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)

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

The central nervous system toxicity and cerebrospinal fluid (CSF) pharmacokinetics of 3-[(4-amino-2-methyl-5-pyrimidinyl)ethyl]-1-(2-chloroethyl)-1- nitrosoureas, a (ACNU) were determined in beagles and compared to those for three other nitrosoureas, 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea, and chlorozotocin. Of the four drugs, ACNU was tolerated best and at doses of 0.2 to 0.8 mg/week for 8 consecutive weeks. We found that the average half-time for CSF elimination of ACNU was 18 min (range, 12 to 38 min). This value exceeded the known rate of ACNU decomposition in aqueous solution (28 to 29 min), implying that the disappearance of ACNU from CSF was due to hydrolytic decomposition and cellular entry and/or transcapillary loss across central nervous system capillaries. The drug exposure integral (C X t) of ACNU in the CSF after a "toxic dose low" of 0.8 mg in the dogs would achieve the equivalent of in vitro cell kills in excess of 3 logs for rat 9L and human glioma 126 cells. As a potential therapeutic agent for meningeal neoplasia, the major limiting factor may be that the CSF elimination of ACNU is rapid compared to its equilibration time from ventricle to spinal- and cerebral convexity-subarachnoid space. Based on these results, we have instituted clinical Phase I trials of intra-CSF ACNU.
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PMID:Central nervous system toxicity and cerebrospinal fluid pharmacokinetics of intraventricular 3-[(4-amino-2-methyl-5-pyrimidinyl)ethyl]-1-(2-chloroethyl)-1-nitro soureas and other nitrosoureas in beagles. 386 Feb 87

The sesquiterpene lactone antineoplastic vernolepin acutely depletes murine tumor cell glutathione (GSH), and lyses the cells by an unknown mechanism that is enhanced synergistically by inhibition of GSH synthesis with buthionine sulfoximine (BSO) (Arrick et al. 1983. J. Clin. Invest. 71:258). We found here that lysis of P815 mastocytoma cells by vernolepin, with or without BSO, required cystine in the culture medium. Addition of catalase markedly suppressed vernolepin-mediated cytolysis in cystine-containing media, suggesting the involvement of hydrogen peroxide in the cytolytic action of vernolepin. Consistent with this, inhibition of tumor cell glutathione disulfide reductase with 1,3-bis(2-chloroethyl)-1-nitrosourea or inhibition of endogenous catalase with aminotriazole synergistically augmented cytolysis by vernolepin. Moreover, H2O2 was released by suspensions of P815 cells in cystine-containing buffer (63 pmol/10(6) cells X h). Omission of cystine reduced the rate of H2O2 accumulation 10-fold. No H2O2 was detected without cells. Cytolysis by vernolepin could be restored in cystine-deficient medium by several other disulfides, themselves noncytolytic, such as disulfiram and oxidized Captopril, as well as by cysteine. In contrast, withholding two other essential amino acids (leucine or tryptophan) or adding cycloheximide did not interfere with cytolysis by vernolepin. These results suggest that cellular uptake of disulfides of physiologic and pharmacologic interest may be followed by their intracellular reduction and autooxidation with generation of H2O2. This previously unrecognized source of intracellular oxidant stress may be an important component of injury to GSH-depleted cells.
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PMID:Hydrogen peroxide from cellular metabolism of cystine. A requirement for lysis of murine tumor cells by vernolepin, a glutathione-depleting antineoplastic. 392 82

Intracarotid 1,3-bis(2-chloroethyl)-1-nitrosurea (BCNU) is now a frequently used chemotherapeutic agent for high-grade glial neoplasms. The toxicity from such therapy has not been well-documented. A 50-year-old man with a left frontoparietal grade 4 astrocytoma received three injections of intracarotid BCNU, 400 mg each, over a 2-month period. No radiation or other chemotherapy was ever given. He tolerated the BCNU injections well, with some reduction of tumor bulk, until the third dose. After his last injection, his condition gradually deteriorated; he became obtunded, and died 5 weeks later. At autopsy, the brain showed extensive cavitation and coagulative necrosis, fibrinoid vascular necrosis, edema, swollen axons, and bizarre cellular morphologic features confined to the BCNU perfusion territory. Grade 4 astrocytoma remained in the right hemisphere and in the left occipital lobe, sites outside the area of BCNU perfusion. Intracarotid BCNU can result in a severe leukoencephalopathy similar to that seen with methotrexate or delayed radionecrosis.
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PMID:Intracarotid BCNU leukoencephalopathy. 394 12

An in vitro assay for examining the sublethal effects of chemotherapeutic agents on vascular endothelial integrity is described. Using vascular endothelial cell monolayers, the kinetics of binding of radiolabeled platelets or metastatic tumor cells were altered when endothelial cells were pretreated for 2 hr with low, clinically relevant concentrations of certain drugs. Electron microscopic examination by scanning electron microscopy revealed that these same drugs caused endothelial cell retraction and exposure of subendothelial matrix. Platelets and tumor cells were found bound only to the exposed areas of subendothelial matrix. Some drugs (bleomycin, 1,3-bis(2-chloroethyl)-1-nitrosourea, vincristine) induced rapid endothelial cell retraction and increased platelet and tumor cell binding to exposed subendothelial matrix, while one of the drugs tested (Adriamycin) caused delayed (1 to 3 days after a 2-hr drug treatment) endothelial cell retraction and increased cell binding. Of the drugs tested, only 5'-fluoro-2'-deoxyuridine which interferes with DNA replication failed to induce endothelial cell retraction and increased tumor cell and platelet binding. The results suggest that certain drug effects on the vascular endothelium can be assessed using the vascular endothelial cell monolayer model.
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PMID:Effects of chemotherapeutic drugs on platelet and metastatic tumor cell-endothelial cell interactions as a model for assessing vascular endothelial integrity. 396 42

8-Carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H) -one (mitozolomide) demonstrates curative action against a range of murine tumor model systems. At single doses of between 20 and 40 mg/kg, the latter of which approximates the 10% lethal dose value in mice, the compound elicited cures against the L1210 and P388 leukemias irrespective of the route of tumor and/or drug administration; in these tests, animals receiving 10(5) cells i.p. survived greater than 60 days after treatment. Potent effects were also observed against the TLX5 lymphoma (s.c.) and B16 melanoma (i.p.). In other experiments, 7 of 10 animals implanted with 2 X 10(5) Lewis lung carcinoma cells survived greater than 60 days while 10 of 10 animals survived greater than 60 days after implantation of the Colon 26 tumor. Potent inhibition of the solid tumor models was also observed with complete cures of the Colon 38, M5076 sarcoma, and ADJ/PC6A plasmacytoma. In cross-resistance studies, the compound was ineffective against an L1210 leukemia made resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea and against a TLX5 lymphoma resistant to dimethyltriazenes but cured animals bearing the L1210 leukemia with derived resistance to cyclophosphamide.
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PMID:Experimental antitumor activity against murine tumor model systems of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3 H)-one (mitozolomide), a novel broad-spectrum agent. 400 40

F-344 rats were treated with whole-brain fractionated or unfractionated 137Cs at several time intervals up to 6 weeks before they received intracerebral grafts of an ethylnitrosourea-induced rat astrocytoma (36B-10). Rats treated with a single dose of 18 Gy at 3- and 2 week intervals prior to tumor implantation died earlier than unirradiated control tumor recipients (P less than 0.05, log rank sum test). Delivered 2 weeks prior to tumor grafting single doses of 10, 15, and 20, but not 5 Gy also reduced animal life span (P less than 0.05). Similarly, a total dose of 38 but not 28.5, 19, or 9.5 Gy, each delivered in five daily fractions 2 1/2 weeks before tumor grafting, shortened survival (P less than 0.05). Chemotherapy with 1,3-bis(2-chloroethyl)-1-nitrosourea (13.3 mg/kg) alone or in combination with a single-dose of irradiation of 18 Gy 3 weeks preceding transplantation showed no effect on animal survival. Unirradiated control tumors demonstrated sheets of densely-packed isomorphic astrocytes, perivascular brain parenchymal invasion, sparse, thin-walled vasculature, frequent mitoses, but little necrosis or hemorrhage. The tumors of rats irradiated before transplantation showed large areas of confluent necrosis associated with microvascular thrombosis, edema, and multifocal acute hemorrhages. These survival results and morphological changes indicate that the cerebral tumor bed effect involves early animal death and extensive morphological changes in the tumors; and they suggest that tumor cell death in irradiated brain tumors may, in part, result from radiation-induced vascular injury.
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PMID:Irradiation and BCNU effects in the stroma in a rat transplanted glioma model: analysis of cerebral tumor bed effect. 403 74

The ability of the in vitro sister chromatid exchange (SCE) assay to predict in vivo tumor drug sensitivity was investigated using a spontaneous hepatocarcinoma in C3Hf/Kam mice and 3 chemotherapeutic agents: melphalan; cis-platinum; and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). For hepatocarcinoma cells grown in monolayer culture, melphalan was the most efficient at inducing SCEs, and BCNU, the least. cis-Platinum induced a range in SCEs that overlapped those of BCNU and melphalan, suggesting that hepatocarcinoma is not a homogeneous population with intermediate sensitivity, but is a mixture of cis-platinum-sensitive and -resistant cells. According to in vitro cell survival curves, hepatocarcinoma was most sensitive to melphalan, less sensitive to cis-platinum, and essentially resistant to BCNU. The relative antineoplastic effects of melphalan, cis-platinum, and BCNU in vivo were compared by the response of artificial and spontaneous pulmonary metastases and solid tumors to these agents. For artificial metastases, there was a dose-dependent decrease in the number of lung nodules in mice treated with melphalan or cis-platinum, with melphalan being the more effective. BCNU had no effect. Spontaneous pulmonary metastases generated from hepatocarcinoma leg tumors were reduced in those mice treated with melphalan, unaffected by cis-platinum, and increased by BCNU. In hepatocarcinoma leg tumors (5 to 6 mm in diameter), melphalan induced the longest growth delay, and BCNU the least. Therefore, the relative effects produced by these three drugs in vivo were the same as predicted by SCE induction in vitro. The SCE assay may thus have potential clinical application.
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PMID:Prediction of in vivo tumor response to chemotherapeutic agents by the in vitro sister chromatid exchange assay. 403 20

Currently numerous clinical trials are in progress utilizing intracarotid (i.c.) 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) for the treatment of malignant gliomas based upon the proposed focal nature of these tumors and the assumption that the i.c. route delivers higher levels of drug to the tumor. To date, however, increased efficacy in an animal model has not been clearly demonstrated for the i.c. delivery of BCNU. We have evaluated the dose-response curve for the i.v. and i.c. administration of BCNU in a commonly utilized experimental brain tumor model, the 9L rat gliosarcoma. An initial toxicity trial utilizing the i.p. 10% lethal dose (LD10) of BCNU by the i.v. and i.c. routes failed to demonstrate any significance in toxicity between the two routes. Tumor-bearing animals were then treated on Day 15-16 after tumor inoculations with 1, 10, 25, 50, 75, and 100% of the LD10 dose by either the i.v. or the i.c. route. Both i.v. and i.c. BCNU gave maximum survival increases at 75-100% LD10 doses, and there was no therapeutic advantage seen from i.c. delivery. However, at 50% of the LD10 dose (6.65 mg/kg), triplicate experiments demonstrated that the i.c. but not the i.v. dose maintained maximum efficacy equivalent to 100% of the LD10 given either i.v. or i.c. When the dose was reduced to 25% of the LD10 dose (3.33 mg/kg), two of three experiments showed efficacy of the i.c. delivery of this lower drug dosage to be equivalent to 100% of the LD10 given i.v. or i.c. The i.v. dosage resulted in a significant reduction in survival in all three trials. At 10% of the LD10 dose (1.30 mg/kg), neither the i.v. nor the i.c. administration retained equivalent efficacy to 100% of the LD10. However, in one of two trials, the i.c. groups had statistically better survival than controls, while in neither experiment was any advantage over controls seen in the i.v. treated groups. At 1% of the LD10 dose, neither the i.v. nor the i.c. route demonstrated any therapeutic efficacy. From our data, the advantage of the i.c. delivery of BCNU in the intracranial 9L rat gliosarcoma appears to be in the fact that significantly lower dosages than those given i.v. may be utilized to achieve equivalent survival with potentially less systemic toxicity.
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PMID:Comparison of intravenous versus intracarotid therapy with 1,3-bis(2-chloroethyl)-1-nitrosourea in a rat brain tumor model. 405 4

Twenty-six adult patients with astrocytomas were treated with BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) 180-240 mg/m2 I.V. every 6-9 weeks, with metronidazole 1.5 g/m2 p.o. 12 h and 1 h before BCNU and again 6 h and 24 h after BCNU. Of twenty-two evaluable patients, 9 (41%) responded with evidence of reduced tumor size on CT scan, 3 (14%) stabilized and 10 (45%) failed. Patients with no prior chemotherapy or radiotherapy, good performance status, low grade tumors, and age less than or equal to 50 years had the highest response rates, although differences were not statistically significant. Median survival and duration of response have not been reached with a median follow-up time of ten months. Hematological toxicity was dose-limiting and was probably not augmented by the metronidazole. There was one death from infection that was possibly drug-related. Gastrointestinal toxicity was substantial, and was probably increased by the metronidazole. While the combination of BCNU and metronidazole were tolerable, the response rate seen was no higher than that noted for BCNU alone, and further studies using this dose-schedule are not recommended in astrocytomas.
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PMID:Treatment of malignant gliomas in adults with BCNU plus metronidazole. 608 25


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