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)

The chemotherapeutic agents 1-3 bis(2-chloroethyl)-1-nitrosourea (BCNU) and cis-diamminedichloroplatinum II (cisplatin) have both shown activity against malignant glioma, especially when given by arterial infusion. The combination of these agents given by this method is logical because their individual major toxicities are directed at different organ systems, and because of their differences in restriction by the blood-brain barrier. Both agents are toxic to the eye, and infusion of both agents simultaneously into the internal carotid artery would deliver doses of the drug to the eye which should be associated with an unacceptable level of ocular toxicity. We have developed a technique utilizing a flexible flow-directed catheter with a tip which is manipulated by hydraulic forces for delivery of the drug into the intracranial carotid artery above the origin of the ophthalmic artery, thus sparing the eye from the high concentration of drug during the first pass through the arterial circulation. In 13 patients with recurrent malignant glioma treated by arterial infusion of both agents (cisplatin 150-200 mg, BCNU 300 mg fixed dose), we have had no damage to the ipsilateral eye. Preliminary results of treatment appear to be good, with definite tumor regression following arterial infusion in 10 of 12 radiographically evaluable cases. Median survival to date is 11 months with 3 patients still surviving. The longest survival is 24 months. The supraophthalmic infusion technique protects the eye and the combination of drugs given by arterial infusion produces a high tumor response rate.
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PMID:Supraophthalmic carotid infusion for recurrent glioma: rationale, technique, and preliminary results for cisplatin and BCNU. 298 27

Primary radiation-induced or radiation leukemia virus (RadLV)-induced T-leukemias/lymphomas were treated in vivo in an early to advanced state by using 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). BCNU was given at various times after the tumor induction procedure. Death from RadLV lymphomas which had been initiated in 33 +/- 3 day old C57BL mice by intrathymic injection of RadLV was scored in untreated, BCNU-treated or BCNU and cellular adjuvant treated mice. Intrathymic RadLV injection in 33 +/- 3 day old mice produced tumors in 98% of injected mice. Median survival time (MST) was increased by BCNU and by BCNU plus bone marrow cell therapy whether done 33 or 47 days after RadLV. There was increased in MST from 108 days to 171 days by BCNU and bone marrow cell therapy given 33 days after tumor initiation and to 195 days when therapy was given 47 days after initiation. In radiation-induced lymphomas produced by 190 rad every week X 4 of 33 +/- 3 day old mice, spleen cell (X 1) therapy or BCNU treatment increased the MST of treated mice from 142 days to 177 days after iv spleen cells or to 195 days after iv-ip spleen cells, and this protocol produced 31% long-term cures. Cellular adjuvant therapy combined with BCNU chemotherapy was effective for curing the lymphomas but cellular adjuvant therapy alone was also highly effective for therapy.
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PMID:Treatment of primary radiogenic C57BL mouse cell leukemia/lymphoma by 1,3-bis(2-chloroethyl)-1-nitrosourea chemotherapy and adjuvant cellular therapy. 300 11

A human gliosarcoma culture was characterized from the time of inception to the time of establishment of the cell line (SF-539 BT). Immunohistochemical analysis of the original tumor showed 2 distinct regions of cells. The gliomatous regions were identified by immunostains for glial fibrillary acidic protein and the sarcomatous regions by immunostains for laminin, collagen type IV, procollagen type III, and fibronectin. In early-passage culture, both types of cells maintained their characteristic immunohistochemical profiles; however, after the fourth subcultivation in monolayer culture, no cells expressing glial fibrillary acidic protein could be identified. All cells had become morphologically uniform and expressed laminin, collagen type IV, procollagen type III, and fibronectin only. The immunostaining profile of clones grown in soft agar was similar to that of cells in monolayer culture. At establishment, SF-539 BT has a saturation density of 1.3 X 10(6) cells/25 sq cm, a doubling time of 32 h, and a plating efficiency of 22% in monolayer culture. The tumor cell line is resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea, has an abnormal karyotype, grows anchorage independently, and forms a tumor that most closely resembles a spindle cell sarcoma in athymic mice. Its ultrastructure in monolayer culture consists of large cells with an expanded rough endoplasmic reticulum and abundant multivesicular bodies; in athymic mice, extracellular collagen fiber formation is prominent. DEAE-cellulose chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of cultures labeled with [3H] proline demonstrated interstitial collagen formation. We conclude that the cell line at establishment is a collagen-producing spindle cell sarcoma that resembles the sarcomatous regions of the original mixed tumor. Further cell separation and characterization studies are needed to determine the pathogenesis of mixed tumors such as gliosarcoma.
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PMID:Establishment and characterization of a cell line from a human gliosarcoma. 301 42

This study primarily describes the cytostatic activity of a bisphosphonate and of an alkylating agent linked bisphosphonate toward mammary carcinomas in vivo. Bisphosphonates had been shown to be therapeutically active in bone metastases. There is no animal tumor model available in which both primary mammary carcinomas and bone metastases can be studied simultaneously. Therefore, the Walker carcinosarcoma model, which was used as a model for bone metastasis in earlier studies, was combined with the M-methyl-N-nitrosourea (MNU) induced mammary carcinoma as a model for the primary tumor. Four-, or six-week treatment of MNU-induced mammary carcinomas in Sprague-Dawley rats with the new aromatic bisphosphonate 4[4-[bis(2-chloroethyl)-amino]-phenyl]-1-hydroxybutane-1, 1-bisphosphonate (BAD) showed higher antitumor activity than treatment with melphalan or with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD) alone. BAD is the APD moiety covalently bound to a molecule derived from melphalan. A combination therapy with 11.75 mg/kg/day APD and 0.6 mg/kg/day melphalan showed the best therapeutic efficacy in this tumor model. In comparison to monotherapy with BAD, APD, or melphalan, a significantly higher rate of complete remissions was achieved. APD, itself, was not genotoxic in 3 employed short term assays. Since bisphosphonates had been shown to be therapeutically active in bone metastases, the antitumor potency of these compounds against experimental primary mammary carcinomas, coupled with the non-genotoxicity of APD and the inhibition of osteolytic bone metastases, might be an important advancement for adjuvant chemotherapy of human mammary carcinomas.
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PMID:Anticancer activity of bisphosphonic acids in methylnitrosourea-induced mammary carcinoma of the rat--benefit of combining bisphosphonates with cytostatic agents. 305 67

In an attempt to improve glioma management, an animal model was developed to evaluate the therapeutic efficacy of intra-arterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Furthermore, the model was used to study the antitumor activity of D,L-alpha-difluoromethylornithine (DFMO), a polyamine-biosynthesis inhibitor, used both as a single agent and in combination with intra-arterial BCNU. An N-methylnitrosourea-induced gliosarcoma (T9) was transplanted stereotaxically into the right caudate nucleus of male Fischer 344 rats. Animals receiving a single low-dose (5 mg/kg) intracarotid injection of BCNU 9 days following tumor implantation had a 57% increase in life span compared with untreated control rats (p less than 0.001). Intracarotid drug delivery was more effective than systemic (intraperitoneal) administration of the same dose of BCNU. When given as a single agent, DFMO demonstrated dose-dependent effectiveness. As part of a combined regimen, DFMO enhanced the antitumor therapeutic activity of both systemic (intraperitoneal) and intra-arterial BCNU. Survival times of animals receiving combined DFMO and intra-arterial BCNU were almost double those of untreated controls, and were significantly better than survival times of animals receiving combined DFMO and intraperitoneal BCNU. These findings suggest methods to optimize current clinical chemotherapy for glioma.
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PMID:Effect of difluoromethylornithine on the antiglioma therapeutic efficacy of intra-arterial BCNU. 309 5

Recent evidence from our laboratory and from others suggested that pretreatment with alpha-difluoromethylornithine (DFMO) sensitizes some human and rodent tumor cell lines to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Many human tumor cells are resistant to chloroethylnitrosourea-induced DNA interstrand cross-linking and cell kill due to their high levels of the DNA repair protein O6-alkylguanine DNA alkyltransferase. We therefore investigated DFMO-mediated sensitization to BCNU in BCNU-sensitive and -resistant cells. Colony formation assays were used to compare BCNU cytotoxicity in DFMO-pretreated and control cultures of two colon tumor lines, HT-29 cells, which have high alkyltransferase levels and thus are BCNU-resistant, and BE cells, which are deficient in this repair capacity and thus are BCNU-sensitive. Polyamine depletion significantly enhanced BCNU cytotoxicity only for the repair-proficient HT-29 cell line. BE cells were 40-fold more sensitive to BCNU than were HT-29 cultures. However, in BE cells, no effect of polyamine depletion was found on cellular response to BCNU treatment at 72 h after DFMO treatment. Reverse-phase high-performance liquid chromatography assays of polyamine concentrations in cell extracts verified that DFMO produced comparable degrees of polyamine depletion for both cell lines. DNA alkaline elution analysis was used to monitor BCNU-induced formation of DNA single strand breaks, DNA interstrand cross-links, and DNA-protein cross-links. Equal concentrations of BCNU produced similar levels of strand breaks and DNA-protein cross-links in DFMO-pretreated and control cultures for both cell lines. These data suggest that DNA in polyamine-deficient HT-29 and BE cells is not more accessible to BCNU than is DNA in controls. No DNA interstrand cross-links were detected in either DFMO-pretreated or control HT-29 cells after BCNU treatment. Further, in BE cells which accumulate BCNU-induced DNA interstrand cross-links, no increase in the measureable levels of cross-links resulted from polyamine deficiency. Our observations suggest that mechanisms other than increased DNA interstrand cross-link formation may be mediating the enhanced efficacy of BCNU in polyamine-deficient HT-29 cell cultures. Our findings may also imply that cellular targets for BCNU other than DNA damage may be responsible for DFMO-induced chemosensitization in the repair-proficient cells.
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PMID:Comparison of DNA interstrand cross-linking and strand breakage by 1,3-bis(2-chloroethyl)-1-nitrosourea in polyamine-depleted and control human adenocarcinoma cells. 311 20

Dose-response studies were performed with the alkylating agents [nitrogen mustard, N,N'-bis(2-chloroethyl)-N-nitrosourea, melphalan, cisplatin (CDDP), 4-hydroperoxycyclophosphamide (4-HC), and trimethyleneiminethiophosphoramide] in both the MCF-7 human breast carcinoma cell line and the EMT6 and FSaIIC murine tumor lines. Increasing selection pressure with the alkylating agents CDDP, melphalan, and 4-HC in vitro produced low levels (6.5- to 9-fold) of drug resistance, despite an intensive and prolonged treatment program. The MCF-7 sublines made resistant to CDDP and 4-HC did not exhibit cross-resistance to other alkylating agents; however, the MCF-7 subline resistant to melphalan was partially cross-resistant to nitrogen mustard, 4-HC, and CDDP. A log-linear relationship was maintained between surviving fraction of MCF-7 cells in culture and drug concentration with alkylating agents, whereas for nonalkylating agents the survival curves tended to plateau at high drug concentrations. Log-linear tumor cell kill was also obtained over a wide dosage range with several alkylating agents in murine tumors treated in vivo. Tumor cell survival assay by colony formation indicated the continuing importance of dose in the action of the drugs even at high levels of tumor cell kill. With some agents, there was a difference between the slopes of the tumor cell killing curves in vivo as compared to in vitro. Cyclophosphamide was far more potent in vitro (4-HC) than in vivo (cyclophosphamide). Trimethyleneiminethiophosphoramide and N,N'-bis(2-chloroethyl)-N-nitrosourea were both more potent in vivo than in vitro. These differences may be explained by the various metabolic patterns of these drugs. Dose of alkylating agents is clearly a crucial variable particularly where multilog tumor cell kill is the goal, and in this regard, the effect of drug dose on the tumoricidal action of the alkylating agents is substantially greater than for nonalkylating agents.
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PMID:Preclinical studies and clinical correlation of the effect of alkylating dose. 318 59

Chloroethylnitrosoureas have been used widely to treat human and experimental animal tumors. We have earlier observed that greater than 90% of the mice transplanted with syngeneic tumors survive following treatment with nitrosoureas such as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and furthermore, they resist subsequent challenge with the same tumor. The present investigation was initiated to determine the mechanism by which BCNU brings about this effect. Treatment of tumor cell targets in vivo or in vitro with BCNU, increased their susceptibility to macrophage (M luminal diameter)-mediated cytotoxicity as measured in a direct cytotoxicity assay or in an antibody-dependent cell-mediated cytotoxicity (ADCC) assay. In contrast, the antitumor cytotoxicity caused by cytotoxic T lymphocytes (CTL), natural killer (NK) cells, or lymphokine-activated killer (LAK) cells, was not altered following BCNU treatment of tumor targets. Studies were also conducted to investigate the direct effect of BCNU in vivo on various cytotoxic effector cells. For this purpose, M luminal diameter, NK, LAK, and CTL activities from BCNU-treated-tumor-bearing mice were screened for cytotoxicity against untreated tumor targets in vitro. It was observed that tumor-specific CTL and LAK cell activity increased in BCNU-treated tumor-bearing mice when compared to untreated controls while the cytotoxic potential of NK cells and M luminal diameters was not altered. The present study suggests that antitumor drugs such as BCNU are not only tumoricidal but also selectively act in a variety of ways at both the effector and target cell level, leading to overall enhanced antitumor immunity and high rate of cures from the syngeneic tumor challenge.
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PMID:Differential effects of BCNU on T cell, macrophage, natural killer and lymphokine-activated killer cell activities in mice bearing a syngeneic tumor. 326 Aug 20

We earlier demonstrated that treatment of C57BL/6 mice bearing a syngeneic tumor, LSA, with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) resulted in over 90% survival of the mice, and 100% of the cured mice rejected secondary rechallenge with the homologous tumor but not with a heterologous syngeneic tumor such as EL-4. In the present study we investigated whether the host's immune system was also essential for successful chemotherapy with BCNU. It was observed that BCNU treatment was effective only in normal tumor-bearing mice (100% survival) but not in irradiated or nude tumor-bearing mice (0% survival), thereby suggesting that the immune system, particularly the T cells, was essential for effective treatment with BCNU. Since BCNU-cured mice lack demonstrable T suppressor (Ts) cells, these mice were next used as a model to investigate the phenotype of the T cells mediating tumor rejection. It was observed that L3T4+ (CD4+) or Lyt-2+ (CD8+) T cells from BCNU-cured mice could provide significant protection (80 and 40% survival, respectively) in irradiated or nude mice but not in normal mice. It was also observed that BCNU-cured LSA mice elicited tumor-specific delayed-type hypersensitivity (DTH) reaction, while, normal mice or LSA tumor-bearing mice failed to elicit DTH reaction. Also, only L3T4+ but not Lyt-2+ T cells from BCNU-cured mice when adoptively transferred into nude mice could elicit a DTH reaction. The present study suggests that for effective chemotherapy against a syngeneic tumor, with a tumoricidal drug such as BCNU, the presence of L3T4+ and Lyt-2+ T cells in the host is essential.
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PMID:Chemotherapy of mice bearing syngeneic tumors with 1,3-bis (2-chloroethyl)-1-nitrosourea is effective only in normal, but not in irradiated or nude, mice: role of L3T4+ (CD4+) and Lyt-2+ (CD8+) T cells. 326 38

In vivo 31P nuclear magnetic resonance spectroscopy was used to examine the bioenergetics of the rat 9L gliosarcoma during untreated growth and in response to chemotherapy with 1,3-bis(2-chloroethyl)-1-nitrosourea. Tumor growth was associated with a decline in the phosphocreatine and nucleoside triphosphate resonances, consistent with an increase in tumor hypoxia during untreated growth. Following chemotherapy with 1,3-bis(2-chloroethyl)-1-nitrosourea (10 mg/kg), tumor levels of phosphocreatine and nucleoside triphosphate rebounded while the level of inorganic phosphate in the tumor declined. Histological comparison of treated and untreated tumor sections 4 days posttreatment showed that the treated tumor had a lower proportion of necrotic cells, a higher proportion of viable cells, and a 5-fold higher level of interstitial space than the control tumor.
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PMID:In vivo 31P nuclear magnetic resonance spectroscopy of subcutaneous 9L gliosarcoma: effects of tumor growth and treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea on tumor bioenergetics and histology. 333 30


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