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PubMed1989

Effect of sodium arsenite on the induction and turnover of ornithine decarboxylase activity in erythroleukemia cells.

Sodium arsenite proved effective in preventing the induction of ornithine decarboxylase (ODC) activity elicited by dilution of Friend erythroleukemia cells in fresh medium. A 50 per cent inhibition was produced at approximately 1 microM arsenite and complete inhibition was obtained at concentrations above 10 microM. However, addition of arsenite 5 h after cell dilution, i.e. when ODC was already induced, appeared to stabilize the enzyme. The half-life of ODC activity, measured after cycloheximide treatment, increased almost six-fold after addition of sodium arsenite. Agents known to provoke oxidative alteration of the thiol-redox status in cells, also caused a similar effect on the induction and stability of ODC.

Animals↗
PubMed2003

The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors.

Irinotecan is a water-soluble derivative of camptothecin, an alkylator originally extracted from the Chinese tree Camptotheca acuminata. Laboratory studies have demonstrated the activity of irinotecan in a broad panel of pediatric and adult central nervous system tumor xenografts in athymic nude mice. These studies led to a Phase II trial that confirmed the activity of this agent in the treatment of recurrent malignant glioma. Subsequent laboratory studies have demonstrated that a combination of irinotecan (CPT-11) and alkylating agents, particularly 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), increases antitumor effects to a level well above the additive effects of the individual agents. These laboratory studies generated a recently completed Phase I trial of CPT-11 + BCNU, which now is being evaluated in a formal Phase II trial for adults with newly diagnosed or recurrent malignant glioma. More recent studies have demonstrated similar interaction between CPT-11 and temozolomide and have led to a Phase I trial of these agents in the treatment of adults with malignant glioma. Studies currently are addressing the role of O(6)-alkylguanine-DNA alkyltransferase (AGT) in reducing the benefits of combining CPT-11 with temozolomide and the potential therapeutic gain from utilizing an inhibitor of AGT.

Adult↗
PubMed2003

Candidemia in women with breast carcinoma treated with high-dose chemotherapy and autologous bone marrow transplantation.

BACKGROUND: Invasive fungal infections, including candidemia, pose a major threat to patients with impaired immune defenses, including bone marrow transplantation (BMT) recipients. During 1992-1997, 845 women with multiple lymph node positive or metastatic breast carcinoma underwent high-dose chemotherapy (HDC) and subsequent autologous BMT at Duke University Medical Center. No systemic antifungal prophylaxis was administered. The purpose of the current study was to evaluate the risk and long-term outcome of candidemia in this patient population. METHODS: Clinical data were collected on patients with candidemia, and a group of age-matched control patients were identified who underwent HDC and BMT for breast carcinoma in the same time period. The difference in crude mortality between these two groups was used to calculate the attributable mortality of candidemia. The genetic relatedness of the fungal blood stream isolates was investigated by DNA fingerprinting. Antifungal susceptibility testing was performed using serial microdilution. RESULTS: Twenty-nine of 845 women developed candidemia (3.4%). The crude mortality of women with candidemia was 35% at 90 days after transplantation but 11% among women in the matched control group who were without infection (P = 0.01), for an attributable mortality rate of 24%. The most common pathogen was Candida tropicalis (50%), followed by Candida albicans (23%). The mortality was highest for women who were infected with C. albicans, followed by C. tropicalis, and other Candida species (P = 0.037). DNA fingerprinting of the yeasts revealed genetic heterogeneity in all species. However, 9 of 15 C. tropicalis isolates had identical DNA fingerprint profiles, suggesting spread of this genotype from a common source. All yeast isolates were susceptible to amphotericin B, and 20 of 30 isolates were susceptible to <or= 8 microg/mL of fluconazole. CONCLUSIONS: Candidemia was relatively infrequent after HDC and autologous BMT in women with for multiple lymph node positive or metastatic breast carcinoma. This was true even in the absence of systemic antifungal prophylaxis. The mortality attributable to candidemia in this patient population was 24% and was higher among patients who were infected by C. albicans compared with patients who were infected by other Candida, non-albicans species.

Adult↗
PubMed2004

Phase II study of neoadjuvant 1, 3-bis (2-chloroethyl)-1-nitrosourea and temozolomide for newly diagnosed anaplastic glioma: a North American Brain Tumor Consortium Trial.

BACKGROUND: Temozolomide (TMZ) and 1, 3-bis (2-chloroethyl)-1-nitrosourea (BCNU) are reported to be active agents in anaplastic glioma (AG). TMZ has also been shown to deplete alkyltransferase, a DNA repair enzyme that contributes to nitrosourea resistance. The objective of the current study was to determine the efficacy and toxicity profile of a combination of these agents before radiotherapy in newly diagnosed AG. METHODS: Eligibility criteria included histologically confirmed newly diagnosed AG with measurable enhancing disease, a Karnofsky performance score (KPS) > or = 60, normal pulmonary function, and normal laboratory parameters. In addition, informed consent was obtained from all patients. BCNU given at a dose of 150 mg/m(2) intravenously was followed after 2 hours by TMZ given at a dose of 550 mg/m(2) orally on Day 1 of a 42-day cycle to a maximum of 4 cycles, unless there was tumor progression or unacceptable toxicity. RESULTS: Forty-one eligible patients were accrued. Their median age was 40 years. Seventy-six percent of patients had a KPS of 90-100. The histology was 81% anaplastic astrocytoma, 12% anaplastic oligodendroglioma, and 7% mixed tumors. Twenty-two percent of patients did not complete 4 cycles because of toxicity, mainly hematologic. Forty-six percent of patients experienced Grade 3 or 4 (according to National Cancer Institute Common Toxicity Criteria) thrombocytopenia. Twenty percent had Grade 4 granulocytopenia. Two patients died while receiving therapy, 1 of progressive disease and the other of Pneumocystis carinii pneumonia. The complete and partial response rates were 2% and 27% respectively. An additional 54% of patients had stable disease. Seventeen percent developed progressive disease (10% after the first cycle and 7% after the second cycle). CONCLUSIONS: This neoadjuvant strategy was associated with significant myelosuppression and a modest response rate in patients with newly diagnosed AG.

Adolescent↗
PubMed2004

2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) inhibits prostate carcinoma cell growth via p53-dependent and p53-independent pathways.

BACKGROUND: Prostate carcinoma is the most commonly occurring malignancy in men. Although 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU), an analog of the chloroethylnitrosoureas, has been used in the treatment of advanced solid tumors, the molecular mechanisms underlying the antineoplastic activity of this agent are not well understood. In the current study, the authors sought to investigate the effects of SarCNU on prostate carcinoma cell growth in vivo and in vitro. METHODS: Male SCID mice underwent subcutaneous implantation (on both flanks) of human CWR-22 and CWR-22R prostate carcinoma xenografts. Mice were treated with either vehicle or 60 or 80 mg SarCNU per kg body weight for 5 days, with tumor growth being assessed every 3 days. Animals were sacrificed 21 days after the final injection, and tumors subsequently were collected, weighed, and processed for analysis. Immunohistochemical analyses were performed to obtain data on the localization of p53 and p21Cip1/Waf1. Cell counting, terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) assays, cell cycle analyses, Western blotting, and in vitro kinase assays were performed to determine the effects of SarCNU on growth, apoptosis, cell cycle arrest, cell cycle-regulated protein levels, and Cdc-2 activity, respectively. RESULTS: SarCNU reduced tumor incidence and inhibited the growth of CWR-22 and CWR-22R xenografts. In addition, treatment with this agent led to increases in p21Cip1/Waf1 levels and p53 phosphorylation at Ser15. In vitro administration of SarCNU to cells with wild-type p53 (LNCaP and primary CWR-22 cells) and cells with mutant p53 (PC-3 cells) resulted in G2/M arrest and the reduction of cellular Cdc-2 activity. Up-regulation of p53 levels, p53 phosphorylation at Ser15, and p21Cip1/Waf1 levels in primary CWR-22 and LNCaP cells, as well as up-regulation of Cdc-2 phosphorylation at Tyr15 in PC-3 cells, was detected. CONCLUSIONS: SarCNU induced G2/M arrest in prostate carcinoma cells via p53-dependent up-regulation of p21Cip1/Waf1 and p53-independent phosphorylation of Cdc-2 at Tyr15. These findings suggest a potential role for SarCNU in the treatment of prostate malignancies.

Animals↗
PubMed1975

1,3-bis(2-chloroethyl)-1-nitrosourea(BCNU), cyclophosphamide, vincristine- and prednisone-(BCOP). A new therapeutic regimen for diffuse histiocytic lymphoma.

Sixty-seven evaluable patients with mixed cellular and histiocytic lymphomas, both nodular and diffuse, were treated with a combined drug regimen of BCNU, cyclophosphamide, vincristine, and prednisone administered for six monthly courses. Of 28 previously untreated patients with diffuse histiocytic lymphoma, 14 (50%) achieved a complete remission, and an additional 7 (25%) had a good partial response for an overall remission rate of 75%. Complete remissions were also obtained among the small number of mixed and nodular histiocytic lymphomas which were treated. The median survival for previously untreated patients with diffuse histiocytic lymphoma who achieved a complete remission is nearly two years and 42% (8/19) of these patients remain in their initial unmaintained remission (range 2-119 weeks). Hematologic toxicity, although acceptable, was the limiting factor. Granulocytes were more often and more severely depressed than platelets.

Carmustine↗
PubMed1975

1.3 Bis-(2 chloroethyl)-1-nitrosourea and streptozotocin chemotherapy.

Streptozotocin (STZ) was combined with 1,3 bis-(2 chloroethyl)-1-nitrosourea (BCNU) and with BCNU and 5-fluorouracil (FU) in a 2- and 3-drug clinical chemotherapeutic trail. The premise that STZ and BCNU are qualitatively different with regard to marrow suppression was the primary rationale of the study. The 2- and 3-drug regimes were associated with a higher incidence of severe leukopenia and thrombopenia (47% and 100%, respectively) and a lower mean nadir for each (1,700/mm3 and 15,000/mm3) than the reported experience with single drug BCNU therapy. However, this synergism did not apply to therapeutic effects. The reasons for potentiation of marrow toxicity may be related to specific aspects of direct drug interaction as well as alterations in pharmacologic reactions.

Adolescent↗
PubMed1993

BCNU-resistant human glioma cells with over-representation of chromosomes 7 and 22 demonstrate increased copy number and expression of platelet-derived growth factor genes.

We used standard karyotypic analyses of first-division cells to identify a subpopulation of cells in primary malignant gliomas with over-representation of chromosomes 7 and 22. These cells are a minor subpopulation in the primary tumor but become the dominant population after treatment in vitro of the cells with the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The selection for a cell with this specific karyotypic abnormality suggests that these chromosomes contain genes important to the growth of BCNU-resistant cells. Southern blot hybridization analyses demonstrate an increased copy number of the genes encoding platelet-derived growth factor (PDGF) A-chain and B-chain, which have been mapped to chromosomes 7 and 22, respectively. Reverse transcription followed by polymerase chain reaction (RT-PCR) analysis demonstrates increased expression of these genes. In addition, these cells secrete a mitogenic factor that stimulates 3H-thymidine uptake in NIH 3T3 cells. This factor is sensitive to anti-PDGF antibodies and beta-mercaptoethanol, but not to anti-EGF antibodies. These data suggest that autocrine and/or paracrine mechanisms occur in human malignant gliomas, and that over-expression of PDGF may play a role in the growth of BCNU-resistant cells in these tumors.

Base Sequence↗
PubMed2002

Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance.

A strategy to overcome multidrug resistance in cancer cells involves treatment with a combination of the antineoplastic agent and a chemomodulator that inhibits the activity of the resistance-causing protein. The aim of our study was to investigate the effects of antimalarial drugs on human recombinant glutathione S-transferase (GSTs) activity in the context of searching for effective and clinically acceptable inhibitors of these enzymes. Human recombinant GSTs heterologously expressed in Escherichia coli were used for inhibition studies. GST A1-1 activity was inhibited by artemisinin with an IC(50) of 6 microM, whilst GST M1-1 was inhibited by quinidine and its diastereoisomer quinine with IC(50)s of 12 microM and 17 microM, respectively. GST M3-3 was inhibited by tetracycline only with an IC(50) of 47 microM. GST P1-1 was the most susceptible enzyme to inhibition by antimalarials with IC(50) values of 1, 2, 1, 4, and 13 microM for pyrimethamine, artemisinin, quinidine, quinine and tetracycline, respectively. The IC(50) values obtained for artemisinin, quinine, quinidine and tetracycline are below peak plasma concentrations obtained during therapy of malaria with these drugs. It seems likely, therefore, that GSTs may be inhibited in vivo at doses normally used in clinical practice. Using the substrate ethacrynic acid, a diuretic drug also used as a modulator to overcome drug resistance in tumour cells, GST P1-1 activity was inhibited by tetracycline, quinine, pyrimethamine and quinidine with IC(50) values of 18, 27, 45 and 70 microM, respectively. The ubiquitous expression of GSTs in different malignancies suggests that the addition of nontoxic reversing agents such as antimalarials could enhance the efficacy of a variety of alkylating agents.

Antimalarials↗
PubMed2003

Pharmacokinetic, biochemical and clinical effects of dimethyltriazenoimidazole-4-carboxamide-bischloroethylnitrosourea combination therapy in patients with advanced breast cancer.

We assessed whether split dosing with the methylating agent DTIC is an effective strategy for inactivating the DNA repair protein O6-alkylguanine DNA-ATase in order to decrease tumour resistance to BCNU. ATase levels in PBMCs were used as a surrogate for tumour ATase depletion to determine whether this correlated with either the pharmacokinetics of DTIC and its major metabolite AIC or other clinical sequelae. Two 1 hr infusions of DTIC (400 mg/m(2)) 4 hr apart followed another 4 hr later by BCNU (75 mg/m(2)) were administered every 6 weeks in 7 patients with heavily pretreated advanced breast cancer. The extent and kinetics of ATase depletion and recovery in PBMCs varied not only between patients but also between cycles in the same patient. Serial FNAs showed heterogeneity in tumour ATase expression but no clear pattern of change in ATase activity. DTIC and AIC exhibited biphasic clearance from the blood, consistent with a 2-compartment pharmacokinetic model. The AUC of AIC was strongly correlated with the percentage decrease in PBMC ATase levels. There were no clinical responses, and toxicity in neutrophils and platelets was marked. Split-dose DTIC therefore does not appear to be a clinically effective approach to overcome O(6)-alkylating agent resistance in advanced breast cancer.

Adult↗
PubMed2003

Development of resistance to a trinuclear platinum complex in ovarian carcinoma cells.

BBR3464 is a trinuclear platinum complex that exhibits a potent cytotoxicity and efficacy against cisplatin-resistant tumors. To better understand the determinants of cellular resistance to BBR3464, we selected a resistant ovarian carcinoma cell line after exposure to the complex. The resistant cells (A2780/BBR3464) exhibited a high level of resistance to the selecting agent, but a marginal cross-resistance to cisplatin. Although cellular accumulation of BBR3464 was similar in parental and in resistant cells, DNA platination was decreased in A2780/BBR3464 cells, suggesting a reduced drug accessibility to DNA. This behavior reflected a partial drug inactivation at cytoplasmic level, as a consequence of increased levels of nucleophilic molecules including metallothioneins and human neurofilament low, but not glutathione. A2780/BBR3464 cells also exhibited a reduced susceptibility to apoptosis, which was consistent with reduced expression of Bax, and an alteration of DNA mismatch repair system, as reflected by lack of expression of MLH1 and PMS2, which could impair the recognition/repair of DNA lesions. Whereas both platinum drugs induced G2/M arrest in the parental cells, BBR3464, but not cisplatin, caused a late G1 arrest of resistant cells. Cisplatin induced an appreciable increase of p21(WAF1) levels in both models, in contrast to BBR3464 that produced a substantial upregulation of p21(WAF1) only in parental cells. An inverse relationship with p21(WAF1) modulation was found for CHK1 in parental cells treated with both agents and in resistant cells treated with cisplatin. This pattern of response is consistent with a regulatory loop involving p53 and p21(WAF1) at G2 checkpoint. In contrast, no modulation of CHK1 was found in A2780/BBR3464 treated with the triplatinum compound. These findings, indicating a different activation of regulatory pathways at DNA damage checkpoints in response to cisplatin and BBR3464, support an altered ability of resistant cells to recognize or tolerate sublethal lesions induced by BBR3464.

Antineoplastic Agents↗
PubMed2005

Pharmaceutical-mediated inactivation of p53 sensitizes U87MG glioma cells to BCNU and temozolomide.

Pifithrin-alpha (PFTalpha) is a small molecule inhibitor of p53. By reversibly blocking apoptosis in response to DNA damage, PFTalpha protects normal cells from lethal doses of gamma-radiation (Komarov et al., Science, 1999;285:1733-7). We examined the effect of PFTalpha on the chemosensitivity of a human cancer in which cell cycle arrest, not apoptosis, is the principle cellular consequence of p53 activation. This was of interest because E6 silencing of p53 sensitizes U87MG astrocytic glioma cells to BCNU and temozolomide (TMZ), cytotoxic drugs that are modestly helpful in the treatment of aggressive astrocytic gliomas. We observed that exposure of U87MG cells to PFTalpha before cytotoxic chemotherapy attenuated p53-mediated induction of p21WAF1 protein levels, sensitizing U87MG cells to BCNU and TMZ. Sensitization of U87MG cells was associated with G1 arrest, delayed entry into S-phase and decreased repair of DNA damage by BCNU. Our findings suggest that in addition to protecting normal cells from the toxic effects of radiation and chemotherapy, small molecule inhibitors of p53, like PFTalpha, might play a role in clinical oncology by sensitizing certain resistant cancers to cytotoxic chemotherapies.

Antineoplastic Agents, Alkylating↗
PubMed1976

An experimental model for meningeal leukemia in rats (L5222). Effect of treatment with BCNU and cyclophosphamide.

An experimental model of meningeal leukemia in rats is developed by intracerebral (IC) inoculation of leukemic cells from the transplantable acute leukemia L5222. The L5222 proliferates exponentially in the central nervous system (CNS) and the disease becomes systemic 2 days following IC inoculation. Chemotherapeutic studies with BCNU and cyclophosphamide yielded cures in a high percentage of cases when treatment began at an early stage of meningeal leukemia. When treatment was started at the advanced stage, only BCNU showed a large number of cures. However, cyclophosphamide resulted in a marked increase of life-span. The activity of cyclophosphamide against meningeal leukemia, which is in contrast to the results obtained by Skipper et. al. (1961) in the L1210 mouse leukemia, suggests that cyclophosphamide crosses in part the blood--brain barrier in a rat bearing meningeal leukemia. After subcutaneous inoculation, BCNU and cyclophosphamide showed the same rate of cures.

Animals↗
PubMed1977

Human pancreatic carcinoma (MIA PaCa-2) in continuous culture: sensitivity to asparaginase.

An undifferentiated human pancreatic carcinoma has been established in continuous culture and is grown in Dulbecco's modified. Eagle's medium fortified with 10% fetal calf serum and 2.5% horse serum. The established cell line (MIA PaCa-2) has a doubling time of 40 h. The cells are large with abundant cytoplasm, exhibit a high degree of aneuploidy and have a tendency to grow on top of other cells. MIA PaCa-2 grows in soft agar with a colony-forming efficiency of 19%. Both MIA PaCa-2 cells and a cell line from another pancreatic carcinoma obtained from National Cancer Institute (NCI) are sensitive to asparaginase, a property not shared by several other human tumor cell lines tested.

Aged↗
PubMed1978

Cytocidal activity and proliferative ability of macrophages infiltrating the EMT6 tumor.

The EMT6 mouse tumor was selected for use in the study of cytocidal activity and proliferative ability of infiltrating macrophages because of its high plating efficiency when explanted to culture. The plating efficiency for cells directly plated in culture from the tumor was 28 +/- 9.3%, irrespective of the size of the tumor. Of the adherent cells derived from the tumor, the fraction that was macrophages increased from 27% at 7 days to 47% at 28 days after initial injection. Time-lapse cinemicrography was used to directly observe adherent cells derived from the tumor, and macrophages were found to be cytocidal. When grown in the presence of L-cell conditioned medium no macrophage colonies were found when cultures were established from untreated mice even though most tumor cell colonies contained macrophages. When mice were first treated with 0.8 mg BCNU prior to establishment of the cultures, in order to reduce the frequency of colony-forming tumor cells, approximately half the colonies found contained only macrophages. These results show that macrophages in this tumor are cytocidal and capable of proliferation.

Animals↗
PubMed1981

Chemotherapy of human colorectal tumor xenografts in athymic mice with clinically active drugs: 5-fluorouracil and 1-3-bis-(-2-chloroethyl)-1-nitrosourea (BCNU). Comparison with doxorubicin derivatives: 4'deoxydoxorubicin and 4'-O-methyldoxorubicin.

The effects of single-agent therapy with two clinically useful drugs, 5-fluorouracil (5-FU) and 1-3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) against nine human colorectal tumors (rectum T 157 and T 348, lung metastasis T 84, lymph-node metastasis T 245, colon, T 183, T 219, T 347, T 362 and T 380) transplanted and passed serially in thymic (nude) mice were studied. In addition, chemosensitivity of the tumors to 5-FU and BCNU was compared with the chemosensitivity of the tumors to two new doxorubicin analogues, 4'-deoxydoxorubicin and 4'-0-methyldoxorubicin. BALB/c nude mice were treated intravenously on a weekly basis for 3-4 weeks, starting when the tumor volume became relatively large (advanced stage of tumor treatment). All the tumors showed a 90-100% take rate and stable growth. In these experiments, 77% (5/9) of the colorectal tumors were biologically sensitive to the treatment with 5-FU but the percentage of statistically significant sensitive tumors was 22%, which is in good agreement with the clinical data reported in the literature (21%). In patients, BCNU has been reported to give up to 13% response. In contrast, we have found a 33% statistically significant response rate in our panel of colorectal tumors. The difference could be related to the higher tolerance of nude mice to certain drugs, including BCNU. The results suggest that the two new doxorubicin derivatives, 4'-deoxydoxorubicin and 4'-0-methyldoxorubicin, should be more active in the patient than both of the clinically used drugs, 5-FU and BCNU. Furthermore, there is a good correlation between the results obtained in the experimental system (human tumor/nude mouse) and in human patients with the active drugs, 5-FU and BCNU.

Adenocarcinoma↗