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)

A series of O(6)-allyl- and O(6)-(2-oxoalkyl)guanines were synthesized and evaluated, in comparison with the corresponding O(6)-alkylguanines, as potential inhibitors of the DNA-repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT). Simple O(6)-alkyl- and O(6)-cycloalkylguanines were weak AGT inactivators compared with O(6)-allylguanine (IC(50) = 8.5 +/- 0.6 microM) with IC(50) values ranging from 100 to 1000 microM. The introduction of substituents at C-2 of the allyl group of O(6)-allylguanine reduced activity compared with the parent compound, while analogous compounds in the O(6)-(2-oxoalkyl)guanine series exhibited very poor activity (150-1000 microM). O(6)-Cycloalkenylguanines proved to be excellent AGT inactivators, with 1-cyclobutenylmethylguanine (IC(50) = 0.55 +/- 0.02 microM) and 1-cyclopentenylmethylguanine (IC(50) = 0.39 +/- 0.04 microM) exhibiting potency approaching that of the benchmark AGT inhibitor O(6)-benzylguanine (IC(50) = 0.18 +/- 0.02 microM). 1-Cyclopentenylmethylguanine also inactivated AGT in intact HT29 human colorectal carcinoma cells (IC(50) = 0.20 +/- 0.07 microM) and potentiated the cytotoxicity of the monomethylating antitumor agent Temozolomide by approximately 3- and 10-fold, respectively, in the HT29 and Colo205 tumor cell lines. The observation that four mutant AGT enzymes resistant to O(6)-benzylguanine also proved strongly cross-resistant to 1-cyclopentenylmethylguanine indicates that the O(6)-substituent of each compound makes similar binding interactions within the active site of AGT.
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PMID:Resistance-modifying agents. 8. Inhibition of O(6)-alkylguanine-DNA alkyltransferase by O(6)-alkenyl-, O(6)-cycloalkenyl-, and O(6)-(2-oxoalkyl)guanines and potentiation of temozolomide cytotoxicity in vitro by O(6)-(1-cyclopentenylmethyl)guanine. 1106 4

Expression of iNOS in glioma and other tumors has been extensively documented but the effects of NO derived from iNOS on tumor-killing mechanisms of chemotherapy drugs remain to be fully defined. We note that increased NO synthesis by cytokine exposure or iNOS overexpression neutralized the cytotoxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), but not cisplatin, in rat C6 glioma cells. Suppression of BCNU cytotoxicity associated with iNOS overexpression could be abolished by pharmacological inhibition of NOS or coexpression of an antisense RNA against iNOS. Both BCNU and CCNU are chloroethylnitrosoureas that kill tumor cells via carbamoylating and alkylating actions. Further studies using compounds that each carry these different activities indicate that iNOS neutralized carbamoylating, but not alkylating, action of chloroethylnitrosoureas. Temozolomide, a novel chemotherapy drug recently available for treating brain tumors, carries only alkylating, but not carbamoylating, action. Overexpression of iNOS in C6 cells failed to neutralize temozolomide cytotoxicity. Results from the present study demonstrate the ability of iNOS-derived NO to confer chemoresistance against the carbamoylating potential of chloroethylnitrosoureas in vitro. Further investigation is needed to test whether iNOS expression, frequently noted in malignant brain tumors, also enhances chemoresistance against chloroethylnitrosoureas in vivo.
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PMID:Inducible nitric oxide synthase neutralizes carbamoylating potential of 1,3-bis(2-chloroethyl)-1-nitrosourea in c6 glioma cells. 1125 58

Temozolomide (TMZ) is a methylating agent of the imidotetrazine class, whose cytotoxic product is O(6)-methylguanine DNA adducts, which initiate a futile recycling of the mismatch repair pathway causing DNA strand breaks and apoptotic cell death in mismatch repair proficient cells. The DNA repair protein O(6)-alkylguanine DNA alkyltransferase (AGT) repairs these adducts in a suicide manner and reduces the cytotoxic action of TMZ. An antitumor threshold is reached when sufficient adducts are formed by TMZ to inactivate AGT. In this study, we evaluated the relation between TMZ dosing and AGT depletion in patients with deep visceral tumors and in peripheral blood mononuclear cells (PBMCs) to determine whether the dose of TMZ was sufficient to inactivate AGT and lead to therapeutic efficacy. To do so, we compared single dose therapy with a novel twice daily regimen in a laboratory correlate-driven Phase I dose escalation study. p.o. bolus dose TMZ 200 mg/m(2) daily times five was compared with the same bolus on day 1 followed by nine doses at 12-h intervals of 50, 75, 90, or 100 mg/m(2). Dose-limiting toxicity in the bid regimen (grade IV thrombocytopenia and neutropenia) was seen at 100 mg/m(2), cumulative dose 1100 mg/m(2), and the maximum tolerated dose was 1010 mg/m(2). The degree of tumor tissue AGT activity depletion measured in biopsies before and on day 5 of therapy varied widely, between 0 (in 3 patients) and 99% (in 1), with the majority of patients (10 of 15) having 52-84% tumor AGT depletion. In contrast, AGT activity in PBMCs fell rapidly during TMZ administration to undetectable levels in all dosage groups on day 5 but did not correlate with tumor AGT depletion. TMZ pharmacokinetics were dose proportional; no accumulation occurred >5-day period in the bid regimen. Two partial responses were seen, lasting 3 and 4 months. Five additional patients achieved prolonged stabilization of disease for 4-6 monthly cycles. This is the first study to document that at maximum tolerated doses, TMZ depletes PBMC AGT but only partially and variably depletes visceral tumor AGT in most patients, even during twice daily dosing. Drug combinations or schedules designed to maximally deplete tumor AGT might improve TMZ efficacy.
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PMID:Temozolomide: the effect of once- and twice-a-day dosing on tumor tissue levels of the DNA repair protein O(6)-alkylguanine-DNA-alkyltransferase. 1148 6

Temozolomide (TZM) is a DNA-methylating agent that has recently been introduced into various clinical trials for treatment of solid or hematologic neoplasias, including brain lymphomas. In the current study, we have investigated whether the antitumor activity of TZM could be selectively enhanced at the central nervous system (CNS) site by intracerebral injection of a poly(ADP-ribose) polymerase (PARP) inhibitor. Mice were injected intracranially with lymphoma cells. The PARP inhibitor NU1025 (1 mg/animal) was delivered intracerebrally, whereas TZM was given as a single or a fractionated dose of 200 mg/kg by intraperitoneal administration. Results indicated that this drug combination significantly enhanced the survival of tumor-bearing mice and that this fractionated modality of treatment was the most effective schedule. Increased survival time was related to a marked reduction of tumor growth, as evidenced by histologic studies. Treatment with TZM alone was ineffective. This is the first report exploring in vivo the combination of TZM with PARP inhibitor for intracerebral neoplasias.
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PMID:Combined treatment with temozolomide and poly(ADP-ribose) polymerase inhibitor enhances survival of mice bearing hematologic malignancy at the central nervous system site. 1187 4

Low-grade gliomas are uncommon primary brain tumors classified as histologic grades I or II in the World Health Organization (WHO) classification. The most common variants are pilocytic and low-grade astrocytomas, oligodendrogliomas, and mixed oligo-astrocytomas located in the cerebral hemispheres. Prognostic factors that predict progression-free and overall survival include young age, pilocytic histology, good Karnofsky performance status, gross total resection, lack of enhancement on imaging, and small preoperative tumor volumes. Edema and vasogenic effects are typically managed with corticosteroids. Dexamethasone is given at an initial dosage of 4 mg given four times daily. Anticonvulsants are given prophylactically after resection and for patients who present with seizures. The rationale for open craniotomy depends on the need for immediate palliation of symptoms by reduction of intracranial pressure or focal mass effect, and/or improved oncologic control. Gross total resection of tumor is generally defined as the absence of residual enhancement on contrast-enhanced postoperative MRI scan. Most retrospective studies suggest that patients who have undergone a gross total resection of tumor have improved survival. Depending upon the proximity of the tumor to eloquent brain, gross total resection may or may not be possible. In these cases a stereotactic biopsy is required to provide the histologic diagnosis. Adjuvant radiotherapy is recommended for patients with incompletely resected grade II tumors or for patients older than age 40 regardless of extent of resection. It may be considered for any pilocytic astrocytoma from which a biopsy has been performed. Phase III randomized prospective trials have shown statistically significantly improved progression-free survival at 5 years with the addition of radiotherapy, though overall survival does not appear different. Based on prospective randomized phase III trials, 50.4 Gy to 54 Gy of conventionally fractionated radiotherapy appears to be a safe and effective regimen with minimal neurotoxicity; 45 Gy may be adequate for biopsied pilocytic astrocytomas. Currently, RTOG trial 98-02 is investigating the efficacy of postradiation PCV chemotherapy (procarbazine, CCNU, and vincristine) in the treatment of newly diagnosed unfavorable low-grade gliomas. Other areas of investigation include Temozolomide chemotherapy and the association of 1p and 19q chromosomal deletions with prolonged survival in oligodendrogliomas and sensitivity to PCV chemotherapy. Radiosurgery and/or experimental chemotherapy may provide some measure of local control in the recurrent disease setting.
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PMID:Low-grade gliomas. 1205 95

The survival of patients affected by cutaneous melanoma has improved dramatically in the last 10 years, because of earlier diagnosis. Despite this, the therapeutic results obtained in metastatic melanoma (MM) are very disappointing due to its poor responsiveness to cytotoxic agents. In this type of solid tumor, tumor chemosensitivity assays have been suggested to be an important tool to predict clinical responsiveness to therapy. Metastatic melanoma cells (MMCs) were obtained from subcutaneous melanoma metastases of five patients and cultured for several consecutive passages. An immunofluorescence and an electron microscopic study were performed in order to establish the ultrastructural and physiopathological features of MMCs. A sulphorodamine-B test was used to measure in vitro sensitivity of MMCs to temozolomide, cisplatin, vindesine, taxol and interpheron alpha-2a. Following a 72 h exposure, maximum activity was obtained with vindesine (median inhibitory concentration, IC(50), 0.23 nM) and taxol (median IC(50) 0.31 nM). Cisplatin median IC(50) values were higher (4.6 microM) than taxol and vindesine, but still in the range of clinically achievable plasma concentrations. Temozolomide inhibited cell proliferation only at very high concentrations (median IC(50) 228 microM). No significant cell growth inhibitory effects (<or=25%) were observed with interferon alpha-2a concentrations up to 8000 IU/ml. MMCs expressed progression markers typical of cutaneous metastatic melanoma and showed poor sensitivity in vitro to most anticancer drugs tested, including temozolomide.
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PMID:Immunophenotypical markers, ultrastructure and chemosensitivity profile of metastatic melanoma cells. 1221 88

Temozolomide (TZM) is a novel methylating agent currently under investigation for treatment of recurrent high-grade gliomas. Although TZM generates a wide spectrum of methyl adducts, its cytotoxicity has been attributed to mismatch repair (MR)-mediated processing of O(6)-methylguanine:T mispairs. N3-methyladenine and N7-methylguanine adducts are promptly repaired by the base excision repair system, unless a poly(ADP-ribose) polymerase (PARP) inhibitor is combined to TZM. In this case, the repair process of N-methylpurines cannot be completed and the deriving DNA strand breaks contribute to cytotoxicity. In this study, we investigated the influence on cell growth and cell cycle of treatment with TZM + PARP inhibitor in glioma cells characterized by different susceptibility to TZM. The results indicated that PARP inhibitor increases growth inhibition induced by TZM in either p53-wild-type or p53-mutant glioblastoma cells, as early as 24 h after drug exposure. The enhancing effect exerted by PARP inhibitor was particularly evident in glioma cells characterized by a defective expression of MR, since these cells are tolerant to O(6)-methylguanine damage and show low sensitivity to TZM. In O(6)-alkylguanine-DNA alkyltransferase (OGAT)-deficient and MR-proficient tumor cells bearing wild-type p53, the drug combination markedly reduced cell accumulation in the G(2)/M phase of cell cycle and induction of the G(2) checkpoint regulator Chk1 kinase. In short-term cultures of glioma cells derived from surgical specimens, PARP inhibitor enhanced chemosensitivity to TZM and this effect was especially evident in OGAT-proficient tumors. Thus, a pharmacological strategy based on the interruption of N-methylpurine repair might represent a novel strategy to restore or increase glioma sensitivity to TZM.
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PMID:Poly(ADP-ribose) polymerase inhibitor increases growth inhibition and reduces G(2)/M cell accumulation induced by temozolomide in malignant glioma cells. 1223 42

Gliomatosis cerebri is a rare form of diffusely infiltrating glioma that is typically resistant to conventional chemotherapy and radiation therapy and carries a poor prognosis. Temozolomide has shown antineoplastic activity against malignant gliomas and more recently was beneficial in one patient with gliomatosis cerebri. To make an objective assessment of the effect of long-term temozolomide administration in a patient with gliomatosis cerebri we used brain proton magnetic resonance spectroscopy and structural MRI. A 46-year-old man with gliomatosis cerebri was treated with temozolomide (200 mg/m(2) per day for 5 days every 28 days). Twenty cycles of temozolomide resulted in a marked reduction in choline and scyllo-inositol content, as detected using brain proton MR spectroscopy, indicating reduced tumor cellularity and/or growth rate. Neurochemical improvements were associated with normalization of the signal intensity in most of the previously affected cerebral regions and regression of mass effect on MRI. A left pyramidal syndrome, present at the start of the treatment, disappeared. Our observation lends support to larger clinical trials evaluating the use of temozolomide to treat this brain tumor.
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PMID:Gliomatosis cerebri: clinical, neurochemical and neuroradiological response to temozolomide administration. 1468 3

Temozolomide (Temodal) is an oral imidazotetrazine. Increased temozolomide exposure and subsequent depletion of O-alkylguanine alkyltransferase may improve the activity of temozolomide. The rationale for investigating temozolomide plus Caelyx is based on their antitumor activity, their formulation and no significant overlapping toxicities. We conducted a study of a prolonged schedule of temozolomide (orally on days 1-7 and 15-21) plus Caelyx (day 1) every 28 days. Twenty-one patients (melanoma n=10, sarcoma n=7 and other n=4) were assigned to four dose levels (DL; temozolomide+Caelyx, mg/m): DL1: 100+30 (n=3 patients), DL2: 100+40 (n=6 patients), DL3: 125+40 (n=6 patients) and DL4: 150+40 (n=6 patients). Dose-limiting toxicities were noted after 2 or more cycles in one patient at DL3 (stomatitis) and one patient at DL4 (grade 4 ANC >/=7 days). Treatment delays and/or dose reductions (due to hematological toxicity) were necessary in five of six patients receiving DL4 compared with one of six patients at DL3, and one patient at DL1 and 2. Thus, the recommended dose was temozolomide 125 mg/m (daily for 7 days every other week) plus Caelyx 40 mg/m (day 1 every 4 weeks). Other toxicities were mild. Antitumor activity was observed in eight patients, including one complete response (melanoma), three partial responses (one melanoma, two sarcomas) and four patients with stable disease (three melanomas, one Ewing), with a duration lasting from 14 to 135+weeks. Two melanoma patients showed tumor stabilization in non-irradiated cerebral lesions. This schedule of temozolomide allowed higher dose intensity (1750 mg/m in 4 weeks) compared to the standard 5-day regimen (1000 mg/m in the same amount of time).
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PMID:Prolonged schedule of temozolomide (Temodal) plus liposomal doxorubicin (Caelyx) in advanced solid cancers. 1516 25

Temozolomide is an oral alkylating agent shown to have modest efficacy in the treatment of glioblastoma multiforme. Tumor necrosis factor alpha (TNF-alpha) is a polypeptide cytokine with synergistic antitumor activity in combination therapy with alkylating agents. We investigated the combined use of Ad.Egr-TNF, a replication-defective adenoviral vector encoding the cDNA for TNF-alpha under the control of chemo-inducible elements of the egr1 gene promoter, and intraperitoneal temozolomide in an intracranial human malignant glioma model. In hind limb U87MG xenografts, temozolomide produced a 6.4-fold greater induction of TNF-alpha after infection with Ad.Egr-TNF compared with Ad.Egr-TNF alone at 96 hours (P < 0.02). TNF-alpha and temozolomide combination leads to a synergistic decrease in U87 cell viability at 72 hours compared with either treatment alone (P < 0.001). Median survival for animals treated with Ad.Egr-TNF alone, temozolomide alone, and Ad.Egr-TNF/temozolomide was 21, 28, and 74 days, respectively (P < 0.001 by log-rank). Flow cytometric assessment of apoptosis revealed a synergistic increase in U87 cell apoptosis in vitro at 72 hours (P < 0.05), and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) evaluation of tumor sections revealed significantly increased TUNEL-positive cells after combination treatment compared with either treatment alone (P < 0.05). In conclusion, combination treatment with transcriptionally activated intratumoral TNF-alpha and systemic temozolomide significantly prolongs survival in an experimental glioblastoma multiforme model.
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PMID:Transcriptional targeting of adenovirally delivered tumor necrosis factor alpha by temozolomide in experimental glioblastoma. 1537 43


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