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)

Survival curves and dose escalation studies of four representative human tumor cell lines exposed to the various alkylating agents are presented. With HN2, at a level of one log of cell kill there was a fivefold range in drug concentration required to achieve this degree of cell kill among the cell lines, from 4.5 microM for the SL6 lung adenocarcinoma to 22 microM for the SW2 small-cell lung carcinoma. Four logs of SCC-25 squamous carcinoma cells were killed by 100 microM CDDP; however, there was only about one log of SL6 cells killed by 500 microM CDDP. To kill one log of G3361 melanoma cells required 24 microM 4-HC and to kill one log of SCC-25 cells required 24 microM, approximately a 16-fold difference. The curves for cell kill by L-PAM appeared to be biphasic, with a break at about 100 microM. There was about a threefold range in drug concentration required to achieve one log of cell kill with L-PAM, from 60 microM in the SCC-25 cell line to 18 microM in the SW2 line. To kill one log of SCC-25 cells required 295 microM BCNU and to kill one log of SW2 cell required 120 microM, about a 2.5-fold difference. The range of maximally tolerated HN2 concentrations were from 1200 microM for the SL6 cell line, 48 times the initial concentration, to 300 microM for the SCC-25 line, 16 times the initial concentration. The G3361 line tolerated the highest level of CDDP, 1900 microM, 48 times the initial concentration. The SCC-25 line, on the other hand, tolerated only 600 microM, 30 times the initial concentration. The SL6 cell line maximally tolerated 36 times the initial concentration of 4-HC (1450 microM), whereas the SCC-25 cell line tolerated only 18 times the initial concentration (720 microM). The G3361 melanoma tolerated 1555 microM, 30 times the initial concentration of L-PAM, and the SCC-25 cell line tolerated 700 microM, 14 times the initial concentration. The SL6 cell line tolerated the highest concentration of BCNU, 4200 microM, 24 times the initial concentration. The SCC-25 cell line tolerated 1450 microM, 8 times the initial concentration. In all cases, the SCC-25 cell line was least able to tolerate exposure to increasing concentrations of alkylating agents. The SL6 and G3361 cell lines showed the greatest tolerance for increasing concentrations of alkylating agents.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Development of alkylating agent-resistant human tumor cell lines. 337 Jul 36

Twenty-one patients with tumor stage mycosis fungoides (MF) with or without lymph node (LN) involvement, were treated with total skin electron beam irradiation (TSEB) followed by six monthly cycles of systemic chemotherapy (CT) of either mechlorethamine (HN2) or cyclophosphamide (CTX) with vincristine (VCR), procarbazine, and prednisone (PRD) (COPP or MOPP). All patients had complete clearing of the skin after TSEB. However, while receiving chemotherapy, two patients developed visceral involvement and eight patients relapsed with limited cutaneous plaques (LCP). The median duration of remission was 12 months from the completion of TSEB, and all patients relapsed with cutaneous plaques within 25 months. Complete remission was again achieved using additional electron irradiation and maintenance therapy in all but one patient. Multiple cutaneous recurrences occurred in all patients. Median survival from the initiation of TSEB is 6 years. Five patients are living beyond 8 years (four off treatment without disease for 1 to 7 years). LN involvement did not influence initial response or survival. Combined modality therapy for tumor stage MF using TSEB followed by systemic CT and subsequent maintenance therapy may lead eventually to prolonged disease-free survival (DFS) in selected patients.
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PMID:Combined modality therapy for tumor stage mycosis fungoides: results of a 10-year follow-up. 339 62

We have examined the mechanism by which stromal cells from the microenvironment of the bone marrow restricted the in vitro growth of certain hemopoietic tumors. A series of leukemia cell lines was used to monitor biological activities of stromal cell lines representing five distinct subtypes. Only an endothelial-like clone derived from mouse stroma (MBA-2.1) was consistently found to produce a cell-surface-associated glycoprotein that selectively inhibited the growth of plasmacytomas. The factor, designated leukemia cell inhibitory activity (LCIA), was not detected in anchorage-dependent cells of nonhemopoietic origin. Tumors of the lymphoid lineage and plasmacytomas in particular were the most sensitive to LCIA. Myeloid, macrophage, and erythroleukemia tumors were resistant to the factor, as were normal hemopoietic target cells including pluripotent stem cells, myeloid progenitor cells, and mitogen-stimulated spleen cells. Fractionation of trypsin-released proteins from MBA-2.1 cells by gel filtration and affinity binding to concanavalin A-Sepharose revealed two types of inhibitors; one was the specific leukemia cell inhibitor (i.e., LCIA); the other, present at a lower titer, was non-target-cell specific. The high sensitivity of plasmacytomas to LCIA versus the resistance of normal stem cells may be utilized for selective elimination of plasma cell tumors from bone marrow inocula.
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PMID:Differentiation stage and lineage-specific inhibitor from the stroma of mouse bone marrow that restricts lymphoma cell growth. 345 88

A growing body of evidence from human and animal cancer cytogenetics indicates that aneuploidy is an important chromosome change in carcinogenesis. Aneuploidy may be associated with a primary event of carcinogenesis in some cancers and a later change in other tumors. Evidence from in vitro cell transformation studies supports the idea that aneuploidy has a direct effect on the conversion of a normal cell to a preneoplastic or malignant cell. Induction of an aneuploid state in a preneoplastic or neoplastic cell could have any of the following four biological effects: a change in gene dosage, a change in gene balance, expression of a recessive mutation, or a change in genetic instability (which could secondarily lead to neoplasia). To understand the role of aneuploidy in carcinogenesis, cellular and molecular studies coupled with the cytogenetic studies will be required. There are a number of possible mechanisms by which chemicals might induce aneuploidy, including effects on microtubules, damage to essential elements for chromosome function (ie, centromeres, origins of replication, and telomeres), reduction in chromosome condensation or pairing, induction of chromosome interchanges, unresolved recombination structures, increased chromosome stickiness, damage to centrioles, impairment of chromosome alignment, ionic alterations during mitosis, damage to the nuclear membrane, and a physical disruption of chromosome segregation. Therefore, a number of different targets exist for chemically induced aneuploidy. Because the ability of certain chemicals to induce aneuploidy differs between mammalian cells and lower eukaryotic cells, it is important to study the mechanisms of aneuploidy induction in mammalian cells and to use mammalian cells in assays for potential aneuploidogens (chemicals that induce aneuploidy). Despite the wide use of mammalian cells for studying chemically induced mutagenesis and chromosome breakage, aneuploidy studies with mammalian cells are limited. The lack of a genetic assay with mammalian cells for aneuploidy is a serious limitation in these studies.
Environ Mutagen 1986
PMID:Chemically induced aneuploidy in mammalian cells: mechanisms and biological significance in cancer. 351 Aug 60

The relationship between chemically induced patterns of tumorigenesis in rodents and of in vitro genetic toxicity was evaluated for 73 substances. tumorigenicity patterns were defined according to sex and species effects, the induction of common or uncommon tumors, and benign or malignant tumors. These results and the genetic toxicity results derived from the testing of chemicals under code were compared. Chemicals that induced tumors in both sexes of both rodent species (trans-sex/species carcinogens) were divided into those that showed multiple responses in genetic toxicity assays and those that showed little or no response. Some of the nongenotoxic trans-sex/species carcinogens exhibit properties that do not necessarily fit classification as only tumor promoters and may involve some other mode(s) of action. Those chemicals showing tumorigenicity in only one of the four groups exposed (uni-sex/species carcinogens) generally showed little or no response in genetic toxicity assays. Uni-sex/species carcinogens may be difficult to identify by in vitro assays because of their high tissue specificity. Chemicals that are tumorigenic in both sexes of both species are logically more likely to be tumorigenic in a third species than are those that are tumorigenic in only one sex of the exposed species. Therefore, while positive genetic toxicity test results are not predictive of all carcinogens, a consistent positive response among the multiple endpoints in these assays is more likely to identify chemicals with the potential for trans-sex/species carcinogenesis. Such trans-sex/species carcinogens may have the most direct implication for human health effects.
Environ Mutagen 1986
PMID:Comparison of multiple parameters of rodent carcinogenicity and in vitro genetic toxicity. 369 43

Studies have shown that the quinone group can produce tumor cell kill by a mechanism involving active oxygen species. This cytotoxic activity can be correlated with the induction of DNA double strand breaks and is enhanced by the ability of the quinone compound to bind to DNA by alkylation. The cytotoxic activity and the production of DNA damage by model quinone antitumor agents were compared in L5178Y cells, sensitive and resistant to alkylating agents, to assess the contribution of alkylation to the activity of these agents. The resistant L5178Y/HN2 cells were found to be two fold and six fold more resistant to the alkylating quinones, benzoquinone mustard and benzoquinone dimustard, respectively, than parent L5178Y cells. In contrast, the L5178Y/HN2 cells showed no resistance to the nonalkylating quinones, hydrolyzed benzoquinone mustard and bis(dimethylamino)benzoquinone. The alkylating quinones produced approximately two fold less cross-linking in L5178Y/HN2 cells compared with L5178Y sensitive cells. DNA double strand break formation by hydrolyzed benzoquinone mustard and bis(dimethylamino)benzoquinone was not significantly different in sensitive and resistant cells. However, the induction of double strand breaks by the alkylating quinones benzoquinone mustard and benzoquinone dimustard was reduced by 5-fold and 15-fold, respectively, in L5178Y/HN2 cells. These results show that the alkylating activity of the alkylating quinones cannot directly explain all of the enhanced cytotoxic activity of these agents. Furthermore, they provide strong evidence that the enhanced formation of DNA double strand breaks by alkylating quinone agents is directly related to the ability of these agents to bind to DNA. This increased formation of strand breaks may account for the enhanced cytotoxic activity of the alkylating quinones.
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PMID:The contribution of alkylation to the activity of quinone antitumor agents. 373 Sep 43

The alkylating agents represent one of the most important classes of antitumor agents and play a major role in combination with other agents in the curative chemotherapy of selected human cancers. By repeatedly exposing cells to escalating doses of an alkylating agent, we have developed four human tumor cell lines which are relatively stably resistant to the drug with which the culture was treated. The response of these cell lines to a variety of alkylating agents was compared to the response of the parent cell lines to the same drug. The Raji/HN2 line was 7-fold resistant to nitrogen mustard and about 3-fold resistant to 4-hydroxyperoxycyclophosphamide, but it was not resistant to N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), melphalan (MEL), busulfan, trimethyleneiminethiophosphoramide, 4-hydroperoxyifosfamide, or cisplatin [cis-diamminedichloroplatinum(II)] (CDDP). The Raji/BCNU line was 5.3-fold resistant to BCNU and 4-fold resistant to both MEL and CDDP. The Raji/CP line was 7-fold resistant to CDDP and 3-fold resistant to both nitrogen mustard and BCNU, but it was not resistant to busulfan, trimethyleneiminethiophosphoramide, or 4-hydroperoxyifosfamide. The SCC-25/CP line, which was 12-fold resistant to CDDP, was 5-fold resistant to MEL and 3-fold resistant to 4-hydroxyperoxycyclophosphamide. The SCC-25/CP line was almost 24-fold resistant to methotrexate after 30-min treatment and about 7-fold resistant to methotrexate after continuous treatment. None of the other cell lines was resistant to methotrexate. The survival of SCC-25 and SCC-25/CP cells exposed to several antineoplastic agents was examined over several logs of survival. The SCC-25/CP cells are highly resistant to CDDP; the ratio of the slopes of the survival curves (SCC-25/CP to SCC-25) of the two lines was 43. At survivals of 1%, resistance to MEL and BCNU became evident in the SCC-25/CP line. At survivals of 0.1%, resistance to mitomycin C and, to a lesser degree, to Adriamycin and vincristine was evident. It is more difficult to produce resistance to alkylating agents, even with extended selection pressure, than to other antineoplastic drugs such as antimetabolites and natural products. We found no evidence of pleiotropic resistance in any alkylating agent-resistant cell line. Our results suggest that a judicious choice of alkylating agents given in sequential or concurrent combination may be a rational treatment strategy with potential applications in the clinic.
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PMID:Alkylating agents: in vitro studies of cross-resistance patterns in human cell lines. 373 Oct 96

The effects of depletion of cellular glutathione (GSH) on the sensitivity of cultured EMT6/SF cells to chemotherapy agents or x rays under hypoxic and aerated conditions were investigated. Buthionine sulfoximine (BSO), a potent inhibitor of the enzyme gamma-glutamyl-cysteine synthetase, was used to deplete cellular GSH. Addition of BSO (50 microM) to EMT6/SF cultures depleted cellular GSH with a half-time of approximately 2 hr. Cellular GSH reached very low levels within hours of addition of BSO. After removal of BSO, cellular GSH recovered with approximately the same kinetics as was seen for depletion. Incubation of EMT6/SF cells with BSO concentrations of up to 1 mM did not reduce the viability or inhibit growth when exposure was limited to times less than 24 hr. However, for longer exposure times, toxicity and growth inhibition were demonstrated in a dose dependent fashion. EMT6/SF cells were treated with chemotherapy agents under either aerated or extremely hypoxic conditions. Cells were more sensitive to cis-dichlorodiammino Pt(II) (DDP), mitomycin C (MitC), L-phenylalanine mustard (L-PAM), and nitrogen mustard (HN2) when treatment was under hypoxic conditions. The magnitude of this sensitization under hypoxic conditions ranged from a dose modifying factor (DMF) of 1.4 (HN2) to 4.1 (MitC), measured at the 0.1 level of cell survival. Hypoxic EMT6/SF cells were more resistant to the cytotoxic effects of actinomycin D (ActD) under hypoxic conditions (DMF = 10 at SF = 0.3). When cellular GSH was depleted to less than 5% of control by treatment with 50 microM BSO for 12-14 hr, cells were sensitized to DDP, L-PAM and HN2 under both aerated and hypoxic conditions. DMF's ranged from 1.4-6.5, depending on the agent. Hypoxic cell sensitization was never significantly greater than that seen in aerated cells, as was the case for X radiation (DMF = 1.3 for hypoxic cells only). GSH depletion also sensitized to MitC, but only under aerated conditions (DMF = 2.1). Hypoxic EMT6/SF cells were not sensitized to MitC by depletion of GSH. GSH depletion afforded slight protection against ActD toxicity under both aerated and hypoxic conditions. These studies suggest that cellular GSH plays an important role in modifying cellular response to cytotoxic drugs. GSH depletion may sensitize tumor cells to some chemotherapy agents, but differential sensitization of tumors compared to normal tissues, based on hypoxic tumor cells as targets, would not be expected based on these in vitro experiments.
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PMID:Effects of glutathione depletion by buthionine sulfoximine on the sensitivity of EMT6/SF cells to chemotherapy agents or X radiation. 374 36

A linear increase in cell uptake of nitrogen mustard, methyl-bis(beta-chloroethyl)amine (HN2), between 1 and 5 min, was observed after in vitro incubation of Ehrlich ascites tumor cells at 37 degrees C in phosphate-buffered saline containing HN2 followed by washing in 0 degrees C phosphate-buffered saline. After a second incubation in 37 degrees C phosphate-buffered saline without HN2, the cells lost about one-half of the drug which had been taken up, that which had not been covalently bound to macromolecules. The basal cytotoxic effect of HN2 on the cells was determined using a standard in vivo test for cell viability. Host survival was measured after 10(5) HN2-treated cells were injected i.p. into recipient mice, compared with injection of 10(5) untreated cells into paired control mice. Five min incubation of cells in vitro with multilamellar liposome vesicles (MLV) composed of L(alpha)dipalmitoyl-phosphatidyl choline in the presence of HN2, significantly increased tumor cell kill and mouse survival over HN2 alone. In contrast, added Ca2+ plus HN2 decreased cytotoxicity and survival. Significant increases in host survival following MLV treatment occurred without significant increase in total HN2 uptake and could be highly correlated with increased amounts of HN2 bound to DNA. Addition of vincristine (an inhibitor of microtubule polymerization) in the presence of HN2 also decreased the cytotoxic effect of HN2. The vincristine inhibition occurred, without altering total cell HN2 uptake, whether L(alpha)dipalmitoyl-phosphatidyl choline MLV were present or not. It is proposed that both Ca2+ and MLV act at membrane sites so as to alter the subcellular distribution and localization of HN2 and its accessibility to critical targets. This has been confirmed for MLV by demonstrating increased alkylation of DNA.
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PMID:Modulation of the cellular toxicity of nitrogen mustard in murine cells. 379 Dec 35

Development of in vitro resistance to HN2 (also called mustargen or mechlorethamine hydrochloride), N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), and cisplatin [cis-diamminedichloroplatinum(II)] was achieved in two human cell lines, the Raji/Burkitt lymphoma and a squamous cell carcinoma of the tongue. A 10- to 20-fold increase in resistance relative to the parental line was achieved in 3-4 months of continuous selection pressure. At this time, further increase in selection pressure resulted in cell death, while removal of drug led to rapid loss of resistance. However, by holding selection pressure constant over 8-12 months, semistable clones ranging in resistance up to 8- to 12-fold were obtained. The half-life for resistance loss upon removal of drug was 2-3 months. In the presence of intermittent low concentrations of the alkylating agent, resistance has been maintained in excess of 9 months. With one exception, the growth kinetics of the resistant clones were slightly slower than those of the parental lines. Cross-resistance studies were performed against HN2, BCNU, cisplatin, phenylalanine mustard, and hydroperoxycyclophosphamide. There was, in general, a lack of cross-resistance. We conclude that stable resistance to alkylating agents is produced with difficulty. We propose that these semistable cloned human tumor lines represent clinically relevant models for the study of alkylating agent resistance and that the cross-resistance patterns among these cells have important therapeutic and mechanistic implications.
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PMID:Alkylating agent resistance: in vitro studies with human cell lines. 385 90


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