Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melanocyte stimulating hormone (alpha-MSH, alpha-melanotropin),Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Ly-Pro-Va l-NH2, regulates melanogenesis within epidermal melanocytes of many animals. An MSH analogue ([Nle4,D-Phe7]alpha-MSH) that exhibits superpotency and prolonged biological activity has been synthesized, biologically characterized, and is presently in clinical trials to determine its possible clinical use in tanning of the skin. It also has potential for the diagnosis, localization, and chemotherapy of melanoma. The effects of this analogue on the growth, metastatic behavior, and invasive potential of a melanotic variant of Cloudman S-91 murine melanoma are reported here. In an intracutaneous murine model of melanoma cell tumor growth, the analogue did not increase primary tumor growth (size) after the period of administration of the peptide hormone analogue and did not affect spontaneous lung metastases. Survival times for the control and melanotropin-treated groups were similar, suggesting that overall tumor burden was not affected by treatment with the hormone analogue. Last, melanoma cell invasion through a human amniotic basement membrane in vitro was not enhanced compared to untreated cells.
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PMID:Effects of a melanotropic peptide on melanoma cell growth, metastasis, and invasion. 133 2

The possible mitogenic activity of fibronectin (FN) in human primary and metastatic melanoma lines and clones and the involvement of integrins in mediating this effect were evaluated. Quescent human melanoma cells cultured in serum-free medium proliferated in a dose- and time-dependent fashion to immobilized FN as indicated by [3H]thymidine incorporation, increment of cell number, and cell cycle analysis. This response to FN was observed with tumor clones isolated from a subcutaneous metastasis and with primary or metastatic melanomas from different patients, but only when tumor cells expressed the alpha 5 subunit of the FN receptor (i.e., VLA-5). Proliferation to FN by a primary tumor (Me4405) expressing all FN receptors and by a tumor clone (2/60) lacking only the alpha 4 subunit was inhibited by monoclonal antibodies to the alpha 5 and beta 1 but not by monoclonal antibodies to other subunits of FN receptors. Mapping of FN regions responsible for the proliferative signal was performed by stimulating melanoma cells with different FN proteolytic fragments and indicated that a significant mitogenic signal was provided by the M(r) 120,000 alpha-chymotrypsin fragment containing the Arg-Gly-Asp sequence. The proliferation of melanoma cells to FN and to FN fragments was also significantly inhibited by peptides containing the Arg-Gly-Asp sequence. These data indicate that FN can stimulate the proliferation of quiescent melanoma cells and that integrins as alpha 5 beta 1 are involved in the response of tumor cells to this extracellular matrix protein.
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PMID:Role of the alpha 5 beta 1 integrin receptor in the proliferative response of quiescent human melanoma cells to fibronectin. 138 57

We have investigated the anti-angiogenic effect of a polymeric peptide based on the Arg-Gly-Asp (RGD) core sequence of fibronectin as a monomer unit, i.e., poly(RGD), in syngeneic mice and in vitro. Single intratumoral administration of poly(RGD) on day 0, 1 or 7 after tumor implantation achieved a significant reduction of B16-BL6 melanoma colonization in the lungs, but did not affect the size of the primary tumor at the time of amputation. The number of capillary blood vessels oriented toward the tumor mass increased during the early growth phase after the intradermal inoculation of the tumor. Poly(RGD) significantly inhibited the formation of tumor neovascularization when co-injected with the tumor cells or separately injected intratumorally or intravenously on day 1 or 3 after tumor inoculation. This inhibitory effect of poly(RGD) was dose-dependent. Poly(RGD) was able to inhibit the haptotactic migration of endothelial cells along a gradient of substratum-immobilized fibronectin but not laminin. Tumor-conditioned medium (CM) by itself did not act as a chemoattractant when it was added in the lower compartment of a Transwell chamber, but promoted the endothelial cell migration to immobilized fibronectin or laminin. Poly(RGD) inhibited the enhanced cell migration to fibronectin but not to laminin in response to CM. Thus, poly(RGD)-mediated inhibition of tumor metastasis may be partly due to the inhibition of tumor-induced angiogenesis at primary and secondary sites.
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PMID:Inhibition of tumor angiogenesis by a synthetic cell-adhesive polypeptide containing the Arg-Gly-Asp (RGD) sequence of fibronectin, poly(RGD). 169 94

We have investigated the anti-metastatic and anti-invasive activities of polypeptide analogues based on the Arg-Gly-Asp (RGD) adhesive signal in fibronectin, poly(RGD), poly(RGDS)[Arg-Gly-Asp-Ser] and poly(RGDT)[Arg-Gly-Asp-Thr]. These polypeptides containing repetitive RGD sequences were able to inhibit experimental and spontaneous lung metastases of B16-BL6 cells more effectively than the corresponding monomer peptides. In the spontaneous metastasis model, multiple i.v. administrations of these polymeric peptides before or after surgical excision of the primary tumor resulted in a significant reduction of lung tumor colonies. However, there was no significant difference in ability to inhibit spontaneous lung metastasis among poly(RGD), poly(RGDS) and poly(RGDT), although the carboxy-terminal amino acid residue (i.e., Xaa in -RGDXaa-) has been shown to play an important role in the expression of cell adhesive character. The treatment with poly(RGD) substantially prolonged the survival time for mice injected s.c. with B16-BL6 melanoma as compared with the untreated control. We also found that the polypeptides were potently able to inhibit the invasion and migration of tumor cells in vitro. Since these polypeptide analogues showed no antigenicity in the host and had no toxic effect on tumor cells in vitro, they may be potentially useful in the prevention of cancer metastasis.
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PMID:Anti-metastatic and anti-invasive effects of polymeric Arg-Gly-Asp (RGD) peptide, poly(RGD), and its analogues. 211 67

We investigated that the antimetastatic and antiadhesive activities of peptides based on Arg-Gly-Asp adhesive signal in fibronectin could be augmented by their polymerization. Poly(Arg-Gly-Asp), which consists of a repetitive sequence of Arg-Gly-Asp, inhibited lung metastases in C57BL/6 mice more effectively than Arg-Gly-Asp tripeptide was able to do, when coinjected or separately injected with B16-BL6 cells. The adhesion of tumor cells to fibronectin was specifically inhibited by adding poly(Arg-Gly-Asp) but not unrelated peptides. In contrast, poly(Arg, Gly, Asp), in which three amino acids are randomly arranged, showed neither inhibition of lung metastases nor any adhesive ability to attach to tumor cells. The inhibitory effect of polymeric peptides containing the Arg-Gly-Asp sequence on lung metastases decreased according to the decreasing repeat units of the Arg-Gly-Asp core sequence. Polymeric peptides with Arg-Gly-Asp entrapped within the liposome membranes also caused a remarkable reduction of metastatic colonies. In a spontaneous metastasis model, multiple i.v. administrations of poly(Arg-Gly-Asp) after tumor inoculation caused the significant reduction of metastatic colonies in the lung but did not affect the growth (size) of primary tumor. We found that the polymerization (multivalency) of the Arg-Gly-Asp core sequence was able to augment the inhibition of tumor lung metastases in experimental and spontaneous metastasis models as well as the cell-adhesive property more effectively than a monovalent unit of Arg-Gly-Asp peptide.
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PMID:Inhibition of the metastasis of murine malignant melanoma by synthetic polymeric peptides containing core sequences of cell-adhesive molecules. 273 23

Since the adhesive interaction between tumor cells and host cells, or extracellular matrix (ECM), presumably plays a crucial role in metastatic formation, we used synthetic or recombinant polypeptide analogues, poly (RGD), CH-271 or SCM-chitin-RGDS based on Arg-Gly-Asp (RGD) sequence. Poly (RGD) effectively inhibited the experimental lung and liver metastasis when coinjected i.v. with different types of tumors. In a spontaneous lung metastasis model using B16-BL6 melanoma, multiple administrations of this polypeptide, before or after surgical excision of the primary tumor, resulted in significant inhibition of tumor metastasis. The mechanism responsible for the inhibition is partly associated with the ability to interfere with cell functions such as adhesiveness, motility, and invasiveness in the process of metastasis. CH-271 fusion polypeptide was much more effective in inhibiting lung or liver metastasis of tumors than cell-binding domain (C-274) or heparin-binding domain (H-271) polypeptides. SCM-chitin-RGDS conjugate significantly reduced the number of tumor colonies in the lungs by coinjection with Colon 26 carcinoma as compared with either RGDS or SCM-chitin alone. Since the polypeptides derived from cell adhesion molecules showed no toxicity to the host, they may provide a promising approach for the control of cancer metastasis.
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PMID:[Inhibition of tumor metastasis by synthetic peptide analogues of cell-adhesive RGD sequence of fibronectin]. 763 3

Since tumor suppressor gene DCC exhibits amino acid sequence homology to the neural cell adhesion molecule, there is a possibility that DCC might be related to tumor metastasis. In the present study, we examined 51 cases of primary esophageal carcinomas with regard to point mutations and loss of the DCC gene. We detected point mutations in two cases by screening using polymerase chain reaction-single strand conformation polymorphism analysis. When we determined the sequences, one case with lymph node metastasis showed an ATG (Met) to ACG (Thr) missense mutation in codon 168. Another case showed a CGA (Arg) to GGA (Gly) mutation in codon 201, which might be a polymorphic change, and two other mutations resulting in no amino acid change. We also examined loss of heterozygosity of the DCC gene. Forty-four of the 51 cases (86%) were informative, and among them 10 cases (23%) showed allelic deletion. The further away the lymph node metastasis was from the primary tumor, the higher the frequency of allelic deletions became. We also found allelic deletions in moderately and poorly differentiated squamous cell carcinomas but not in well differentiated ones. These results indicate that alterations of the DCC gene are related to the degree of lymph node metastasis and the degree of differentiation.
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PMID:Point mutations and allelic deletion of tumor suppressor gene DCC in human esophageal squamous cell carcinomas and their relation to metastasis. 818 90

We have investigated the inhibitory effect of the N-terminal modified Arg-Gly-Asp-Ser (RGDS) analogues, AcDRGDS and AcDRLDS, on tumor cell adhesion to the components of extracellular matrix and basement membrane, and also tested the antimetastatic effect of their conjugates with trimesic acid, Ar(DRGDS)3 and Ar(DRLDS)3. AcDRGDS significantly inhibited tumor cell adhesion to fibronectin, vitronectin and RGDS substrates, but not to CS1 substrate which is a ligand for the alpha 4 beta 1 tumor surface integrin receptor. In contrast, AcDRLDS variant peptide significantly inhibited tumor cell adhesion to laminin, in addition to RGDS-mediated adhesion to fibronectin and vitronectin. AcDRLDS also inhibited tumor cell adhesion to CS1 as well as the RGDS sequence within the fibronectin molecule in a concentration-dependent manner, although the inhibitory effect was less than that of the CS1 (EILDV) peptide. Ar(DRLDS)3 inhibited the laminin- and fibronectin-mediated invasion and migration of tumor cells, whereas Ar(DRGDS)3 selectively inhibited fibronectin-mediated invasion and migration. Ar(DRGDS)3 and Ar(DRLDS)3 were much more effective in inhibiting experimental lung or liver metastases of various types of murine and human tumors than the original RGDS-containing peptides or Ar(COONa)3. Multiple administrations of Ar(DRGDS)3 or Ar(DRLDS)3 potently inhibited spontaneous lung metastasis produced by intra-footpad injection of B16-BL6 cells without affecting the primary tumor size at the time of surgical excision, as compared with RGDS peptide or untreated control. Thus, Ar(DRGDS)3 and Ar(DRLDS)3 substantially increased the exhibiting any antimetastatic effect of the peptides without direct cytotoxicity.
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PMID:Antimetastatic activities of synthetic Arg-Gly-Asp-Ser (RGDS) and Arg-Leu-Asp-Ser (RLDS) peptide analogues and their inhibitory mechanisms. 878 88

Since the adhesive interaction between tumor cells and host cells, or extracellular matrix (ECM), presumably plays a crucial role in metastatic formation during a series of complex events, we used synthetic or recombinant polypeptide analogues, poly(RGD) or CH-271-based on Arg-Gly-Asp(RGD) sequence or functional domains in fibronectin. Use of these analogues regulated the mechanisms involved in cell adhesion during the metastatic process. Poly(RGD) effectively inhibited the experimental lung and liver metastasis when coinjected i.v. with different types of tumors. In a spontaneous lung metastasis model using B-16-BL6 melanoma, multiple administrations of this polypeptide, before or after surgical excision of the primary tumor, resulted in significant inhibition of tumor metastasis without affecting the growth of the primary tumor. Further, it substantially prolonged the survival time of mice. The mechanism responsible for the inhibition of tumor metastasis by the polypeptides is partly associated with the ability to interfere with cell functions such as adhesiveness, motility, and invasiveness in the cellular adhesive process of metastasis. The combination of CH-271 fusion polypeptide and anticancer drugs, i.e., anti-adhesion therapy and chemotherapy, caused a dramatic inhibition of lung and liver metastasis of tumors when compared with either treatment alone, or in the control. Since the polypeptides derived from cell adhesion molecules showed no short-term toxicity to the host, they may provide a promising approach for the control of cancer metastasis.
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PMID:Prevention of cancer metastasis in mice with fibronectin-related substances. 898 70

Progression of prostate cancer during endocrine therapy is a major clinical problem, the molecular mechanisms of which remain poorly understood. Amplification of the androgen receptor (AR) gene was recently described in recurrent prostate carcinomas from patients who had failed androgen deprivation therapy. To evaluate the hypothesis that amplification of the AR gene is a cause for the failure of androgen deprivation therapy in prostate cancer, we studied whether AR amplification leads to gene overexpression, whether the amplified AR gene is structurally intact, and whether tumors with AR amplification have distinct biological and clinical characteristics. Tumor specimens were collected from 54 prostate cancer patients at the time of a local recurrence following therapy failure. In 26 cases, paired primary tumor specimens from the same patients prior to therapy were also available. Fifteen (28%) of the recurrent therapy-resistant tumors, but none of the untreated primary tumors, contained AR gene amplification as determined by fluorescence in situ hybridization. According to single-stranded conformation polymorphism analysis, the AR gene was wild type in all but one of the 13 AR amplified cases studied. In one tumor, a presumed mutation in the hormone-binding domain at codon 674 leading to a Gly --> Ala substitution was found, but functional studies indicated that this mutation did not change the transactivational properties of the receptor. AR amplification was associated with a substantially increased level of mRNA expression of the gene by in situ hybridization. Clinicopathological correlations indicated that AR amplification was most likely to occur in tumors that had initially responded well to endocrine therapy and whose response duration was more than 12 months. Tumors that recurred earlier or those that showed no initial therapy response did not contain AR amplification. The median survival time after recurrence was two times longer for patients with AR amplification in comparison to those with no amplification (P = 0.03, Willcoxon-Breslow test). In conclusion, failure of conventional androgen deprivation therapy in prostate cancer may be caused by a clonal expansion of tumor cells that are able to continue androgen-dependent growth despite of the low concentrations of serum androgens. Amplification and the increased expression of a wild-type AR gene may play a key role in this process.
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PMID:Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. 900 May 75


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