astrocytes (NHA) derived from fetal brain are resistant to B1620. Anti-proliferative effect of B1620 on in vitro growth of astrocytoma cells was examined by MTT assays and soft agar colony formation assay. B1620 inhibited anchorage-dependent growth of six astrocytoma cell lines with a median effective dose (IC50) ranging from 2.0 to 20.7 microM. However, growth of NHA was not significantly affected by B1620 even at the concentration of 100 microM. All astrocytoma cells showed apoptotic figures after Hoechst 33258 staining, when treated for 5 days at each IC50 concentration against B1620. Anchorage-independent growth of these astrocytoma cell lines was inhibited at a much lower concentration than that of anchorage-dependent growth. Daily treatment of U87 xenograft-bearing athymic mice with B1620 at 100 or 50 mg kg(-1) resulted in significant inhibition of tumor growth. A histological study of the B1620-treated tumor tissue showed decreased vascularity with numerous TUNEL-positive apoptotic cells. These results suggest that the mechanism of the growth-inhibitory effect of B1620 is anti-angiogenesis, apoptosis induction and reversion of the transformed phenotype. The potential clinical use of B1620 could be expanded to malignant astrocytomas.
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PMID:In vitro and in vivo growth inhibition of human malignant astrocytoma cells by the farnesyltransferase inhibitor B1620. 1262 48

Decorin is a well-known, ubiquitous proteoglycan that is a normal component of the ECM. Upon transgenic expression of decorin, tumor cells with diverse histogenetic background overexpress p21WAF1, a potent inhibitor of cyclin-dependent kinase activity, become arrested in G1, and fail to generate tumors in immunocompromised animals. Because decorin is a secreted protein, it has been recently suggested that decorin could act as an autocrine and paracrine regulator of tumor growth. Here, we demonstrate that adenovirus (Ad)-mediated transfer and expression of human decorin cDNA induced in vivo apoptosis of xenograft tumor cells in nude mice. This oncolytic activity was observed when the Ad vector encoding the decorin cDNA was injected intratumorally (i.t.) or i.v. Importantly, i.t. injection of the decorin Ad vector led to growth inhibition of the injected tumor associated with similar growth inhibition of a distant contralateral tumor, demonstrating a distant decorin antitumoral effect. Immunochemistry against human decorin and decorin quantitation in tumors confirmed that decorin migrated to the tumor distant site. Furthermore, decorin effect was specific to tumor cells, because neither apoptosis nor growth inhibition were observed in nontumoral human cells such as hepatocytes, endothelial cells, and fibroblasts, despite p21 overexpression.
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PMID:In vivo selective and distant killing of cancer cells using adenovirus-mediated decorin gene transfer. 1263 84


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