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)

Gemcitabine is a nucleoside analog that is active in the treatment of various solid tumors. In general it is well tolerated and has few side effects. Pulmonary toxicity reported with gemcitabine use is usually mild and self-limiting. We present a case of severe pulmonary dysfunction after intravenous administration of a single dose of gemcitabine in a 58-year-old female patient with metastatic carcinoma of the pancreas. She developed tachypnea, marked hypoxemia, and an interstitial infiltrate on chest radiograph consistent with pulmonary edema, 4 days after receiving this drug. Diuretics and corticosteroids were beneficial in treating the acute respiratory failure. Pulmonary damage was completely resolved by means of clinical and radiological assessment. Because of the severity of this side effect, no further treatment with gemcitabine was given. Eventually, the patient died because of obstruction of the bowel due to progression of tumor growth. Publications concerning severe pulmonary toxicity due to gemcitabine are sparse. Pathophysiology and treatment are considered and a review of the literature is presented.
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PMID:Severe acute lung injury induced by gemcitabine. 1082 80

MDM2 is over-expressed in several human tumors. Its product is a negative-feedback regulator of p53, which interferes with the control of cell proliferation and apoptosis, interacting not only with p53 but also with retinoblastoma (Rb) and E2F. Moreover, mutations in the ARF-Ink4a locus may also allow MDM2 to override p53 functions. In this study, we have used a novel oligonucleotide anti-sense MDM2, with mixed-backbone structure and demonstrate that it causes inhibition of MDM2 expression, induction of both p53 and p21/WAF1 expression and a dose-dependent, growth-inhibitory effect in human GEO colon-cancer cells. We also show that anti-sense MDM2 has a co-operative growth-inhibitory effect with different classes of cytotoxic drugs acting by different mechanisms. Moreover, anti-sense MDM2 induces apoptosis and markedly enhances the apoptotic activity of different cytotoxic drugs. Finally, we show that anti-sense MDM2 has anti-tumor activity in vivo in nude mice bearing GEO xenografts and potentiates the anti-tumor effect of cytotoxic drugs. Indeed, despite the short treatment period, the combination of anti-sense MDM2 and cytotoxic drugs causes a marked delay in tumor growth and prolongation of mice survival, lasting several months after treatment cessation. The anti-tumor effect is associated with inhibition of MDM2 expression in tumor specimens of animals treated with anti-sense MDM2, alone or in combination with a cytotoxic drug. Our results provide the rationale for development of a novel mixed-backbone anti-sense MDM2 into a clinical setting in therapeutic combination strategies with conventional cytotoxic drugs.
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PMID:A novel MDM2 anti-sense oligonucleotide has anti-tumor activity and potentiates cytotoxic drugs acting by different mechanisms in human colon cancer. 1107 52

Many human tumors harbor mutations that result in deregulation of Cdk4 activity. Most of these mutations involve overexpression of D-type cyclins and inactivation of INK4 inhibitors. In addition, a mutation in the Cdk4 protein has been described in patients with familial melanoma (Wolfel, T., Hauer, M., Schneider, J., Serrano, M., Wolfel, C., et al. (1995) Science 269, 1281-1284; Zuo, L., Weger, J., Yang, Q., Goldstein, A. M., Tucker, M. A., et al. (1996) Nat. Genet. 12, 97-99). This mutation, R24C, renders the Cdk4 protein insensitive to inhibition by INK4 proteins including p16(INK4a), a major candidate for the melanoma susceptibility locus. Here we show that knock-in mice expressing a Cdk4 R24C allele are highly susceptible to melanoma development after specific carcinogenic treatments. These tumors do not have mutations in the p19(ARF)/p53 pathway, suggesting a specific involvement of the p16(INK4a)/Cdk4/Rb pathway in melanoma development. Moreover, by using targeted mice deficient for other INK4 inhibitors, we show that deletion of p18(INK4c) but not of p15(INK4b) confers proliferative advantage to melanocytic tumor growth. These results provide an experimental scenario to study the role of Cdk4 regulation in melanoma and to develop novel therapeutic approaches to control melanoma progression.
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PMID:Invasive melanoma in Cdk4-targeted mice. 1160 89

p53 represents an ideal target for anti-cancer drug design, because p53 is mutated in more than half of human tumors. Most of the remaining tumors, although carrying wild-type p53, have defects in the p53-mediated apoptotic pathway. Activation of p53 activity by either chemotherapy or radiotherapy induces p53-dependent apoptosis in tumor cells with wild-type p53. Supplying exogenous wild-type p53 in cancer cells by gene delivery is effective in suppressing tumor growth of both mutant and wild-type p53-containing tumors. Blockage of p53 degradation pathways either by overexpression of ARF or interruption of MDM2:p53 interaction is effective in inducing p53 triggered tumor cell death. Since unlike most other tumor suppressor genes, mutant p53 is over expressed in tumor cells, a promising approach involves restoring tumor-suppressing function to mutant p53. The activity of the mutant p53 in tumor cells is restorable based on the fact that PAb241 antibody against the carboxy-terminus of p53 and peptides corresponding to the p53 carboxy-terminus can restore specific DNA-binding ability to some mutant p53 proteins. High throughout screening of chemical libraries has led to the identification of a group of small synthetic molecules such as CP-31398, which can restore p53 function to mutant p53 by stabilizing the active conformation of the protein that is destabilized in many mutants. Subsequent identification of PRIMA-1 provides further evidence to the possibility of developing anti-cancer drugs that may rescue mutant p53. Further understanding of the mechanisms by which CP-31398 and PRIMA-1 restore p53 activity may not only lead to discovery of more potent analogs but may also suggest new strategies for p53-targeting in tumor therapy.
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PMID:Restoring p53-dependent tumor suppression. 1450 81

A role for the NF-kappaB family of transcription factors as tumor promoters is firmly established. However, other data suggest that NF-kappaB can also inhibit tumor growth. Moreover, NF-kappaB activity is modulated by tumor suppressors, such as p53 and ARF, whereby NF-kappaB subunits repress, rather than activate, the expression of tumor-promoting genes. This suggests a dual function of NF-kappaB during tumor progression - in the early stages, NF-kappaB inhibits tumor growth but, as further mutations lead to a loss of tumor suppressor expression, the oncogenic functions of NF-kappaB become unleashed, allowing it to actively contribute to tumorigenesis. Here, I discuss this hypothesis, its implications for NF-kappaB function, and how this might influence the use of NF-kappaB-based anticancer therapies.
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PMID:NF-kappaB: tumor promoter or suppressor? 1510 37

Long-term cultures of telomerase-transduced adult human mesenchymal stem cells (hMSC) may evolve spontaneous genetic changes leading to tumorigenicity in immunodeficient mice (e.g., hMSC-TERT20). We wished to clarify whether this unusual phenotype reflected a rare but dominant subpopulation or if the stem cell origin allowed most cells to behave as cancer stem cells. Cultures of the hMSC-TERT20 strain at population doubling 440 were highly clonogenic (94%). From 110 single-cell clones expanded by 20 population doublings, 6 underwent detailed comparison. Like the parental population, each clone had approximately 1.2 days doubling time with loss of contact inhibition. All retained 1,25-(OH)(2) vitamin D(3)-induced expression of osteoblastic markers: collagen type I, alkaline phosphatase, and osteocalcin. All shared INK4a/ARF gene locus deletion and epigenetic silencing of the DBCCR1 tumor suppressor gene. Despite in vitro commonality, only four of six clones shared the growth kinetics and 100% tumorigenicity of the parental population. In contrast, one clone consistently formed latent tumors and the other established tumors with only 30% penetrance. Changing the in vitro microenvironment to mimic in vivo growth aspects revealed concordant clonal heterogeneity. Latent tumor growth correlated with extracellular matrix entrapment of multicellular spheroids and high procollagen type III expression. Poor tumorigenicity correlated with in vitro serum dependence and high p27(Kip1) expression. Aggressive tumorigenicity correlated with good viability plus capillary morphogenesis on serum starvation and high cyclin D1 expression. Thus, hMSC-TERT20 clones represent cancer stem cells with hierarchical tumorigenicity, providing new models to explore the stem cell hypothesis for cancer.
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PMID:Tumorigenic heterogeneity in cancer stem cells evolved from long-term cultures of telomerase-immortalized human mesenchymal stem cells. 1583 42

Transgenic rats expressing the pX gene of human T lymphocyte virus type-I (HTLV-I) under control of the rat lymphocyte-specific protein tyrosine kinase type-I promoter (lck-pX rats) developed benign epithelial thymomas. When the thymuses of newborn lck-pX rats were transplanted into the subcapsular space of the kidney in other thymectomized lck-pX rats, similar tumors developed in the transplanted thymuses. Following the tumor growth, dissemination in the abdominal cavity and distant metastasis occurred. The tumors were histopathologically similar to the original thymomas, but prominent nuclear atypia and high mitotic activity were present. The Ki-67 index was twice as high as that in the originals. The tumors were transplantable into the subcutis of lck-pX rats, although transplantation of the originals never succeeded. All evidence indicated that malignant transformation of thymoma was induced by the heterotopic transplantation. Expression of the pX transgene in the transformed tumors were significantly reduced. Among host genes, the expression of p16ink4a/ARF, which was significantly upregulated in the originals, was never detected in the transformed tumors. Genomic Southern blots and PCR suggest that homozygous deletion of the p16ink4a/ARF gene may play important roles in malignant transformation in this model. Our model described here is a useful unique model for in vivo malignant transformation.
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PMID:Malignant transformation of thymoma in recipient rats by heterotopic thymus transplantation from HTLV-I transgenic rats. 1592 52

Pancreatic ductal adenocarcinoma (PDAC) is still a devastating and incurable disease with a median survival of 3-6 months and a 5-year survival rate of 1-4% when all stages are considered. Although crucial advances in our understanding of the molecular pathogenesis of the disease have been made, the exceptional aggressiveness of PDAC remains largely unexplained. Some key results will probably direct future PDAC research activities. For example, recent identification of pancreatic tumor stem cells has stimulated the debate over the cell of origin. Further, powerful new genetically engineered mouse models support the concept that stepwise progression of epithelial precursor lesions leads to invasive PDAC as a result of accumulating mutations in K-ras, INK4A/ARF, TP53 and DPC4; these models accentuate the initiating function of the K-ras mutation. Established PDAC exhibits all the classic hallmarks of cancer, including self-sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion, and metastasis. This review provides an overview of the molecular machinery that PDAC utilizes to acquire these tumorigenic capacities. Moreover, recent advances have identified essential elements of key pathways partly recapitulating developmental signals, and of the tumor microenvironment that promotes tumor growth through the complex interplay of its different cellular components. In spite of progress in molecular research, there is still a dichotomy between the encouraging results obtained with targeted interference of numerous oncogenic pathways in vitro and a lack of significant improvement in clinical detection and survival. Thus our primary challenge remains to translate the solid knowledge of genetic and epigenetic alterations in PDAC into clinical tools which can be used for early diagnosis and effective therapy.
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PMID:Molecular pathogenesis of pancreatic cancer: advances and challenges. 1769 65

ARLTS1 (ADP-ribosylation factor-like tumor suppressor gene 1) is a member of the ARF family of the Ras superfamily of small GTPases that are known to be involved in multiple regulatory pathways altered in human carcinogenesis. Here, we review recent work that has provided insights into the role of this small gene as an emerging player in both familial and sporadic cancers of several histotypes. ARLTS1 is a low penetrance gene that is primarily dysregulated in sporadic lung cancer by promoter hypermethylation. Two ARLTS1 polymorphisms are also associated with familial cancer risk. Down-regulation of ARLTS1 is seen in all lung cancer cell lines studied and in a significant proportion (37%) of primary lung tumors. Restoration of ARLTS1 expression in ARLTS1-deficient lung cancer cell lines by either demethylation or adenoviral transduction leads to apoptosis via caspase-dependent mechanisms. Furthermore, ARLTS1 re-expression induces an in vivo decreased tumor growth in preclinical models of lung cancer. Microarray analysis of gene expression patterns in cells transduced with ARLTS1 demonstrates that various pathways involved in cell survival, proliferation and development mediate its pro-apoptotic effects.
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PMID:ARLTS1 - a novel tumor suppressor gene. 1837 53

Molecular targeting agents have become formidable anticancer weapons, which show much promise against the refractory tumors. Functional peptides are among the more desirable of these nanobio-tools. Intracellular delivery of multiple functional peptides forms a basis for potent, non-invasive mode of delivery, providing distinctive therapeutic advantages. Here, we examine growth suppression efficiency of human glioblastomas by dual-peptide targeting. We did simultaneous introduction of two tumor suppressor peptides (p14(ARF) and p16(INK4a) or p16(INK4a) and p21(CIP1) functional peptides) compared with single-peptide introduction using Wr-T-mediated peptide delivery. Wr-T-mediated transport of both p14(ARF) and p16(INK4a) functional peptides (p14-1C and p16-MIS, respectively) into human glioblastoma cell line, U87DeltaEGFR, reversed specific loss of p14 and p16 function, thereby drastically inhibiting tumor growth by >95% within the first 72 h, whereas the growth inhibition was approximately 40% by p14 or p16 single-peptide introduction. Additionally, the combination of p16 and p21(CIP1) (p21-S154A) peptides dramatically suppressed the growth of glioblastoma line Gli36DeltaEGFR, which carries a missense mutation in p53, by >97% after 120 h. Significantly, our murine brain tumor model for dual-peptide delivery showed a substantial average survival enhancement (P < 0.0001) for peptide-treated mice. Wr-T-mediated dual molecular targeting using antitumor peptides is highly effective against growth of aggressive glioblastoma cells in comparison with single molecule targeting. Thus, jointly restoring multiple tumor suppressor functions by Wr-T-peptide delivery represents a powerful approach, with mechanistic implications for development of efficacious molecular targeting therapeutics against intractable human malignancies.
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PMID:Potent synergy of dual antitumor peptides for growth suppression of human glioblastoma cell lines. 1856 17


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