Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In view of non-specific toxicity of most chemotherapeutic agents against normal cells, the development of targeted chemotherapy is warranted. Efficient targeting of chemotherapeutic drugs to the cancerous area could be of great benefit for patients with advanced or metastatic tumors. Targeted cytotoxic peptide conjugates are hybrid molecules composed of a peptide carrier which binds to receptors on tumors and a cytotoxic moiety. New cytotoxic analogs of LHRH, AN-152 in which doxorubicin (DOX) is linked to [d-Lys(6)]LHRH, and AN-207 which consists of 2-pyrrolino-DOX (AN-201) coupled to the same carrier, show high-affinity binding and are much less toxic and more effective in vivo than their respective radicals in inhibiting tumor growth in LHRH receptor-positive models of human ovarian, mammary, or prostatic cancer. These results suggest that targeted cytotoxic LHRH analogs such as AN-207 could be considered for treatment of these cancers. The presence of receptors for bombesin-like peptides on a wide variety of tumors prompted us to use some of our bombesin/gastrin-releasing peptide antagonists as carrier molecules. Cytotoxic bombesin analogs, such as AN-215 containing AN-201, might find application in the treatment of small cell lung carcinoma (SCLC), and colorectal, gastric, pancreatic, mammary, and prostatic cancers. Since somatostatin receptors are found in various human neoplasms and the receptor subtypes to which octapeptide analogs bind with high affinity have been identified, we synthesized several cytotoxic somatostatin analogs including AN-162 and AN-238 containing DOX and 2-pyrrolino-DOX respectively, linked to octapeptide RC-121. Cytotoxic somatostatin analog AN-238 efficaciously inhibits growth of human breast or prostate cancers expressing somatostatin receptors-2 and -5 and can be used for receptor-targeted chemotherapy. Cytotoxic somatostatin analogs might also find applications for the therapy of human pancreatic, colorectal, and gastric cancer as well as brain tumors and non-SCLC. Cytotoxic compounds linked to analogs of hormonal peptides like LHRH, bombesin, and somatostatin that can be targeted to certain tumors possessing receptors for those peptides could be an important addition to oncological armamentarium.
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PMID:Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors. 1040 15

As small cell lung carcinoma (SCLC) is frequently a widespread disease at diagnosis, highly radiosensitive and often only partially responsive to chemotherapy, radioimmunotherapy (RIT) would appear to be a promising technique for treatment. We report the preliminary results of a Phase I/II trial of RIT in SCLC using a two-step method and a myeloablative protocol with circulating stem cells transplantation. Fourteen patients with proved SCLC relapse after chemotherapy were treated with RIT. They were first injected i.v. with a bispecific (anti-carcinoembryonic antigen/anti-diethylenetriaminepentaacetic acid) monoclonal antibody (20-80 mg in 100 ml of saline solution) and then 4 days later with di-(In-diethylenetriaminepentaacetic acid)-tyrosyl-lysine hapten labeled with 1.48-6.66 GBq (40-180 mCi) of I-131 and diluted in 100 ml of saline solution. In patients receiving 150 mCi or more, circulating stem cells were harvested before treatment and reinfused 10-15 days later. Treatment response was evaluated by CT and biochemical data during the month before and 1, 3, 6, and 12 months after treatment. All patients received the scheduled dose without immediate adverse reactions to bispecific antibody or 1-131 hapten. Toxicity was mainly hematological, with two cases of grade 2 leukopenia and three cases of grade 3 or 4 thrombopenia. Body scanning 8 days after injection of the radiolabeled hapten generally showed good uptake at the tumor sites. Estimated tumor dose was 2.6-32.2 cGy/mCi. Among the 12 patients evaluated to date, we have observed 9 progressions, 2 partial responses (one almost complete for 3 months), and 1 stabilization of more than 24 months. Efficiency and toxicity were dose-related. The maximal tolerable dose without hematological rescue was 150 mCi. These preliminary results are encouraging, and dose escalation is currently continuing to reach 300 mCi. RIT should prove to be an interesting therapeutic method for SCLC, although repeated injections and hematological rescue will probably be required, as well as combination with other treatment modalities.
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PMID:Radioimmunotherapy of small cell lung carcinoma with the two-step method using a bispecific anti-carcinoembryonic antigen/anti-diethylenetriaminepentaacetic acid (DTPA) antibody and iodine-131 Di-DTPA hapten: results of a phase I/II trial. 1054 73

N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine (MDP-Lys (L18), romurtide) is a synthetic muramyl dipeptide derivative, and has immunomodulating activities including activation of cells of monocyte-macrophage lineage. We examined the effect of intrapleural instillation of MDP-Lys (L18) against malignant pleurisy associated with lung cancer. Six patients with cytologically-positive malignant pleural effusion (four with adenocarcinoma, one with small cell carcinoma and one with large cell carcinoma) were treated with single intrapleural instillation of MDP-Lys (L18) of 200 microg. Clinically, no reaccumulation of pleural effusion for at least 4 weeks was observed in four patients. No major side effects were observed. Total cell number elevated remarkably 4 h after instillation, and main increased population was that of neutrophils. Levels of chemotactic cytokines, such as interleukin (IL)-8, and monocyte chemotactic protein (MCP)-1 and levels of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, elevated in pleural effusion, and peak IL-1beta and IL-6 levels tended to be higher in clinical responders than non-responders. These results suggest MDP-Lys (L18) instilled by intrapleural route had a potential local immunomodulatory activity. Further study is warranted to further determine the critical factors which correlate with the clinical response.
Lung Cancer 2000 Feb
PMID:Intrapleural therapy with MDP-Lys (L18), a synthetic derivative of muramyl dipeptide, against malignant pleurisy associated with lung cancer. 1068 89

Matriptase is an epithelial-derived, integral membrane serine protease. The enzyme was initially isolated from human breast cancer cells and has been implicated in breast cancer invasion and metastasis. In the current study, using active matriptase isolated from human milk, we demonstrate that matriptase is able to cleave various synthetic substrates with arginine or lysine as their P1 sites and prefers small side chain amino acids, such as Ala and Gly, at P2 sites. For the most reactive substrates, N-tert-butoxycarbonyl (N-t-Boc)-gamma-benzyl-Glu-Ala-Arg-7-amino-4-methylcoumarin (AMC) and N-t-Boc-Gln-Ala-Arg-AMC, the K(m) values were determined to be 3. 81 and 4.89 microm, respectively. We further demonstrated that matriptase can convert hepatocyte growth factor/scattering factor to its active form, which can induce scatter of Madin-Darby canine kidney epithelial cells and can activate c-Met tyrosine phosphorylation in A549 human lung carcinoma cells. In addition, we noted that matriptase can activate urokinase plasminogen activator but has no affect on plasminogen. These results suggest that matriptase could act as an epithelial, upstream membrane activator to recruit and activate stromal-derived downstream effectors important for extracellular matrix degradation and epithelial migration, two major events of tissue remodeling, cancer invasion, and metastasis.
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PMID:Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, an epithelial membrane serine protease. 1096 9

The protein coding segment of the TP53 genes from the glioma-derived cell lines M059J and M059K was sequenced. The sequences from both cell lines were identical over 5039 bp, including the gene segment containing exons 2 through 9, exon 10, and the proximal segment of exon 11. In both cells, the first nucleotide of codon 286 (GAA, Glu) is changed to an A (AAA, Lys). Comparison with the same TP53 segment from the A549 human lung carcinoma cell line revealed several differences in intron sequence.
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PMID:Human TP53 from the malignant glioma-derived cell lines M059J and M059K has a cancer-associated mutation in exon 8. 1293 31

Three indolocarbazole compounds bearing a tripeptide or a lysine group attached to one of the indole nitrogens via a propylamino chain and two rebeccamycin derivatives bearing a lysine residue on the sugar moiety were synthesised with the aim of improving the binding to DNA and the antiproliferative activities. Four tumour cell lines, from murine L1210 leukemia, human HT29 colon carcinoma, A549 non-small cell lung carcinoma and K-562 leukemia, were used to evaluate the cytotoxicity of the drugs. Their effects on the cell cycle of L1210 cells and their antimicrobial properties against two Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, a Gram-negative bacterium Escherichia coli and a yeast Candida albicans were also investigated.
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PMID:Synthesis and biological activities of indolocarbazoles bearing amino acid residues. 1175 31

Previous studies suggested that suboptimal DNA repair capacity is associated with cancer risk and that the Asp312Asn and Lys751Gln polymorphisms in the xeroderma pigmentosum complementary group D (XPD) gene may influence DNA repair capacity. We therefore tested the hypothesis that these two XPD polymorphisms are associated with susceptibility to lung cancer in a hospital-based, case-control study in a Chinese population. Genotypes were determined by polymerase chain reaction-based restriction fragment length polymorphism methods in 383 healthy controls and 351 patients with lung cancer. We found that those who carried at least one 312Asn variant allele had an increased risk of squamous cell carcinoma (SCC) of the lung compared with those with the 312Asp/Asp genotype (adjusted odds ratio (OR), 1.80; 95% confidence interval (CI), 1.10-2.96). Compared with those having the 751Lys/Lys genotype, subjects carrying at least one variant 751 Gln allele were at a borderline increased risk of SCC of the lung (adjusted OR, 1.52; 95% CI, 0.94-2.46). Furthermore, stratified analysis suggested a multiplicative interaction between tobacco smoking and the Asp312Asn polymorphism on risk of SCC of the lung. The adjusted ORs of SCC of the lung for the variant XPD 312Asn genotype alone, for smoking > or = 29 pack-years alone, and for both the factors combined were 1.04 (95% CI, 0.37-2.94), 4.74 (95% CI, 2.88-9.49), and 14.32 (95% CI, 5.80-35.2), respectively. Similar results were evident for the Lys751Gln polymorphism that was in the linkage disequilibrium with the variant 312Asn allele. These data suggest that the two polymorphisms in the XPD gene may influence risk of smoking-related SCC of the lung.
Lung Cancer 2002 Nov
PMID:Polymorphisms of the DNA repair gene XPD and risk of lung cancer in a Chinese population. 1239 22

The formation of DNA adducts is thought to be a critical step for the induction of chemically induced cancer. O(6)-Methylguanine-DNA methyltransferase (MGMT) is a ubiquitously expressed enzyme that repairs DNA adducts formed by alkylating carcinogens. Thus, genetic polymorphisms of the MGMT that could result in differences in MGMT activity are potential risk factors for cancer. In the present study, we established a convenient and reliable genotyping method for the MGMT codon 178 polymorphism, a Lys (AAG) to Arg (AGG) substitution, using restriction fragment length polymorphism (RFLP), and studied differences in the distribution of this polymorphism in 92 Caucasian lung cancer patients and 85 controls. Frequencies of the "A" and "G" alleles (MGMT codon 178, AAG and AGG, respectively) were 0.91 and 0.09, respectively. The genetic polymorphism of the MGMT codon 178 was linked with that of the MGMT codon 143 (P < 0.05). The distribution of the MGMT codon 178 genetic polymorphism was not significantly different between lung cancer patients and controls. Thus, our study suggests that the MGMT codon 178 (and possibly 143) polymorphisms do not appear to markedly affect lung cancer risk for this population. In addition, we found an apparent 10bp-deletion in the intron before exon 5 by DNA sequencing. Because this "deletion" was observed in all sequenced samples (N = 20), the previously reported human (Caucasian) MGMT gene sequence should be revised to exclude this 10bp segment.
Lung Cancer 2004 Jun
PMID:Lack of association between Caucasian lung cancer risk and O6-methylguanine-DNA methyltransferase-codon 178 genetic polymorphism. 1514 May 40

Angiogenesis, the formation of new capillaries from preexisting blood vessels, is involved in many pathological conditions, for example, tumorigenesis, diabetic retinopathy, and rheumatoid arthritis. Angiostatin, which contains the kringle 1-4 domains of plasminogen, is known to be a potent inhibitor of angiogenesis and a strong suppressor of various solid tumors. In this study, we expressed recombinant protein containing the kringle 1-3 domains of human plasminogen in Escherichia coli and investigated its biological activities. The protein was successfully refolded from inclusion bodies and purified at a 30% overall yield, as a single peak by HPLC. The purified recombinant protein had biochemical properties that were similar to those of the native form, which included molecular size, lysine-binding capacity, and immunoreactivity with a specific antibody. The recombinant protein was also found to strongly inhibit the proliferation of bovine capillary endothelial cells in vitro, and the formation of new capillaries on chick embryos. In addition, it suppressed the growth of primary Lewis lung carcinoma and B16 melanoma in an in vivo mouse model. Our findings suggest that the recombinant kringle 1-3 domains in a prokaryote expression system have anti-angiogenic activities, which may be useful in clinical and basic research in the field of angiogenesis.
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PMID:Characterization and biological activities of recombinant human plasminogen kringle 1-3 produced in Escherichia coli. 1517 78

Immunoconjugates are being explored as novel cancer therapies with the promise of target-specific drug delivery. The immunoconjugate, huN901-DM1, composed of the humanized monoclonal IgG1 antibody, huN901, and the maytansinoid drug, DM1, is being tested in clinical trials to treat small cell lung carcinoma (SCLC). huN901-DM1 contains an average of three to four DM1 drug molecules per huN901 antibody molecule. The drug molecules are linked to huN901 through random modification of huN901 at epsilon-amino groups of lysine residues, thus yielding a heterogeneous population of conjugate species. We studied the drug distribution profile of huN901-DM1 by electrospray time-of-flight mass spectrometry(ESI-TOFMS), which showed that one to six DM1 drug molecules were attached to an antibody molecule. Both light and heavy chains contained linked drugs. The conjugation sites in both chains were determined by peptide mapping using trypsin and Asp-N protease digestion. Trypsin digestion identified modified lysine residues, since these residues were no longer susceptible to enzymatic cleavage after conjugation with the drug. With respect to Asp-N digestion, modified peptides were identified by observing a mass increase corresponding to the modification. The two digestion methods provided consistent results, leading to the identification of 20 modified lysine residues in both light and heavy chains. Each lysine residue was only partially modified. No conjugation sites were found in complementarity determining regions (CDRs). Using structural models of human IgG1, it was found that modified lysine residues were on the surface in areas of structural flexibility and had large solvent accessibility.
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PMID:Structural characterization of the maytansinoid-monoclonal antibody immunoconjugate, huN901-DM1, by mass spectrometry. 1608 51


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