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PubMed1987

The prognostic value of response to the first cycle of chemotherapy in small cell lung cancer. Results of a multicenter German trial.

The prognostic significance of evaluation of response according to chest X-ray after only one cycle of treatment was investigated in patients with small cell lung cancer (SCLC). Three hundred and six patients entered a multicenter randomized German trial testing alternating vs. sequential chemotherapy. Decrease of tumor size after the first cycle was seen to be 78% in the alternating group and 70% in the sequential group. Stable disease occurred in 25% of the sequentially treated and 19% of the alternatingly treated patients. No substantial differences in pretreatment characteristics were noticed between patients with stable disease in sequential and alternating treatment. In sequential therapy, median survival was 323 days for patients with decrease of tumor size after the first cycle and 219 days for patients with no change. Only five out of 21 patients with no change after one cycle responded to continuous administration of this regimen including one complete remission. In alternating therapy, median survival was 347 days for patients with decrease in tumor size after the first cycle and 378 days for patients with no change indicating no difference in prognosis. Twelve out of 18 patients with no change responded to continuous administration of alternating treatment including six complete remissions. We concluded that response to the first cycle according to chest X-ray is a reliable and prognostically valid response criterion if sequential therapy is used. In this treatment modality no change in tumor size after the first cycle indicates poor prognosis, and improvement of the patients' outcome may be achieved by a switch to a second non-cross resistant drug combination.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Combination therapy of ACNU and ifosfamide in tumor bearing mice with M2661 breast cancer, B16 malignant melanoma or C38 colon cancer.

Three murine tumor lines, B16 melanoma, C38 colon cancer and M2661 breast cancer, were used to evaluate the therapeutic efficacy of the drug combination ACNU and ifosfamide. For each tumor type five treatment groups of 12 mice each were studied, which respectively received 16.5 mg/kg ACNU, 150 mg/kg ifosfamide, 33 mg/kg ACNU, 300 mg/kg ifosfamide or 16.5 mg/kg ACNU + 150 mg/kg ifosfamide. One group served as controls. Growth delay was measured as the endpoint. In the B16 and C38 tumor lines both drugs were active and showed additive antitumor effects. However, no synergism was observed. Neither ACNU or ifosfamide or the combination of both had any activity against the M2661 tumor line.

Animals↗
PubMed1987

Detection of DNA sites damaged by 1-(4-amino-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) using a DNA sequencing procedure.

A DNA sequencing technique was applied to the highly reiterated DNA from HeLa S3 cells in order to detect DNA damage induced by the antitumor drug, 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). A DNA reiterated fragment of 92 base pairs (bp) was isolated by gel electrophoresis after EcoRI and EcoRI restriction endonuclease digestion. In the defined sequence of the 92 bp fragment, ACNU caused damage and modifications primarily at guanine moieties, leading to alkali-labile sites as determined by subsequent piperidine reaction on an extended Maxam-Gilbert sequencing gel. These results indicate that guanine moieties in double-stranded DNA are preferentially vulnerable to ACNU over other base moieties.

Base Sequence↗
PubMed1987

Minimal long-term cardiopulmonary dysfunction following treatment for Hodgkin's disease.

UNLABELLED: We studied the long term cardiopulmonary function, at rest and during exercise, of 57 patients who were at least 1 year (mean 5 years) post-treatment for Hodgkin's disease. To establish the maximum degree of dysfunction we studied 40 patients who had extensive intrathoracic disease treated with radiotherapy alone (Exten-X; n = 20) or combined modality therapy (Exten-XC; n = 20). Patients without intrathoracic disease given either prophylactic mantle therapy (Proph-X, n = 10) or no chest irradiation ( CONTROL: n = 7) were used as controls. An abnormal electrocardiogram, by virtue of a conduction defect, was observed in seven patients, six in the Exten-X or Exten-XC groups. Borderline abnormalities including ST-T changes, prolonged QT interval, or axis deviation occurred in 14 patients distributed evenly throughout the groups. Resting mean pulmonary function test values were normal in all treatment groups. Exercise tolerance, as indicated by peak oxygen consumption (VO2), was significantly lower for the Exten-XC group compared to Proph-X (p less than 0.01). However, the mean value of VO2 for group Exten-XC was only 15% below that predicted. Of the 12 patients with abnormally low VO2 (greater than 20% below their predicted value), 11 were in the Exten-X or Exten-XC group with no difference between the two groups. Patients who received radiotherapy to at least one lung field, using either the thin lung block technique or open field irradiation, had significantly lower exercise tolerance than those treated with full thickness blocks (p less than 0.05). Despite these abnormalities only a single patient complained of marked dyspnea. We conclude that extensive treatment to the mantle field, especially when followed by chemotherapy in patients with extensive intrathoracic Hodgkin's disease, can result in minimal cardiopulmonary dysfunction in approximately one-third of patients.

Adolescent↗
PubMed1995

Timing of hypertonic glucose and thermochemotherapy with 1-(4-amino-2-methylpyrimidine-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) in the BT4An rat glioma: relation to intratumoral pH reduction and circulatory changes after glucose supply.

PURPOSE: Intraperitoneal hypertonic glucose has previously been shown to induce hyperglycemia, hemo-concentration, and to influence systemic and tumor circulation, and, thus, enhance the effect of thermochemotherapy with 1-(4-amino-2-methylpyrimidine-5-yl)methyl-3-(2-chloroethyl)-3-nitrosoure a (ACNU) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). However, the optimal timing and the precise mechanisms responsible are not known. The effect of different time intervals between glucose load and thermochemotherapy with ACNU in the treatment of BT4An tumors, therefore, was investigated. Changes of serum glucose (Se-glucose), hemoglobin, systemic circulation parameters, tumor pH, and tumor temperature, induced by intraperitoneal glucose and/or hyperthermia, were measured to assess their effect on tumor growth. METHODS AND MATERIALS: (a): Inbred BD IX rats with BT4An tumors on the hind leg were treated with ACNU 7 mg/kg intravenously just before waterbath hyperthermia, and intraperitoneal hypertonic glucose (6 g/kg) at different time intervals before (240-0 min) or immediately after thermochemotherapy. (b): Intratumoral pH and temperature were measured at different intervals after intraperitoneal glucose, and during hyperthermia with or without previous glucose. (c): Hemoglobin, hematocrit, and Se-glucose were measured at different times after intraperitoneal glucose. (d): Mean arterial pressure, pulse pressure, and heart rate were measured for 120 min after intraperitoneal glucose. RESULTS: (a): The number of tumor controls and the growth delay was greatest with glucose 45 min before thermochemotherapy, and least with a time interval of 240 min. Glucose after thermochemotherapy delayed tumor growth. (b): After intraperitoneal glucose alone, intratumoral pH decreased gradually from 6.76 to 5.86 after 240 min. Hyperthermia 120 min after glucose induced a rapid further pH drop, while hyperthermia alone had no significant influence on pH. Intratumoral temperature was higher during hyperthermia in animals given glucose. (c): A substantial rise of Se-glucose and hemoglobin developed. The hemoconcentration was maintained also after reduction of Se-glucose towards normal values. (d): An initial tachycardia, and a reduction of the mean arterial pressure of about 10% 5-45 min after was measured. CONCLUSION: The data indicate that a complex interaction between gradually reduced tumor pH, hyperglycemia, hemoconcentration, and reduced tumor blood flow, and not a breakdown of systemic circulation, is responsible for the effect of intraperitoneal glucose on thermochemotherapy with ACNU. Interestingly, enhancement of thermochemotherapy effect was also seen when intraperitoneal glucose was given after heat and ACNU.

Animals↗
PubMed1994

Effects of therapy on the 1H NMR spectrum of a human glioma line.

Currently it is difficult to predict the efficacy of any therapeutic modality in individual patients. If it could be shown that successful therapy causes some chemical alteration in the tumor before gross alteration in size becomes radiologically visible, the therapeutic regimen could potentially be modified, sparing the patients longer trials of ineffective therapy. We used proton nuclear magnetic resonance spectroscopy to detect the presence of simple metabolites (such as lactic acid, creatine/phosphocreatine, N-acetyl aspartate, and the "choline" pool) in extracts of a human glioma grown subcutaneously in athymic ("nu/nu") mice. By comparing the tumor spectra obtained from untreated mice with tumor spectra from mice treated with chemotherapy or irradiation, we have shown a significant decrease in the lactate/creatine and lactate/choline values in tumors of similar size following treatment. Such information could prove valuable as a means of monitoring tumor therapy when obtained noninvasively from spatially localized in vivo spectra.

Animals↗
PubMed1990

DNA breaks and repair in the mouse leukemia L1210 cells exposed to three different types of interstrand DNA cross-linkers.

DNA breaks and repair in mouse leukemia L1210 cells treated with 3 different types of cross-linkers, mitomycin C (MMC), 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitroso ure a hydrochloride (ACNU) and SN-07 (a macromolecular antibiotic), were studied. Measured in D37 values, MMC gave the highest number of cross-links per lethal 'hit' directly after the 1-h treatment in the alkaline elution assay, followed by ACNU and SN-07. A good dose-response increase in induced interstrand DNA cross-linking frequency was observed in cells treated with 2.5-10 micrograms/ml MMC and with 10-100 micrograms/ml ACNU for 1 h with and without 24-h post-incubation. After 6-h post-incubation, the highest frequency of cross-linking was observed in cells treated with 2.5 micrograms/ml MMC and 30 micrograms/ml ACNU, while cross-link production continued in the cells treated with SN-07 for 12-h post-incubation. No significant increase in DNA breaks was observed in cells treated with MMC throughout 24-h post-incubation. The highest frequency of single-strand DNA breaks in cells treated with ACNU was observed immediately after the treatment and they disappeared after 6-h post-incubation. After 24-h post-incubation, a marked enhancement of the DNA breaks was observed in cells treated with SN-07 and the cells contained double-strand DNA breaks also. RNA synthesis was not affected in the cells treated with 10 micrograms/ml MMC and slightly inhibited to 70% of control in those treated with 100 micrograms/ml ACNU, while DNA synthesis in both cells was significantly inhibited after 24-h post-incubation. By contrast, both RNA and DNA synthesis were completely inhibited in cells treated with 8.0 micrograms/ml SN-07.

Animals↗
PubMed1994

Intracellular localization and function of DNA repair methyltransferase in human cells.

An antibody preparation specific for human O6-methylguanine-DNA methyltransferase (EC 2.1.1.63) was obtained by immunoaffinity purification on two types of affinity columns with the purified human and mouse methyltransferase proteins as ligands. The antibodies were used in Western blotting analysis of fractionated cell extracts. More than 90% of the methyltransferase protein was recovered in the cytoplasmic fractions with both human HeLa S3 cells and MR-M cells, the latter overproducing the enzyme 36 times as much as the former. Cytoplasmic localization of the methyltransferase in HeLa S3 cells was further confirmed by in situ immunostaining. By Western blotting analysis of fractionated cell extracts from HeLa S3 cells treated with alkylating agents, we found that amounts of the enzyme decreased more rapidly in the nuclear fraction than in the cytoplasmic fraction, and recovery of the enzyme level in the cytoplasmic fraction was slower than that in the other. These results suggest that the methyltransferase protein is degraded in the nucleus after it commits the repair reaction and that the cytoplasmic enzyme is transported into the nucleus as the nuclear methyltransferase is used up in this manner.

Biological Transport↗
PubMed1995

Enhancement of ACNU treatment of the BT4An rat glioma by local brain hyperthermia and intra-arterial drug administration.

To evaluate the role of intra-arterial (i.a.) chemotherapy, intravenous (i.v.) chemotherapy, and local brain hyperthermia in the treatment of gliomas, the effect of i.v. versus i.a. drug delivery, with or without local brain hyperthermia, was evaluated in BD IX rats with BT4An gliomas implanted in the right frontal lobe. The rats were given ACNU 18 mg/kg i.a. in the right carotid artery or i.v. in the inferior cava with or without local microwave hyperthermia at 42.4 degrees C for 45 min. ACNU i.v. alone had no notable effect on survival. Survival was prolonged when ACNU without hyperthermia was given i.a. instead of i.v. (P < 0.05). Thermochemotherapy with ACNU i.a. was more effective than with ACNU i.v. (P < 0.01). Survival improved as hyperthermia enhanced the i.v. drug effect (P < 0.01), and hyperthermia also improved the i.a. ACNU effect (P < 0.01). Post-treatment survival was more than doubled for the group given combined i.a. ACNU and hyperthermia, compared to controls. Thermochemotherapy, particularly with i.a. drug administration, seems to be a promising new approach for the treatment of primary brain tumours. However, more knowledge about tolerance of human brain tissue to hyperthermia is necessary before this treatment modality is used in patients with a reasonable life expectancy.

Animals↗
PubMed2006

Acquisition of resistance to antitumor alkylating agent ACNU: a possible target of positron emission tomography monitoring.

Early detection of tumor response to chemotherapy is of great importance for appropriate treatment of tumors. In this study, characteristics of two positron emission tomography (PET) tracers, [(18)F]2-fluoro-2-deoxy-D-glucose (FDG) and[(18)F]3'-fluoro-3'-deoxy-thymidine (FLT), in the early detection of tumor cell response as well as tolerance development to chemotherapy was compared using rat C6 glioma cells and 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosoureahydrochloride (ACNU). ACNU is an alkylating agent known to induce drug resistance through expression of O(6)-methylguanine-deoxyribonucleic acid methyl transferase (O(6)-MGMT). We established an ACNU-resistant C6 glioma cell line (C6/ACNU) and investigated the effect of ACNU on the uptake of FLT and FDG. In C6 cells, DNA synthesis presented as [(3)H]thymidine ([(3)H]Thd) incorporation into DNA was quickly suppressed by ACNU. In C6/ACNU cells, the suppression was recovered promptly, indicating that DNA alkylation occurs initially but highly expressed O(6)-MGMT repairs DNA, leading to the recovery of DNA synthesis. The patterns of FLT uptake in C6 and C6/ACNU were difficult to distinguish in the very early stage of the treatment, though it was reported that FLT uptake well correlated with proliferation in certain conditions. FDG uptake showed different patterns between the resistant and control cells, with significantly decreased uptake in C6 cells and unchanged uptake in C6/ACNU cells at 18-24 h after the treatment. Though difficult to be directly translated into clinical situation, the present study will provide a base to develop an appropriate protocol to assess tumor response to treatment by PET and to design effective treatment plans.

Animals↗
PubMed1998

CD95-mediated apoptosis: no variation in cellular sensitivity during cell cycle progression.

Sensitivity of CD95-mediated apoptosis has been reported to vary during cell cycle progression (FEBS Lett. (1997) 412, 91-93). Here, we report that three human glioma cell lines with different p53 status (i) undergo growth arrest and synchronous cell cycle re-entry after prolonged serum deprivation, (ii) do not exhibit cell cycle-related changes in CD95 expression at the cell surface, and (iii) do not exhibit cell cycle-related changes in susceptibility to DC95 ligand-induced apoptosis. In contrast, cell cycle-specific activity was demonstrated for various cancer chemotherapy drugs. Further, CD95 expression and susceptibility to CD95 ligand-induced apoptosis does not vary during cell cycle progression of Jurkat T cells, HeLa cervical carcinoma and HepG2 hepatocellular carcinoma cells. These results do not support a role for the cell cycle phase as an important predictor of vulnerability to CD95-mediated apoptosis.

Antibiotics, Antineoplastic↗
PubMed1990

Expression and cloning of complementary DNA for a human enzyme that repairs O6-methylguanine in DNA.

A cell line with an increased resistance to alkylating agents and an extremely high level of O6-methylguanine-DNA methyltransferase activity was isolated after transfection of methyltransferase-deficient Mer- cells with a cDNA library, prepared from methyltransferase-proficient human Mer+ (Raji) cells. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis analysis revealed that a protein, with a molecular weight of approximately 25,000, accepted 3H label from DNA that had been treated with [3H]methylnitrosourea. Since the cDNA for methyltransferase was integrated into the chromosomal DNA, it was recovered by using the polymerase chain reaction. When the cDNA placed in an expression vector p500 was introduced into Mer- cells, the cells acquired an increased resistance to alkylating agents and exhibited a high level of O6-methylguanine-DNA methyltransferase activity. From the transformants the cDNA could be recovered as a part of the autonomously replicating plasmid. The nucleotide sequence of the cDNA was determined, and an open reading frame comprising 207 amino acid residues was found. The molecular weight of methyltransferase, calculated from the predicted amino acid sequence, was 21,700. The predicted amino acid sequence of the human methyltransferase exhibits an intensive homology with those of the bacterial counterparts, Ada and Ogt proteins of Escherichia coli and Dat protein of Bacillus subtilis, especially around possible methyl acceptor sites.

Base Sequence↗
PubMed1998

Efficient protection of cells from the genotoxicity of nitrosoureas by the retrovirus-mediated transfer of human O6-methylguanine-DNA methyltransferase using bicistronic vectors with human multidrug resistance gene 1.

Retrovirus-mediated transfer of O6-methylguanine-DNA methyltransferase (MGMT; E.C. 2.1.1.63) and a human multidrug-resistance gene (MDR1) confers resistance to nitrosoureas and natural product antitumor agents, respectively. In a previous study, we constructed two bicistronic retroviral vectors, Ha-MDR-IRES-MGMT and Ha-MGMT-IRES-MDR, that allow co-expression of the MGMT gene and the MDR1 gene to protect cells from the toxicity of combination chemotherapy. Each cell transduced with Ha-MDR-IRES-MGMT or Ha-MGMT-IRES-MDR showed high-level resistance to vincristine and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosou rea (ACNU), indicating that the two drug-resistance genes can be functionally co-expressed from these vectors. In the present study, we examined whether the expression of MGMT from these MDR1-MGMT bicistronic retroviral vectors could protect cells from the genotoxicity of nitrosoureas. Three independent Ha-MDR-IRES-MGMT-transduced clones and three independent Ha-MGMT-IRES-MDR-transduced clones of HeLa MR cells showed 12-23-fold and 27-30-fold higher MGMT activity than the parental cells. These clones are more resistant to ACNU mutagenicity measured by the frequency of the emergence of 6-thioguanine-resistant colonies after ACNU treatment over the frequency seen in the parental cells. The ACNU-induced sister chromatid exchange (SCE) was markedly suppressed in these clones. Murine bone marrow cells were transduced with either Ha-MDR-IRES-MGMT or Ha-MGMT-IRES-MDR. Non-selected populations of the transduced cells showed only marginal increases in drug resistance and MGMT activity. Remarkable increase in drug resistance and MGMT activity were observed after a short exposure of the transduced cells to vincristine. The Ha-MDR-IRES-MGMT-transduced, vincristine-selected bone marrow cells showed 27-fold resistance to vincristine, 7-fold resistance to ACNU, and 10-fold higher MGMT activity than the non-transduced, non-selected cells. The Ha-MGMT-IRES-MDR-transduced, vincristine-selected cells showed 8-fold resistance to vincristine, 16-fold resistance to ACNU and 19-fold higher MGMT activity than the non-transduced, non-selected cells. The rates of ACNU-induced SCE in the vincristine-selected cells were as follows: non-transduced cells (non-selected) and HaMDR-transduced cells>Ha-MDR-IRES-MGMT-transduced cells>Ha-MGMT-IRES-MDR-transduced cells. Again, the only marginal levels of increases in the rates of ACNU-induced SCE were observed in non-selected population of the transduced cells. These results indicate that the MDR1-MGMT bicistronic retrovirus vectors would be useful to protect normal hematopoietic cells from nitrosourea-induced mutagenesis, and drug-selectable bicistronic constructs would have great advantage over non-selectable vectors.

Animals↗
PubMed1999

Secondary myeloid/natural killer cell precursor acute leukemia following essential thrombocythemia.

The de novo leukemic transformation of essential thrombocythemia is a rare event, and usually associated with previous treatments. We describe a patient who received treatments with nitrosourea for long-standing essential thrombocythemia and subsequently developed extramedullary tumors, tentatively diagnosed as lymphoblastic lymphoma. Combination chemotherapy was initially successful, but relapsed with marked bone marrow involvement. Surface marker analysis revealed that the tumor cells had CD5, CD7, CD33, CD34, and CD56 antigens but lacked other T-cell, and B-cell markers. Immunogenotypical studies revealed germline configurations for both T-cell receptors and immunoglobulin genes. These clinical and phenotypical features are consistent with a myeloid/natural killer cell precursor leukemia, a recently proposed distinct clinical entity. To our knowledge, this is the first report of secondary leukemia of myeloid/ natural killer cell precursor origin, and suggest that myeloid/natural killer cell precursor might be a potent target of therapy-related leukemia.

Antigens, CD↗
PubMed1981

Pharmacokinetics of a new water-soluble nitrosourea derivative (ACNU) in human gliomas.

The pharmacokinetics of a newly developed water-soluble nitrosourea derivative (ACNU) following a single intravenous injection was investigated in 11 patients with gliomas. A major portion of ACNU was excreted within 2 hours. The distribution rate was very fast, and the elimination rate tended to be slow. More than 50% of ACNU moves into the tissue compartment. ACNU tended to move into glioma tissue well. The ACNU level in glioma tissue was above 1.0 microgram/gm 30 to 60 minutes ater injections. ACNU was detected at a higher concentration in malignant gliomas than in benign gliomas. These results suggest that ACNU is taken up by tumor tissue relatively rapidly and eliminated slowly, which leads to effective manifestation of its antitumor activity.

Astrocytoma↗
PubMed2003

Prospective trial of radiotherapy after hyperbaric oxygenation with chemotherapy for high-grade gliomas.

Twenty-one patients with high-grade gliomas were enrolled in a prospective trial of radiotherapy after hyperbaric oxygenation (HBO). Radiotherapy was administered in daily 2-Gy fractions up to a total dose of 60 Gy, and each fraction was delivered immediately after HBO. The current study indicated that radiotherapy immediately after HBO with chemotherapy was feasible for high-grade gliomas.

Adult↗
PubMed2003

Primary malignant melanoma of the oral mucosa.

PURPOSE: The occurrence of primary oral melanoma is very rare. Large clinical series suggesting appropriate treatment modalities are lacking; the clinician has to rely on case reports to gain insight into the management of this tumor, which is much more aggressive than its skin counterpart. Patients and methods The cases of 5 patients with primary oral melanoma during a 6-year period were retrospectively reviewed. Four patients presented with tumors located in the maxilla. Preoperative workup included microscopic examination of incisional biopsy specimens for the confirmation of the diagnosis and thorough imaging of the body to rule out distant metastases. Histologically significant vertical invasion was found in all patients. No patient had distant metastases initially, and only 1 patient presented with neck disease. Primary treatment included wide local excision in 4 patients and therapeutic modified radical neck dissection in the 1 patient with neck node involvement on presentation. One patient was treated primarily with radiation therapy due to medically compromised status. Adjuvant immunochemotherapy (DAV protocol) was administered to 4 patients. Radiation therapy was used in an adjuvant fashion in 3 patients. RESULTS: All of the patients developed distant metastases to the lung and liver and eventually died of their disease. Survival ranged from 14 to 38 months (mean, 25.6 months). Local recurrence occurred in 1 patient and was attributed to positive surgical margins. Contralateral neck disease developed in the patient who underwent therapeutic neck dissection. CONCLUSIONS: The prognosis of primary oral melanoma remains poor despite adequate locoregional control of the disease. It seems that diagnosis is made late in the course of the disease when the primary tumor has already shed microscopic distant metastases.

Aged↗