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)

A novel biodegradable poly(lactic acid) microsphere formulation was evaluated for in vivo cytokine immunotherapy of cancer in a human tumor xenograft/ severe combined immunodeficiency (SCID) mouse model. Co-injection of interleukin-2 (IL-2)-loaded microspheres with tumor cells into a subcutaneous site resulted in the complete suppression of tumor engraftment in 80% of animals. In contrast, bovine-serum-albumin(BSA)-loaded particles or bolus injections of poly(ethylene glycol)/IL-2 were ineffective in preventing tumor growth. The antitumor effect of IL-2 released by the microspheres was shown to be mediated by the mouse natural killer cells. This is the first evidence that the rejection of human tumor xenografts can be provoked by the sustained in vivo delivery of IL-2 from biodegradable microspheres. The use of poly(lactic acid) microspheres to deliver cytokines to the tumor environment could provide a safer and simpler alternative to gene therapy protocols in the treatment of cancer.
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PMID:Cytokine immunotherapy of cancer with controlled release biodegradable microspheres in a human tumor xenograft/SCID mouse model. 952 Feb 88

We previously reported that EBC-1, a non-small cell lung cancer (NSCLC) cell line, produces immunoreactive neutrophil elastase (NE). In the present study, we examined the effects of ONO-5046.Na, a specific NE inhibitor, on the in vivo growth and spontaneous pulmonary metastasis of EBC-1 transplanted into severe combined immunodeficiency (scid) mice. In control mice, EBC-1 tumors inoculated subcutaneously grew steadily throughout 8-week observation period. The daily intraperitoneal injection of ONO-5046.Na (50 mg/kg/day) from day 1 completely suppressed the tumor growth. When ONO-5046.Na treatment was initiated 14 days after EBC-1 inoculation, it also caused a significant delayed growth of this cell line. Furthermore, ONO-5046.Na treatment completely inhibits the appearance of metastatic foci in lung at 8 weeks not only when it was administered from day 1 but also when treatment was initiated 14 days after tumor inoculation, when solid tumors started to grow. The weight of the mice treated with ONO-5046.Na was similar to that of the control mice at 8 weeks, and they appeared as healthy as the control mice during the treatment. These results indicated that a NE inhibitor, ONO-5046.Na, inhibited both primary and metastatic growth of NSCLC with no marked side effects.
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PMID:Complete inhibition of spontaneous pulmonary metastasis of human lung carcinoma cell line EBC-1 by a neutrophil elastase inhibitor (ONO-5046.Na). 961 36

Agonist antihuman gp130 transducer monoclonal antibodies (MoAbs) were used in SCID mice to grow myeloma cells whose survival and proliferation is dependent on gp130 transducer activation. The agonist anti-gp130 MoAbs neither bound to murine gp130 nor activated murine cells and, as a consequence, did not induce interleukin-6 (IL-6)-related toxicities in mice. They have a 2-week half-life in vivo when injected in the peritoneum. The agonist antibodies made possible the in vivo growth of exogenous IL-6-dependent human myeloma cells as well as that of freshly explanted myeloma cells from 1 patient with secondary plasma cell leukemia. Tumors occurred 4 to 10 weeks after myeloma cell graft and weighed 3 to 5 g. They grew as solid tumors in the peritoneal cavity and metastasized to the different peritoneal organs: liver, pancreas, spleen, and intestine. Tumoral cells were detected in blood and bone marrow of mice grafted with the XG-2 myeloma cells. Tumoral cells grown in SCID mice had kept the phenotypic characteristics of the original tumoral cells and their in vitro growth required the presence of IL-6 or agonist anti-gp130 MoAbs. Myeloma cells from 4 patients with medullary involvement persisted for more than 1 year as judged by detectable circulating human Ig. However, no tumors were detected, suggesting a long-term survival of human myeloma cells without major proliferation. These observations paralleled those made in in vitro cultures as well as the tumor growth pattern in these patients. This gp130 transducer-dependent SCID model of multiple myeloma should be useful to study various therapeutical approaches in multiple myeloma in vivo.
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PMID:A gp130 interleukin-6 transducer-dependent SCID model of human multiple myeloma. 961 71

Gene replacement therapy is potentially a very powerful tool, targeting specific molecular mediators of cancer development and progression. p21WAF1 (p21) is a cyclin-dependent kinase inhibitor that is induced by p53 upon DNA damage or p53 overexpression, resulting in cell cycle arrest at the G1 checkpoint and inhibition of further cell proliferation. Using a replication-deficient recombinant adenovirus (AdV) ((rAd)-p21) as a p21 gene delivery system, we have evaluated the effect of p21 introduction in lung cancer cells in vitro as well as in vivo. In in vitro experiments, two human non-small cell lung cancer (NSCLC) cell lines, NCI-H460 and NCI-H322, showed dose-dependent p21 induction and concomitant cell growth inhibition following rAd/p21 infection. Flow cytometric analysis of the cell cycle revealed a significant increase in the percentage of NCI-H460 cells in G0/G1 following rAd/p21 infection compared with untreated cells, suggesting that p21-induced growth inhibition was due to G0/G1 arrest. We also tested the therapeutic efficacy of rAd/p21 in an in vivo human NSCLC model in SCID mice. Tumor-bearing mice were established by subcutaneous injections of NCI-H460 cells and treated by repeated intratumoral injections of rAd/p21. Intratumoral delivery of rAd/p21 significantly suppressed tumor growth and prolonged survival in rAd/p21-treated mice. Our in vitro and in vivo results provide strong preliminary evidence for the growth inhibition of NSCLC by rAd/p21. Collectively, these results justify further studies to evaluate the efficacy of rAd/p21 for gene therapy in human lung cancer.
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PMID:Inhibition of tumor cell growth by p21WAF1 adenoviral gene transfer in lung cancer. 962 2

We report here the role of the CXC chemokine, epithelial neutrophil activating peptide (ENA-78), as an angiogenic factor in human non-small cell lung cancer (NSCLC). In freshly isolated human specimens of NSCLC, elevated levels of ENA-78 were found that strongly correlated with the vascularity of the tumors. In a SCID mouse model of human NSCLC tumorigenesis, expression of ENA-78 in developing tumors correlated with tumor growth in two different NSCLC cell lines. Furthermore, passive immunization of NSCLC tumor-bearing mice with neutralizing anti-ENA-78 antibodies reduced tumor growth, tumor vascularity, and spontaneous metastases, while having no effect on the proliferation of NSCLC cells either in vitro or in vivo. These findings suggest that ENA-78 is an important angiogenic factor in human NSCLC.
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PMID:Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. 969 Oct 82

To study the role of cell-surface expression of a tumor-selective heat-shock protein 70 (Hsp70) in vivo, the colon-carcinoma cell line CX2, and the clonal sub-lines CX+ and CX-, which differ in Hsp70 cell-surface expression, but not in MHC and adhesion-molecule expression, were implanted into immunodeficient SCID/beige mice by s.c., i.p., i.v. and orthotopic (o.t.) inoculation. On day 18 after s.c. injection, all animals developed s.c. tumors, ranging in size from 2.5 to 3 cm2. Phenotypic characterization of single-cell suspensions generated from freshly isolated tumor material revealed that the pattern of cell-surface expression is identical to that of the injected tumor cells from cell culture. Comparable results were obtained following i.p. inoculation of CX+ and CX- cells. Macroscopic and microscopic evaluation of lymph nodes, lung, liver and spleen at autopsy of tumor-bearing mice showed no tumor burden except the primary tumor, following s.c. or i.p. injection. After i.v. inoculation of CX+ and of CX- cells, weak tumor growth was observed in lung and liver, the Hsp70 cell-surface-expression pattern on these tumors being identical to that of the injected cells. However, o.t. injection of colon-carcinoma cell lines CX+ and CX- into the cecum resulted in tumor growth at the injection site and in spread of distant metastases in lung, liver and spleen. Most interestingly, and in contrast to the primary colon carcinomas, metastases of CX+ and of CX- tumor cells both revealed strong Hsp70 plasma-membrane expression, although the total amount of cytoplasmic Hsp70 was comparable.
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PMID:Differential Hsp70 plasma-membrane expression on primary human tumors and metastases in mice with severe combined immunodeficiency. 971 69

Cell growth and viability are dependent on the function of the multicatalytic proteinase complex (proteasome), a multisubunit particle that affects progression through the mitotic cycle by degradation of cyclins. Exposure of rodent fibroblasts and human lymphoblasts in culture to benzyloxycarbonyl-leucyl-leucyl-phenylalaninal (Z-LLF-CHO), a cell-permeable peptidyl aldehyde inhibitor of the chymotrypsin-like activity of the proteasome, resulted in the induction of apoptosis in a rapid, dose-dependent fashion. Fibroblasts transformed with ras and myc, lymphoblasts transformed by c-myc alone, and a Burkitt's lymphoma (BL) cell line that overexpresses c-Myc were up to 40-fold more susceptible to apoptosis than were either primary rodent fibroblasts or immortalized nontransformed human lymphoblasts, respectively. To determine whether such preferential apoptosis could impact upon tumor growth in vivo, toxicological studies were performed in mice with severe combined immunodeficiency and showed that mice tolerated single interscapular doses of Z-LLF-CHO without unacceptable toxicity. Severe combined immunodeficient mice bearing s.c. BL tumors in the flank were treated interscapularly with Z-LLF-CHO or a comparable dose of the peptidyl alcohol (Z-LLF-OH), which does not induce proteasome inhibition or apoptosis. Single doses of Z-LLF-CHO induced statistically significant (P < 0.0001) early tumor regression and a significant (P < 0.0001) delay in tumor progression. Analysis of tumor specimens revealed increased apoptosis in BL tumors from mice treated with Z-LLF-CHO. These results, showing a 42% tumor growth delay, indicate that proteasome inhibitors have the potential of curbing the growth of a c-myc-related tumor.
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PMID:Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor. 976 62

Gene transfer offers the possibility of novel therapies for head and neck squamous cell carcinoma (HNSCC). To this end, we demonstrate that a replication deficient adenovirus vector (Ad.RSVlacZ) can efficiently transduce foreign genes into human HNSCC cell lines in vitro, and that adenoviral mediated transfer of herpes simplex virus thymidine kinase (Ad.RSVtk) followed by exposure to ganciclovir results in tumor cell killing in vitro and in vivo. Exposure to Ad.RSVlacZ resulted in lacZ expression at multiplicities of infection (MOIs) of 10 and 100 for the cell lines HEp-2 and FaDu, respectively. This increased to 97% (HEp-2) and 49% (FaDu) at an MOI of 10,000. For HEp-2, maximum expression occurred during the first 48 hours after exposure (52% at 24 hours, 48% at 48 hours; MOI 500), then declined by 40% per day. This rapid decline may be caused by dilution of the gene through cell proliferation, because normalizing for the increase in total protein shows that the total number of cells expressing lacZ is stable from days 1 to 4. FaDu and HEp-2 were then transduced by AD.RSVtk and exposed to 20 microM ganciclovir for 24 hours. Significant tumor cell killing, as measured by a colony forming assay, occurred at an MOI of 2 for HEp-2 and 20 for FaDu. At an MOI of 200, 100% of HEp-2 and 97% of FaDu cells were killed. Next, subcutaneous tumor nodules derived from FaDu and HEp-2 were established in the flanks of SCID mice. Direct intratumoral injection of Ad.RSVtk followed by 7 days of ganciclovir therapy resulted in an adenovirus dose dependent reduction of tumor growth, and an actual size reduction of established tumor nodules at the highest does (10(10) plaque forming units). In conclusion, an adenovirus vector can efficiently transduce HNSCC cell lines in vitro. Maximum marker gene expression occurred during the first 48 hours after transduction. Transduction by Ad.RSVtk followed by exposure to ganciclovir resulted in tumor cell killing in vitro and in vivo.
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PMID:Tumor reduction in vivo after adenoviral mediated gene transfer of the herpes simplex virus thymidine kinase gene and ganciclovir treatment in human head and neck squamous cell carcinoma. 978 85

Genomic aberrations at the chromosome 16q arm are one of the most consistent abnormalities observed by loss of heterozygosity and comparative genomic hybridization analyses in human prostate cancer, suggesting that there are tumor suppressor or metastasis suppressor genes encoded by this chromosomal region. To functionally identify such suppressor genes, we have conducted microcell-mediated chromosome transfer to introduce human chromosome 16 into the highly metastatic Dunning rat prostatic cancer cell line, AT6.1. The metastatic ability of the resultant microcell hybrid clones was then tested in a standard spontaneous metastasis assay using SCID mice. When the microcell-mediated chromosome transfer hybrid cells containing whole human chromosome 16 were injected, the number of metastatic lesions in the lung was significantly reduced as much as 99% on average. Therefore, chromosome 16 has a strong activity to suppress the metastatic ability of AT6.1 cells while it did not affect the tumorigenesis and tumor growth rate. A PCR analysis of various microcell hybrid clones with sequence-tagged site markers indicates that the metastasis suppressor activity is located in the q24.2 region of chromosome 16. Our results are consistent with the previous finding that the region of human chromosome 16q has frequent loss of heterozygosity in prostate cancer patients and suggest that there is a metastasis suppressor gene in this region that may play an important role in the progression of prostate cancer.
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PMID:Human chromosome 16 suppresses metastasis but not tumorigenesis in rat prostatic tumor cells. 978 3

In the present study, we developed an antitumor immunoconjugate that appears to be promising as a novel curative antitumor agent against a variety of human solid tumors. We generated a new antihuman endoglin (EDG) monoclonal antibody (mAb) K4-2C10 (or termed SN6f) that cross-reacts with mouse endothelial cells. Such cross-reactive anti-EDG mAbs have not been reported previously. This mAb was used to target tumor-associated vasculature in SCID mice inoculated with human tumors. No anti-EDG mAb or its immunoconjugates have previously been successfully used for targeting vasculature in vivo. In this study, MCF-7 human breast cancer cells were inoculated s.c. into SCID mice. K4-2C10 did not react with the MCF-7 cells but showed a weak reactivity with mouse endothelial cells. The mAb reacted with the proliferating endothelial cells more strongly than with the quiescent endothelial cells. The mAb exhibited much stronger reactivity (>10-fold) with human endothelial cells than with mouse endothelial cells and reacted strongly with vascular endothelium of tumor-associated blood vessels in a variety of human malignant tissues. Conjugates of K4-2C10 with ricin A chain (RA) and deglycosylated ricin A chain (dgRA) showed a weak but specific cytotoxic activity against murine endothelial cells in vitro; the 50% inhibitory dose of the RA and dgRA conjugates was 54 nm and 29 nm, respectively. Remarkable antitumor efficacy was observed when a small amount (a total of 60 microgram corresponding to 24% of the LD50 dose) of the dgRA conjugate was administered i.v. into SCID mice that had been inoculated s.c. with MCF-7. Unconjugated mAb K4-2C10 was not significantly effective in the inhibition of the tumor growth. The immunotoxin (IT) completely inhibited growth of the tumor in all of the treated mice (n = 8). Furthermore, similar antitumor efficacy was observed when the IT was administered i.v. into the tumor-inoculated SCID mice that had been pretreated with unconjugated K4-2C10 to block the potentially available weak binding sites of normal tissues. The strong therapeutic effects of the IT were reproduced in another set of therapeutic experiments. No significant side effects were observed in the mice. The differences in the tumor growth between the control group and the IT-treated groups were statistically significant. The IT showed antiangiogenic activity in the dorsal air sac method. The results indicate that K4-2C10 IT effectively treated the tumor-bearing mice by selectively inhibiting the tumor-associated blood vessels and by disrupting tumor-associated angiogenesis. The strong antitumor efficacy of the K4-2C10 IT is remarkable in view of the fact that K4-2C10 and its IT showed only a weak reactivity with mouse endothelial cells, and a relatively small amount of the IT was administered i.v. to treat s.c. tumors. We anticipate that the K4-2C10 IT will show much stronger antitumor efficacy and antiangiogenic activity in patients with solid tumors and other angiogenesis-associated diseases. The present results demonstrate for the first time that an anti-EDG mAb or its immunoconjugate can effectively target tumor-associated vasculature in vivo.
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PMID:Long-lasting complete inhibition of human solid tumors in SCID mice by targeting endothelial cells of tumor vasculature with antihuman endoglin immunotoxin. 981 81


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