Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Lomustine”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 487 records · Page 27Linked to original sources
PubMed1987

Survey of the effect of adding Fluosol-DA 20%/O2 to treatment with various chemotherapeutic agents.

The tumor growth delays (TGDs) observed with a series of antineoplastic agents with or without Fluosol-DA and carbogen breathing (95% oxygen, 5% carbon dioxide) in the FSaIIC fibrosarcoma are shown. All but two of eleven alkylating agents examined showed some degree of positive effect by the addition of Fluosol-DA and carbogen breathing to drug treatment. The largest effects were seen with busulfan and procarbazine. Melphalan and the nitrosoureas, carmustine, lomustine, semustine, and chlorozotocin, gave increases in TGD ranging from 2- to 6-fold with the addition of Fluosol-DA and carbogen breathing. Modest increases were seen with cytoxan and dacarbazine. Cisplatin showed no additional TGD with Fluosol-DA and carbogen breathing, and mitomycin showed a negative effect. The addition of Fluosol-DA and carbogen breathing to bleomycin treatment increased the TGD produced by 5- to 6-fold compared to the drug alone. With vincristine and etoposide at three different doses, TGDs increased 2.4- to 3-fold in combination with Fluosol-DA and carbogen breathing. Increases of 1.3- to 1.4-fold in the TGD were observed with methotrexate and 5-fluorouracil with Fluosol-DA and carbogen breathing. Adding Fluosol-DA and carbogen breathing to treatment with several of the drugs examined resulted in significant enhancement of TGD and therefore may lead to an improved therapeutic outcome when added to certain currently used clinical regimens.

Alkylating Agents↗
PubMed1988

Chemotherapy for advanced adenocarcinoma of the lung: the Copenhagen study and review of the literature.

The Copenhagen Lung Cancer Study Group conducted a prospective randomized trial comparing three chemotherapy regimens: (A) vindesine (VDS) 4 mg/m2 IV weekly X 8, then every second week; (B) lomustine (CCNU) 70 mg/m2 orally, cyclophosphamide (CTX) 1000 mg/m2 IV every 4 weeks, methotrexate (MTX) 20 mg/m2 orally days 15 and 18 of each course; and (C) CCNU + CTX + MTX + VDS in the same schedule as above, but with lower doses of CCNU (50 mg/m2), CTX (750 mg/m2), and VDS (2 mg/m2). Two hundred fifty-nine patients were accrued with unresectable adenocarcinoma-type non-small cell lung cancer (NSCLC); 218 were evaluable for response. Overall response rates on the chemotherapy arms were: (A) 22%, (B) 23%, and (C) 27%. Median survival rates were: 29 weeks, (B) 29 weeks, and (C) 34 weeks. Peripheral neuropathy was the major toxicity in arm A, and myelosuppression in arms B and C. The independent influence of 27 pretreatment variables were analyzed by the Cox multivariate regression model, which revealed that six have prognostic impact: performance status, nonradical resection, liver metastases, serum LDH (lactate dehydrogenase), WBC (white blood count), and serum AST (aspartate aminotransferase). The data clearly demonstrate prognostic variables in this disease and emphasize the need for better chemotherapy.

Adenocarcinoma↗
PubMed1986

Sensitivity of proliferating cultured murine pancreatic tumor cells to selected antitumor agents.

Cultured cell populations derived from the refractory murine pancreatic ductal adenocarcinoma (Panc 02) were propagated in modified Eagle's minimal essential medium supplemented with 20% fetal bovine serum and had a doubling time of 19.1 +/- 4.7 hours (mean +/- SD). The Panc 02 cell populations were tested against 8 antitumor agents and exhibited different sensitivities to the agents in a 24-hour growth-inhibition assay. The concentration that inhibits the growth of the test culture by 50% relative to the growth of the control culture (IC50) in micromolars was determined for each agent. The IC50 values were: doxorubicin (ADR), 0.055; vincristine (VCR), 0.042; 5-fluorouracil, 1.92; cytarabine, 5.35; melphalan, 10.5; cisplatin, 17.0; carmustine (BCNU), 46.2; and lomustine (CCNU), 52.6. These IC50's were estimated to be pharmacologically attainable concentrations in mice. On a micromolar basis, the Panc 02 cells were the most sensitive to VCR and ADR and the least sensitive to BCNU and CCNU. By the use of a colony-forming assay and a 24-hour exposure period and the evaluation of each agent at 1/3 X IC50, 1 X IC50, and 3 X IC50, the degree of cell killing was greater than predicted on the basis of the IC50's determined in the growth-inhibition assay. The use of a 1-hour exposure period resulted in a very minimal reduction in viability of the cell populations except for BCNU and CCNU. It was concluded that the degree of cell killing was a function of drug concentration and time of exposure and that the pancreatic tumor in vivo should be sensitive to these agents, provided effective concentrations and exposure periods can be achieved at the tumor target sites.

Animals↗
PubMed1986

Subunit composition of plasma von Willebrand factor in patients with the myeloproliferative syndrome.

In order to evaluate the role of proteolysis in acquired von Willebrand's disease (vWD) associated with the myeloproliferative syndrome, we have determined the relative quantity of von Willebrand factor (vWF) fragments as compared with the intact 225 kDa subunit in four patients. The plasma vWF of each individual lacked large multimers; each had a prolonged bleeding time; and both platelet and leukocyte counts were elevated. Plasma was obtained from blood drawn into 1 mmol/L leupeptin, 6 mmol/L N-ethylmaleimide, and 5 mmol/L EDTA to prevent in vitro proteolysis. vWF was isolated from plasma by immunoadsorbent chromatography, reduced, subjected to SDS-5% polyacrylamide gel electrophoresis, and immunoblotted with a mixture of 55 anti-vWF monoclonal antibodies. In three patients with essential thrombocytosis (ET) the 176 and 140 kDa fragments were increased in proportion to the intact 225 kDa subunit indicating increased proteolysis. Treatment of one ET patient with CCNU (Lomustine) decreased the platelet count and, to a lesser extent, the white blood cell count. This was associated with a correction of the bleeding time, a partial correction of the multimeric abnormality, and a lessening of vWF cleavage. In a patient with polycythemia rubra vera (PRV) the proportion of the 176 kDa fragment was increased to the upper limit of normal but there was no definite evidence of increased proteolysis. These studies provide evidence that proteolysis plays a role in the acquired von Willebrand's disease associated with the myeloproliferative syndrome. However, other mechanisms must also be considered.

Bleeding Time↗
PubMedDate not supplied

Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) salvage of mechlorethamine, vincristine, prednisone, and procarbazine (MOPP)-resistant advanced Hodgkin's disease.

Thirty-nine patients with advanced Hodgkin's disease were treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Thirty-one of these patients had previously failed to respond to MOPP (mechlorethamine, vincristine, prednisone, and procarbazine) treatment (29 patients) or to CCVPP (lomustine, cyclophosphamide, vincristine, procarbazine, and prednisone) treatment (two patients). Twenty-seven patients were considered evaluable: eight (30%) achieved complete remission (CR), two (7%) achieved partial remission (PR), and 17 (63%) had no response. All of the complete responders are still in continuous unmaintained CR, while 14 of the 19 partial responders and nonresponders have died. The overall median survival was 21 months; it was 16 months for partial responders and nonresponders. The remaining eight patients had ABVD substituted to MOPP early in treatment, because of allergy to procarbazine: six patients achieved CR and two achieved PR. Our results are in keeping with the literature data and confirm the effectiveness of ABVD as primary and salvage treatment in advanced Hodgkin's disease.

Adult↗
PubMedDate not supplied

Differentiated treatment of myeloma. A non-randomised phase two study.

Seventeen consecutive, well stratified stage II and III myeloma patients were given differentiated, combination chemotherapy (cyclophosphamide, vincristine, daunorubicin, etoposide, teniposide, lomustine (CCNU), procarbazine, cytosine arabinoside, and prednisolone), which was more intensive in advanced stages and changed as soon as the patients became refractory. A comparison was made to a previous series of 17 consecutive patients treated with a simple regime of melphalan-prednisolone. Within the first 15 months only one patient in the study group given differentiated treatment died in contrast to 6 patients in the melphalan control group. The median survival times after diagnosis were 45 and 29 months, the 3-year survival 58 and 43%, respectively, and the survival for the first 15 months significantly (p less than 0,05) better in the group given differentiated treatment. The significant difference remained, when comparable patient groups were selected.

Adult↗
PubMed1982

Autologous bone marrow transplantation in acute myeloid leukemia in relapse or in complete remission.

We report ten cases of acute myeloid leukemia treated by intensive therapy followed by autologous bone marrow transplantation. Seven patients were in first relapse, and three were in complete remission. The conditioning regimen consisted of either chemotherapy alone (6-thioguanine, cytarabine, lomustine, and cyclophosphamide [TACC; eight patients]) or cyclophosphamide and total-body irradiation (two patients). All the patients in first relapse achieved complete remission (CR). The median remission duration was 9.9 months (range, 5-14), and the median survival was 14.4 months (range, 9-23.8). Of the three patients autografted during CR, one relapsed at Month 5 and two others remain in CR and are well at 18+ and 18.3+ months. High-dose chemotherapy followed by autologous bone marrow transplantation seems to be a valuable treatment for acute myeloid leukemia, if it is used immediately after the CR to consolidate the remission.

Adolescent↗
PubMed1983

Mutagenic responses of thirteen anticancer drugs on mutation induction at multiple genetic loci and on sister chromatid exchanges in Chinese hamster ovary cells.

The mutagenic responses of 13 antineoplastic drugs, namely, chlorambucil, busulfan, lomustine, dacarbazine, Adriamycin, daunomycin, bleomycin, VM-26, VP16-213, ellipticine, actinomycin D, mitomycin C, and cis-diamminedichloroplatinum(II) have been determined in two different assay systems in Chinese hamster ovary cells which measure mutation induction at multiple genetic loci and the frequencies of sister chromatid exchanges. The five genetic loci whose responses have been measured include those conferring resistance to 6-thioguanine (Thgr or TGr), ouabain, emetine, methylglyoxal bis(guanylhydrazone), and 5,6-dichlororibofuranosylbenzimidazole; of these, only the Thgr marker affects a function (hypoxanthine-guanine phosphoribosyltransferase, hgprt locus) which is not essential for cellular growth. All of these drugs showed a dose-dependent increase in mutation frequency at the hgprt locus, but their responses at other genetic loci differed greatly and showed marked specificity for different chemical classes of the drugs. The observed locus-specific differences in response to these drugs suggest that they may differ in terms of their accessibility or affinity to different chromosomal regions. All of these drugs also led to a significant increase in the frequency of sister chromatid exchanges, and a very good correlation was observed between the activity of these drugs in the sister chromatid exchange assay and the mutagenic response of the hgprt locus. Of the drugs which were examined, VM-26, VP16-213, chlorambucil, mitomycin C, and cis-diamminedichloroplatinum(II) showed a particularly strong response in both of these assay systems. In terms of the minimum concentration which gave a mutagenic response, the drugs differed from each other by a factor of about 100,000, with actinomycin D, VM-26, and daunomycin being mutagenic in the range of 3 x 10(-8) to 1 x 10(-7) M, whereas dacarbazine produced a weak mutagenic response only at about 2 x 10(-3) M.

Animals↗
PubMed1982

Phase I study of a 5-day schedule of mitoxantrone (dihydroxyanthracenedione).

Mitoxantrone (1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione dihydrochloride) in animal studies appears to have a mechanism of action and broad antitumor spectrum similar to the anthracyclines and in preliminary animal studies is without cardiotoxicity. To determine the maximally tolerated dose, mitoxantrone was given to 25 patients with various advanced solid tumors. Sixteen patients had received prior doxorubicin and/or lomustine (CCNU). Myelosuppression was the major toxic effect. All 13 patients who received mitoxantrone doses greater than or equal to 2.73 mg/m2 x 5 days experienced moderate (2000--3000 cells/mm3) or severe (less than 2000 cells/mm3) leukopenia. Thrombocytopenia was also encountered in three of these 13 patients (severe in one, less than 50,000 cells/mm3). At dose levels less than 2.73 mg/m2 x 5 days, myelosuppression was seen in four of 12 patients (three with mild leukopenia and one with mild thrombocytopenia). The blood cell count nadir occurred at 10 days and full recovery occurred by Day 21. Minor clinically insignificant ECG changes occurred in five patients. Minor and transient antitumor effects were seen in five patients. The maximum tolerated dose of mitoxantrone over a 5-day course is 2.73 mg/m2, with leukopenia being the limiting toxic effect.

Adult↗
PubMed1995

Radiotherapy and adjuvant chemotherapy for childhood medulloblastoma. The Royal Marsden Hospital experience.

PURPOSE: We reviewed the outcome of children with medulloblastoma treated from 1970 to 1985 with combined radiotherapy and chemotherapy. PATIENTS AND METHODS: Fifty-seven children with a median age of 8 years (range 1 to 16 years) at diagnosis were analyzed regarding survival, site and time of recurrence, treatment toxicity, prognostic factors and performance status. RESULTS: The overall 5- and 10-year-survival was 66% and 54%, respectively. Patients with subarachnoid metastases or positive cerebrospinal fluid cytology (M1-3) had a shorter survival compared with those without it (p < 0.1). Furthermore, survival appeared to improve with the addition of lomustine (CCNU) to vincristine chemotherapy with a 5-year-survival of 70% versus 31% (relative risk 3.4, 95% confidence interval 1.4 to 8.1) although it should be noted that these were consecutive not randomized patients treated. Of the 52 patients achieving remission, 17 relapsed either in primary (2), spine (5) or a combination of these (10). Two patients developed bone metastases without central nervous system recurrence. Performance status measured crudely appeared to be good in long-term survivors. Of 31 patients that survived for long-term follow-up and had their performance evaluated, 28 had no or minor residual neurological signs and the remaining 3 were disabled. CONCLUSION: Combined modality treatment for medulloblastoma in childhood was able to cure 54% of patients with a good performance status in the majority of survivors.

Adolescent↗
PubMed1995

[Male fertility after chemotherapy during childhood].

Chemotherapy has considerably improved the prognosis of solid tumours in children, but may have very adverse effects, particularly on fertility. A study was conducted at the Gustave Roussy Institute to identify the toxic effect of chemotherapy on male fertility. At present, 205 patients, treated during childhood have entered the study. Basal FSH-LH have been assayed to assess possible germ cell damage although azoosperia can not be eliminated. Results were normal in 127 patients (62%) and increased basal FSH levels were found in 78 (38%). Endocrine function was not altered: all patients were either impubertal or intrapubertal at diagnosis and subsequently achieved normal puberty. Multivariate analysis revealed an obvious toxic effect of 2 alkylating drugs: cyclophosphamide and procarbazine. No toxic effect was observed for vincristine, dohorubicin or actinomycin D. Age and pubertal status at diagnosis were not correlated with toxic effects. At present, no conclusion for other drugs may be made but results high dose metotrexate are promising. For lomustine and cisplatin, less favourable, though nonsignificant, results have been obtained. Complete recovery is possible several years later.

Adolescent↗
PubMed1993

Anticancer drug sensitivity profiles of new and established melanoma cell lines.

Metastatic melanoma is notable for its resistance to chemotherapy, and methods for determining resistance in cultures would be advantageous. We investigated the chemosensitivities of seven newly derived low passage lines and eight established melanoma lines. A 96-well microculture system utilising [3H]-thymidine incorporation was used to determine IC50 values (50% inhibitory concentrations) for lomustine, mitomycin C, 4-hydroperoxycyclophosphamide, cisplatinum, 5-fluorouracil, vincristine, doxorubicin, etoposide, amsacrine and the amsacrine analogue CI-921. Cytokinetic parameters were determined using 5-bromodeoxyuridine and flow cytometry. The presence of "transport" and "atypical" multidrug resistance was investigated with an IC50 ratio method, using pairs of drugs with differing sensitivity to these multidrug resistance mechanisms. A wide range of chemosensitivity for each of the antitumor agents was observed, and a spectrum of activity was observed in each of the assays for multidrug resistance. Unexpectedly, a number of cell lines displayed coordinate sensitivity or resistance to cytotoxic agents with unrelated mechanisms of action. Resistance mechanisms apart from "transport" and "atypical" multidrug resistance may be required to account for the observed 40-fold range in overall chemosensitivity of the melanoma lines.

Antineoplastic Agents↗
PubMed1993

Involvement of human liver cytochrome P450 3A in vinblastine metabolism: drug interactions.

Vinblastine biotransformation was investigated by using a human liver microsomes library. The drug was converted into one major metabolite (M) upon incubation with the microsomes. A large interindividual variation in vinblastine metabolism was observed among the samples tested, with a 4.4 ratio between the lowest and the highest metabolic rates. The biotransformation of vinblastine followed Michaelis-Menten kinetics (Km = 6.82 +/- 0.27 microM and Vmax = 0.64 +/- 0.06 nmol/min/mg protein). The involvement of the cytochrome P450 3A subfamily in vinblastine metabolism was demonstrated by the following body of evidence: (a) the competitive inhibition of vinblastine biotransformation by cytochrome P450 3A specific probes with Ki values of 0.17, 22.5, 14.8, and 35.3 microM for ketoconazole, erythromycin, troleandomycin, and vindesine, respectively; (b) the immunoinhibition of vinblastine metabolism by polyclonal anti-cytochrome P450 3A antibodies; (c) the highly significant correlation between the level of cytochrome P450 3A determined by Western blots and vinblastine metabolism (r = 0.759, P < 0.001); (d) the highly significant correlation between erythromycin N-demethylase activity (mediated by cytochrome P450 3A) and vinblastine metabolism (r = 0.83, P < 0.001); (e) the significant correlation between the CYP3A4 mRNA level and vinblastine metabolism (r = 0.60, P < 0.1). Although vincristine and navelbine (members of the Vinca alkaloid family) also inhibit the metabolism of vinblastine, suggesting the involvement of the cytochrome subfamily in their respective metabolisms, other anticancer drugs currently associated with vinblastine in chemotherapy (etoposide, Adriamycin, lomustine, and teniposide) also interfere with vinblastine biotransformation. These metabolic drug interactions may alter the antitumor activity and/or toxicity of the drug during anticancer chemotherapy.

Adolescent↗
PubMed1996

Glial cell-specific differences in repair of O6-methylguanine.

Normal and malignant cells of the oligodendrocyte lineage show increased sensitivity to alkylating agents compared to astrocytes. One of the most mutagenic DNA lesions formed following exposure to alkylating agents is O6-alkylguanine. To determine whether the increased sensitivity to nitrosoureas seen in oligodendrocytes is due to decreased repair capacity for O6-alkylguanine, removal of this lesion from DNA was assessed in primary cultures of rat oligodendrocytes, astrocytes, and microglia. Glial cells were exposed to 1 mM N-methyl-N-nitrosourea for 1 h and allowed 8 or 24 h for repair. Repair was evaluated using an immunoslot blot technique and a monoclonal antibody which recognizes O6-methylguanine (O6MeGua). Astrocytes removed O6MeGua more efficiently (approximately 80% in 24 h) than either oligodendrocytes (approximately 20%) or microglia (approximately 4%). Determination of O6-alkylguanine-DNA-alkyltransferase (AT) activity revealed that astrocytes contain 0.4 pmol/mg protein, which is average by comparison to other cell types. Both oligodendrocytes and microglia exhibited very low levels of AT (oligodendrocytes, 0.08; microglia, 0.01 pmol/mg protein). These data are the first to show that within different populations of glial cells, O6MeGua adduct removal is substantially reduced in both oligodendrocytes and microglia. Rapid removal of O6MeGua in astrocytes coupled with persistence of this mutagenic lesion in oligodendrocytes following exposure of the developing central nervous system to nitrosoureas could contribute to the observed formation of oligodendrogliomas. Inefficient removal of O6MeGua in oligodendrogliomas might also account for their response to chemotherapeutic regimens involving alkylating agents such as procarbazine, lomustine, and carmustine. The lack of repair of O6MeGua in microglia suggests that primary lymphomas of the central nervous system might be sensitive to treatment with alkylating drugs whose toxicity depends on repair of this adduct.

Alkylating Agents↗
PubMed1998

Practical guidelines for the treatment of malignant gliomas.

The treatment of patients with malignant gliomas is palliative and encompasses surgery, radiotherapy, and chemotherapy. Outcome measures have demonstrated improvement in both survival and neurologic performance in patients undergoing complete or near-complete tumor resection. After surgery, involved-field radiotherapy (radiotherapy administered to the tumor and to the tissue in a 3-cm radius surrounding the tumor) has been shown to further improve survival rates when given in a total dose of 6000-6500 cGy. Survival is further improved by the coadministration of the chemoradiopotentiator hydroxycarbamide (hydroxyurea). The role of adjuvant or boost stereotactic radiotherapy is unclear, despite its frequent use. In addition, adjuvant chemotherapy has been shown to improve survival rates in approximately one-quarter of patients with glioblastoma multiforme and in the majority of patients with anaplastic astrocytoma. No a priori method exists, however, to predict which patient will benefit from adjuvant chemotherapy. As a consequence, all physiological young patients with good performance status or limited neurologic disability are treated with chemotherapy. The best results of adjuvant chemotherapy are achieved with a nitrosourea chemotherapy, either carmustine (BCNU) or a combination of procarbazine and lomustine (CCNU) and vincristine, known as PCV-3 therapy. Salvage chemotherapy is reserved for patients with tumor progression, some of whom benefit from a re-operation. Occasional patients with recurrent gliomas may be palliated by stereotactic radiotherapy.

Algorithms↗
PubMed1998

Long-term results from MOPPEBVCAD chemotherapy with optional limited radiotherapy in advanced Hodgkin's disease.

The purpose was to verify the 5-year results of the MOPPEBVCAD chemotherapy regimen with limited radiotherapy in relation to the promising preliminary data. Mechlorethamine, vincristine, procarbazine, prednisone, epidoxorubicin, bleomycin, vinblastine, lomustine, melphalan, and vindesine were delivered according to a schedule derived through hybridization, intensification, and shortening of the corresponding alternating CAD/MOPP/ABV regimen. Radiotherapy was restricted to sites of bulky involvement or to areas that responded incompletely to chemotherapy. This multicenter, controlled, nonrandomized trial involved 145 eligible patients. Radiotherapy was administered to 47 patients, 46 of whom were in complete remission after chemotherapy. Remissions were complete in 137 patients (94%), partial in 4 (3%), and null in the remaining 4. Tumor-specific, overall, relapse-free, and failure-free survival at 5 years were 0.89, 0.86, 0.82, and 0.78, respectively. Hematologic toxicity was considerable, whereas nonhematologic side effects were fully acceptable. Most of the unfavorable prognostic factors lost their clinical weight. Only age and lymphocyte depletion histologic type were statistically correlated with major follow-up endpoints; performance status and bone marrow involvement were subordinate to age. Seven patients developed a second cancer (including 3 myelodysplasias). MOPPEBVCAD with selected radiotherapy is a highly effective regimen in advanced Hodgkin's disease. Early and late toxicity are no more severe than what would be expected with other alternating or hybrid regimens. A comparison with ABVD, which is currently considered the standard regimen for advanced Hodgkin's disease, is needed.

Adolescent↗
PubMed1998

Cellular resistance against the novel hybrid anthracycline N-(2-chloroethyl)-N-nitrosoureidodaunorubicin (AD 312) is mediated by combined altered topoisomerase II and O6-methylguanine-DNA methyltransferase activities.

N-(2-Chloroethyl)-N-nitrosoureidodaunorubicin (AD 312), a novel semisynthetic compound with combined anthracycline and nitrosourea alkylating functionalities, circumvents resistance conferred by either reduced DNA topoisomerase II (topo II) or increased P-glycoprotein expression with less myelosuppression and cardiotoxicity than adriamycin (doxorubicin; ADR). Cellular resistance to AD 312 could arise from a novel mechanism that confers resistance to both functions simultaneously, or one or more mechanisms common to anthracyclines and/or alkylating agents. The mechanism contributing to AD 312 resistance was investigated following selection of AD 312-resistant murine J774.2 macrophage-like cells and human NCI-H460 non-small-cell lung carcinoma cells. Murine J/312-400 (> 4.7-fold) and human H/312-40 cells (6.3-fold) were cross-resistant to topo II inhibitors (ADR, teniposide, etoposide) and nitrosoureas (carmustine, lomustine) but remained sensitive to vinblastine, colchicine, and camptothecin. There was approximately a twofold decrease in topo II decatenation activity and protein. Decreased net intracellular drug accumulation was not observed. There were no increases in glutathione content or glutathione-S-transferase activity. Increased O6-methylguanine-DNA methyltransferase (MGMT) activity (2.3-fold) was detected in J/312-400, and AD 312 resistance was partially reversed by O6-benzylguanine, a potent inhibitor of MGMT activity. The results suggest that AD 312 resistance arose through selective pressure by both cytotoxic functions in a serial manner.

Animals↗
PubMed1998

Pharmacokinetics of O6-benzylguanine and its active metabolite 8-oxo-O6-benzylguanine in plasma and cerebrospinal fluid after intrathecal administration of O6-benzylguanine in the nonhuman primate.

O6-Benzylguanine (O6BG) irreversibly inactivates the single-turnover DNA repair protein alkylguanine-alkyltransferase. Thus, O6BG increases tumor-cell sensitivity to alkylating agents such as carmustine, lomustine, procarbazine, and temozolomide. We investigated the pharmacokinetic behavior of O6BG and O6-benzyl-8-oxoguanine (8-oxo-O6BG) in cerebrospinal fluid (CSF) and plasma after intraventricular administration of O6BG in a nonhuman primate model. In our study, three animals received a single 1-mg dose of O6BG into the lateral ventricle. CSF from the 4th ventricle and plasma samples were collected after administration, and O6BG and 8-oxo-O6BG concentrations were measured by high-performance liquid chromatography. Four additional animals received 1 mg of O6BG via the intralumbar route weekly for 6 weeks to assess the feasibility and toxicity of this route of administration. The peak O6BG CSF concentration was 412+/-86 microM, the t1/2 was 0.52+/-0.02 h, the clearance was 0.22+/-0.01 ml/min, and the area under the concentration-time curve was 319+/-15 microM x h in 4th ventricular CSF. The peak CSF concentration of 8-oxo-O6BG in CSF was 1.9+/-0.4 microM, the t1/2 was 0.76+/-0.03 h, and the area under the concentration-time curve was 5.0+/-1.1 microM x h. Both O6BG and 8-oxo-O6BG were detected in the plasma 0.5-3 h after intraventricular O6BG administration. The plasma peak concentration of O6BG was 0.4 microM at 30 min, and the concentration was <0.1 microM by 3 h. The plasma concentration of 8-oxo-O6BG was 0.2 microM at 30 min and 0.6 microM at 3 h. The animals tolerated the single intraventricular dose and 6 weekly intralumbar doses of O6BG without toxicity. We concluded that intrathecal administration of O6BG is well tolerated in the nonhuman primate and seems to have a substantial pharmacokinetic advantage over systemic administration for meningeal tumors.

Animals↗