Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-Canavanine (CAV), the L-2-amino-4-guanidinooxy structural analogue of L-arginine (ARG), is a potent ARG antagonist which occurs in the jack bean, Canavalia ensiformis. This ARG antimetabolite is active against L1210 murine leukemia and a solid colonic tumor in the rat. Our initial studies using a microtiter assay show that CAV exhibits a 50% inhibitory concentration of approximately 2 mM against the human pancreatic adenocarcinoma cell line, MIA PaCa-2, when these cells are grown in Dulbecco's modified Eagle's medium containing 0.4 mM ARG. When the ARG concentration is reduced to 0.4 microM, the 50% inhibitory concentration for CAV falls precipitously to 0.01 mM. The pronounced increase in the ability of CAV to inhibit MIA PaCa-2 cell growth at the lower ARG concentration may result from enhanced CAV competition with ARG for incorporation into newly synthesized cellular proteins. At 0.4 microM ARG, 30 mM CAV almost completely inhibits cell growth by 6 h. In contrast, with 0.4 mM ARG, complete inhibition does not occur until after 48 h. A dramatic reversal of growth inhibition caused by a very high concentration of CAV was observed when cells treated with CAV were replenished with a high concentration of ARG. Our results suggest that CAV has real potential as a lead compound for the development of analogues with enhanced activity against human pancreatic cancer.
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PMID:Inhibition of the growth of human pancreatic cancer cells by the arginine antimetabolite L-canavanine. 767 Dec 64

Nude mice bearing xenografts of the MIA PaCa-2 human pancreatic cancer cell line were treated with sustained-release formulations (microcapsules) of luteinizing hormone releasing hormone (LH-RH) agonist [D-Trp6]-LH-RH, somatostatin analogue RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2), or combination of both analogues. Other groups of mice received daily subcutaneous injections of LH-RH antagonist SB-75 [Ac-D-Nal(2)',D- Phe(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10-LH-RH] or bombesin antagonist RC-3095. At necropsy, in mice given microcapsules releasing 25 micrograms/day of [D-Trp6]-LH-RH, tumor weight and volume were decreased, but not significantly, as compared with control mice. Microcapsules of RC-160, releasing 25 micrograms/day, significantly reduced tumor volume, percentage change in tumor volume, and tumor weight. Combination of RC-160 and [D-Trp6]-LH-RH inhibited tumor growth to a somewhat greater extent than RC-160 alone. Bombesin antagonist RC-3095, at a dose of 25 micrograms/day, did not influence the growth of tumors. In mice receiving 100 micrograms/day of antagonist SB-75, there was a significant decrease in tumor weight and volume and a significant reduction in the weight of ovaries and uteri. Specific binding of [125I]RC-160 and [125I][D-Trp6]-LH-RH, but not [125I]Tyr4-bombesin, was found on MIA PaCa-2 cells in culture. [D-Trp6]-LH-RH, SB-75, and RC-160 inhibited the growth of MIA PaCa-2 cells in vitro. Neither bombesin nor RC-3095 influenced the growth of MIA PaCa-2 cells in cultures. The results indicate that the LH-RH antagonist SB-75 could be tried for treatment of pancreatic cancer. Our findings confirm the efficacy of somatostatin analogue RC-160 in inhibiting the growth of pancreatic cancers and suggest that the combination of RC-160 and agonist [D-Trp6]-LH-RH might possibly increase the therapeutic response.
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PMID:Somatostatin analogue RC-160 and LH-RH antagonist SB-75 inhibit growth of MIA PaCa-2 human pancreatic cancer xenografts in nude mice. 809 55

Human pancreatic carcinoma xenograft models were developed from established MIA PaCa-2 and PANC-1 cell lines (ATCC, Rockville, MD). Tumors were maintained by serial trocar implantation in CD1 nu/nu mice, and attempts were made to test all drugs under optimal schedules at maximum tolerated doses. In both models, adriamycin, cisplatin, and 5-fluorouracil were inactive (< 60% inhibition of tumor weight), whereas gemcitabine (LY188011] produced modest activity (69% inhibition in MIA PaCa-2 and 76% inhibition in PANC-1. Major differences in tumor sensitivity were noted with diarylsulfonylureas (DSU) and taxol. The DSU (Sulofenur [LY186641] and LY295501) produced complete inhibition in the MIA PaCa-2 xenograft, but were inactive in PANC-1. Conversely, taxol produced 80% inhibition of PANC-1 tumor growth, but was inactive against MIA PaCa-2. In general, in vivo antitumor activity roughly correlated with in vitro tumor cytotoxicity with the exception of DSU. We have previously shown that DSU are extensively bound to albumin and that in vitro cytotoxic activity in serum-containing medium is not predictive of in vivo antitumor activity. The MIA PaCa-2 and PANC-1 xenograft models may be useful for selecting potential candidates for therapy of human pancreatic cancer.
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PMID:Evaluation of new anticancer agents against the MIA PaCa-2 and PANC-1 human pancreatic carcinoma xenografts. 812 42

The aim of this study was to survey the expression of an embryonic cytokine gene, MK, in the normal organs and neoplastic tissues of adults. Northern analysis showed that MK mRNA was exclusively expressed in the kidney among murine organs including thymus, lung, heart, spleen, liver, and kidney. In situ hybridization analysis revealed that MK expression was localized in the proximal tubules and metaplastic Bowman's epithelium, but not in other nephron segments such as glomeruli, loop of Henle, distal tubules, and collecting ducts. To investigate whether MK expression is a marker of tubular cell lineage, several cell lines originating from renal tubules were tested. No expression of MK was detected in PtK1 and LLC-PK1 cells derived from marsupial and porcine proximal tubules or in MDBK and MDCK cells from bovine and canine distal/collecting tubules. Unexpectedly, the MK gene was expressed in a human renal cell carcinoma line, VMRC-RCW, and the expression was up-regulated in the presence of retinoic acid. To elucidate the involvement of MK in the development of tumors, we further examined its expression in a variety of human neoplastic cell lines: YMB-1-C (breast cancer), EBC-1 (lung squamous cell carcinoma), RERF-LC-OK (lung adenocarcinoma), SBC-3 (lung small cell carcinoma), HSC-2 (mouth squamous cell carcinoma), NUGC-2 (gastric cancer), COLO201 (colon cancer), HepG2 (hepatoma), MIA PaCa-2 (pancreatic cancer), MCAS (ovarian cancer), HeLa (cervical cancer), BeWo (chorionic carcinoma), ITO-II (testicular tumor), T24 (urinary bladder tumor), and G-401 (Wilms' tumor). Strong signals were detected in COLO201, HepG2, ITO-II, T24, G-401, and weaker but distinct signals were detected in YMB-1-C, HSC-2, and MCAS cells. The MK gene was, therefore, widely expressed in neoplastic cells originating from genital organs, intestinal tract, liver, mammary gland, and urinary tract, and the expression was not restricted to adenocarcinomas, but was also observed in other types of tumor cells. These findings suggest that a retinoic acid responsive gene, MK, may play a role in the pathophysiology of renal proximal tubules and tumorigenesis in many types of neoplasms.
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PMID:A retinoid responsive cytokine gene, MK, is preferentially expressed in the proximal tubules of the kidney and human tumor cell lines. 843 39

Platelet cytotoxicity was examined in vitro using various tumour cell lines as target cells. Thrombin-activated platelets as well as unstimulated platelets exerted a cytotoxic effect on some tumour cell lines including K562, KU812, LU99A and KG1, but other tumour cell lines including U937, MIA PaCa-2 and MOLT-4 were completely insensitive to this effect. Electron microscopic examinations showed that unstimulated platelets adhered to target K562 cells but thrombin-activated platelets did not. Morphological changes of K562 cells induced by unstimulated and thrombin-activated platelets were indistinguishable. When platelets and K562 cells were co-cultured in the same vessel but were prevented from coming into direct cell-to-cell contact by means of a membrane barrier, cytotoxicity of unstimulated platelets was completely blocked but that of thrombin-activated platelets was still detectable. However, no cytotoxic activity to K562 cells was detected in the supernatants obtained after stimulation of platelets with either target cells or thrombin for 4 hr. Extracellular Ca2+ ion was not required for the platelet-mediated cytotoxicity. Esterase inhibitors SBTI and TPCK had no effect on the formation of platelet-target cell adhesion but inhibited the cytotoxicity of unstimulated platelets. In contrast, the inhibitors had no effect on the cytotoxic activity of thrombin-activated platelets. These results suggest that direct contact between platelets and target cells is essential for unstimulated platelets but not for thrombin-activated platelets to exert cytotoxicity and that some esterases play a role in the cytotoxic process of unstimulated platelets. They also provide evidence that some cytotoxic effectors are soluble and easily inactivated factors liberated by activated platelets. Our findings indicate that platelets may be one of the cytotoxic effector cells against certain neoplasia.
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PMID:Cytotoxicity of unstimulated and thrombin-activated platelets to human tumour cells. 849 82

The chemical derivatization of biologically active microbial metabolites continues to be a promising approach to the identification of new drugs. We recently synthesized the novel antiproliferative compound SDZ 281-977, 5-[2-(2,5-dimethoxy-phenyl)ethyl]-2-hydroxy-benzoic acid methylester, a derivative of the EGF receptor tyrosine kinase inhibitor lavendustin A. Here we report on our studies of the anticancer efficacy and the mode of action of SDZ 281-977. The growth of both the human pancreatic tumor cells MIA PaCa-2 and the human vulvar carcinoma cells A431 was inhibited in the low micromolar range. Tumors from these cells were induced in nude mice and were shown to respond to orally or intravenously administered SDZ 281-977. In contrast, no antitumor effect was detected in rats bearing dimethylbenzanthracene-induced mammary tumors. Studies in mice indicated that SDZ 281-977 was neither immunosuppressive nor hematosuppressive at doses effectively inhibiting tumor growth. Surprisingly, the mode of action of SDZ 281-977 apparently does not involve inhibition of EGF receptor tryosine kinase, because, in contrast to lavendustin A, SDZ 281-977 failed to inhibit this enzyme in a cell-free assay. The mechanism of the antiproliferative effect can be explained on a cellular level by the ability of the compound to arrest cells in mitosis. SDZ 281-977 is thus the first example of an antimitotic agent derived from the potent tyrosine kinase inhibitor lavendustin A. The therapeutic potential of SDZ 281-977 is enhanced by the fact that it is not subject to multidrug resistance, because tumor cells expressing the multidrug resistance phenotype were as sensitive to SDZ 281-977 as their nonresistant counterparts. In conclusion, SDZ 281-977 represents a novel lavendustin A derivative with potent antiproliferative properties in vitro and in vivo that may be explained on the basis of its antimitotic effects. SDZ 281-977 may be a candidate drug for the treatment of selected cancers, including those expressing the multidrug resistance phenotype.
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PMID:SDZ 281-977: a modified partial structure of lavendustin A that exerts potent and selective antiproliferative activities in vitro and in vivo. 857 57

Activating mutations of Ki-ras have been detected in most human pancreatic adenocarcinomas. Since Ras protein requires farnesylation to function, we investigated the effects of manumycin, a potent farnesyl:protein transferase inhibitor, on the growth in nude mice of a human pancreatic cancer cell line, MIA PaCa-2, with a point mutation in the Ki-ras gene. Tumor-bearing mice received intraperitoneal injection of 1 or 5mg/kg manumycin daily for 5 days, or 2 mg/kg manumycin daily for 2 weeks. Growth of inoculated tumors was significantly inhibited by the treatment. The treatment significantly (P<0.05) lowered the numbers of bromodeoxyuridine-incorporating tumor cells. Manumycin did not have apparent hepatotoxicity in vivo. Farnesyl:protein transferase inhibitors could offer a new approach for cancer chemotherapy.
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PMID:Suppression of human pancreatic cancer growth in BALB/c nude mice by manumycin, a farnesyl:protein transferase inhibitor. 860 57

Transforming growth factor-beta (TGF-beta) receptors constitute a family of transmembrane proteins that bind TGF-beta ligands. In this study we assessed the growth responsiveness to TGF-beta 1 in pancreatic cancer cell lines and characterized the levels of expression of TGF-beta receptors in these cell lines and in human pancreatic cancer tissues. COLO 357 cells were most sensitive to the growth inhibitory actions of TGF-beta 1, PANC-1 cells exhibited moderate sensitivity, Hs766T cells exhibited slight sensitivity and MIA PaCa-2 and T3M4 cells were resistant to TGF-beta 1. Only COLO 357 cells expressed high levels of ALK5, the major type I TGF-beta receptor (T beta RI). Hs766T and PANC-1 cells expressed high levels of SKR1, another T beta RI subtype. Only MIA PaCa-2 cells did not exhibit the type II TGF-beta receptor (T beta-RII) transcript, whereas type III TGF-beta receptor (T beta-RIII) mRNA levels were elevated in this cell line and in HS766T cells. All the cell lines expressed TGF-beta 1, but TGF-beta 2 and TGF-beta 3 mRNA levels were variable. ALK5 and SKR1 mRNA levels were 6.8- and 9-fold greater in the pancreatic tumors in comparison with the corresponding levels in the normal pancreas. However, in the cancer cells, ALK5 immunoreactivity was faint, whereas T beta RII immunoreactivity was focal and intense. Conversely, in ductal cells adjacent to cancer cells ALK5 immunoreactivity was strong, whereas T beta RII immunoreactivity was weak. Since ALK5 heterodimerization with T beta RII is crucial for TGF-beta-mediated signaling, our findings suggest that low levels of ALK5 in pancreatic cancer cells within a tumor may protect against growth inhibition.
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PMID:Attenuated ALK5 receptor expression in human pancreatic cancer: correlation with resistance to growth inhibition. 876 Jun

Irinotecan (CPT-11) is a semi-synthetic derivative of camptothecin currently in clinical trials. In vitro, CPT-11 presented preferential cytotoxicity toward some solid tumor cells (mouse colon 38 and pancreas 03; human pancreas MIA PaCa-2) as compared to leukemia cells (L1210), whereas SN-38, a metabolite of CPT-11, was not solid tumor selective. In vivo, schedule of administration studies in P388 leukemia and mammary adenocarcinoma 16/C (MA16/C) showed that CPT-11 was not markedly schedule dependent. In order to determine its spectrum of anticancer activity, CPT-11 was evaluated against a variety of mouse and human tumors. The end points used were total log cell kill (Lck) for solid tumors and increase in life span (% ILS) for leukemia. Intravenous CPT-11 was found highly active against both early and advanced stage pancreatic ductal adenocarcinoma 03 (P03), with 60% long-term survivors and 100% complete regressions, respectively. Other responsive tumors included: colon adenocarcinomas 38 and 51 (both 1.0 Lck); MA16/C (3.4 Lck); MA13/C (1.0 Lck); human Calc18 breast adenocarcinoma (2.8 Lck); Glasgow osteogenic sarcoma (1.8 Lck); Lewis lung carcinoma (1.4 Lck); B16 melanoma (1.4 Lck); P388 leukemia (170% ILS) and L1210 leukemia (64% ILS). Of interest, CPT-11 was active against tumors with acquired resistance to vincristine (P388/Vcr), to doxorubicin (P388/Dox) and to docetaxel (Calc18/TXT). CPT-11 was also found highly active after oral administration in mice bearing P03 and MA16/C tumors. Pharmacokinetic evaluations performed i.v. at the highest non-toxic dosage in mice bearing P03 tumors revealed CPT-11 peak plasma concentrations (Cmax) of 8.9 micrograms/ml and a terminal half-life of 0.6 h. The metabolite SN-38 plasma concentrations presented a Cmax of 1.6 micrograms/ml and a terminal half-life of 7.4 h. Although the CPT-11 tumor levels were similar to the plasma concentrations for early time points, drug levels decreased more slowly in the tumor compared to plasma (half-life, 5.0 h). SN-38 tumor levels reached concentrations in the range of 0.32-0.34 micrograms/g and decayed with a half-life of 6.9 h. No significant difference in plasma or tumor pharmacokinetics of either CPT-11 or SN-38 were noted after one or five daily i.v. injections. Overall, these data show that CPT-11 has good activity in experimental models, when administered both by the i.v. and the oral routes. Compared to humans, a similar schedule of administration independence was observed and similar CPT-11 levels could be reached at efficacious dosages although metabolite SN-38 levels were found higher in mice.
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PMID:Experimental antitumor activity and pharmacokinetics of the camptothecin analog irinotecan (CPT-11) in mice. 882 13

The effects of a synthetic lipid A on tumor necrosis factor (TNF) production and antitumor activity against human pancreatic cancer cells were investigated. Lipid A (10 mg/kg) was injected into normal rats and mice and serum TNF levels were measured. Lipid A-induced inhibition of Molt 4 and MIA paca-2 cells in culture were measured by counting viable cells. Activity of lipid A against transplanted human pancreatic cancer cells (MIA paca-2, Panc-1) was examined by determining tumor volume, necrosis, and survival rate after intraperitoneal injections of lipid A (10 and 20 mg/kg) over 4 weeks. Serum TNF levels increased 80-fold in rats and 100-fold in mice after intravenous lipid A injection. Although specific tumor growth inhibition by lipid A was not observed in vitro, tumor growth was significantly inhibited, and the survival rate was improved in pancreatic cancer cell-transplanted nude mice treated with lipid A compared with controls. Synthetic lipid A induces TNF production and has antitumor activity against transplanted pancreatic cancer cells. Further studies of this lipid A as an agent for pancreatic cancer are warranted.
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PMID:Effects of a new synthetic lipid A on endogenous tumor necrosis factor production and antitumor activity against human pancreatic cancer cells. 883 Mar 32


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