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At least 829 records · Page 46Linked to original sources
PubMed1985

A pilot study to determine clinical tolerability of intensive combined modality therapy for locally unresectable gastric cancer.

Eighteen patients with unresectable carcinoma of the stomach whose known malignant disease was confined to structures immediately adjacent to the primary tumor and could be encompassed within a radiotherapy field were treated with an intensive sequential combined modality regimen. The regimen consisted of 5-FU plus adriamycin chemotherapy, followed by high dose megavoltage radiation therapy with 5-FU given as a radiation sensitizer, followed by maintenance chemotherapy with 5-FU plus adriamycin plus methyl CCNU (FAMe). Our primary objective was to determine patient tolerability. Severe and prolonged anorexia, nausea, and decreased performance status occurred during and after high dose radiotherapy given twice daily in 150-170 cGy (rad) fractions when given with 5-FU. Lengthening intervals between treatment segments, and the use of one daily dose of radiation therapy combined with 5-FU or two fractions daily without 5-FU seemed to decrease nutritional complications. Control of tumor at the primary site appeared to be achieved in most patients. Distant metastases represented the predominant mode of treatment failure with only two patients currently without progression of malignant disease. Our treatment regimen as initially conceived was too toxic for general use. Improved therapeutic results in locally unresectable gastric cancer will require the development of more effective therapy for occult distant metastases.

Adenocarcinoma↗
PubMed1985

Benznidazole with CCNU: a clinical phase I toxicity study.

It has been shown in a variety of model systems that benznidazole (BENZO) is capable of enhancing the cytotoxicity of a number of drugs, including nitrosoureas. We report an escalating dose toxicity study of the combination of BENZO and CCNU on 34 patients in whom the usual clinical dose of CCNU (130 mg/m2) was given together with escalating doses of BENZO (up to a maximum dose of 40 mg/kg). We have observed no BENZO-related toxicity and no evidence that, in the dose range studied, BENZO enhances the gastrointestinal or hematological toxicity of CCNU. It is possible to administer the usual dose of CCNU together with doses of BENZO that can be shown to have a clear effect on the pharmacokinetics of CCNU and which might be expected, from the results of animal experiments, to produce enhancement of its cytotoxicity. A Phase III study of the combination is in progress.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Potentiation of CCNU toxicity by AF-2 in V79 spheroids: implications for mechanisms of chemosensitization.

Spheroids of Chinese hamster V79-171 cells were incubated for 1.5 hr. with 0-10 micrograms/ml of the nitrofuran AF-2 (a potent radiosensitizer and hypoxic cell cytotoxin) under 1-10% oxygen, then exposed to 0-3 micrograms/ml CCNU for a further 30 minutes in the presence of the AF-2 and a fluorescent bisbenzimide stain. Single cells from the disaggregated spheroids were then sorted by a dual laser cell sorter for subsequent analyses of clonogenicity. Two sorting criteria were intercompared: sorting on the basis of cell position in the spheroid (defined by the bisbenzimide uptake), or on the basis of the bound AF-2 (which is itself fluorescent). These studies indicated chemosensitization was not observed in the absence of AF-2 toxicity, cellular oxygen content modified AF-2 toxicity more than AF-2 potentiation of CCNU toxicity, and cellular susceptibility to intracellular AF-2 dominated the net response.

Animals↗
PubMed1986

Combinations of CCNU, MISO, and fractionated radiotherapy.

Studies were performed to determine whether the radiation sensitizer misonidazole (MISO) could enhance the tumor response of the KHT sarcoma to a treatment combining fractionated radiotherapy and the chemotherapeutic agent 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). A single dose of CCNU (20 mg/kg) was given 24 hr prior to the start of a multi-fraction radiation protocol in which 10 fractions were delivered once a day in 12 days overall treatment time. Daily radiation doses ranged from 1.0 to 4.0 Gy. MISO was administered at a dose of 1.0 mmol/kg, either once as a chemopotentiator simultaneously with CCNU, or repeatedly as a radiosensitizer 30-40 min prior to each radiation dose. Tumor response to treatment was assessed using tumor regrowth delay as the end point. The results indicate that, at 1.0 mmol/kg, MISO failed to radiosensitize the tumors in each of the fractionation schedules evaluated; that is, there was no difference between the regrowth delay curves obtained when CCNU treatment was followed by fractionated radiation, administered either alone or with MISO prior to each radiation dose fraction. However, when a single dose of 1.0 mmol/kg MISO was combined with CCNU 24 hr prior to the start of radiotherapy, regrowth delay was increased for all fractionated radiation schedules, particularly, at the larger dose fraction sizes. Comparison of the dose response curves suggests that MISO, used as a chemopotentiator, effectively reduced the proportion of radiobiologically hypoxic cells in the tumors prior to the start of the radiation therapy. These findings indicate that chemopotentiation can be used effectively in a combination with fractionated radiotherapy.

Animals↗
PubMed1986

Interaction of nitroimidazole sensitizers with drug metabolizing enzymes--spectral and kinetic studies.

We have investigated the effect of a range of 2-nitroimidazoles on CCNU metabolism, using an in vitro mouse liver microsomal preparation. CCNU is hydroxylated to at least 5 monohydroxylated metabolites. For the major metabolite, cis-4-hydroxy CCNU, values of Km and Vmax were 0.026 mM and 1.92 nmol/min/mg protein, respectively. MISO and other 2-nitroimidazoles inhibited the hydroxylation of CCNU in a dose-dependent manner and their potencies as inhibitors were governed by their lipophilicities. In order of increasing potency I50 values were 15.5, 6.4, 5.8, 1.4, 0.4, and 0.37 mM for SR 2508, Ro 03-8799, MISO, Ro 07-1902, Ro 07-1127, and BENZO, respectively. Chemosensitization potency correlated well with the extent of inhibition at achieved plasma concentrations in mice, suggesting a causal relationship between enzyme inhibition and chemosensitization. All the nitroimidazoles exhibited type II optical difference spectra with phenobarbitone-induced mouse liver microsomes. However, with increasing lipophilicity of the nitroimidazole both the wavelength at maximum absorbance (lambda max) and the isosbestic point of the type II spectrum were shifted to longer wavelengths, suggesting that a type I binding component may become more significant. Our previous work has shown that changes in CCNU pharmacokinetics contribute to chemosensitization by nitroimidazoles in mice, and that altered pharmacokinetics also occur in man. The present results provide strong evidence that the mechanism involves binding to liver microsomal cytochrome P-450, leading to inhibition of CCNU metabolism.

Animals↗
PubMed1986

Cross-link formation and chemopotentiation of EMT-6/Ro cells exposed to MISO after CCNU treatment in vitro.

Experiments were designed to measure cross-link formation following combined treatment of EMT-6/Ro tumor cells with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and misonidazole (MISO) in vitro. To avoid MISO-induced glutathione (GSH) depletion, which might contribute to enhanced monoadduct formation by reducing the protective GSH pools, a post-incubation (i.e. treatment with CCNU for one hour in air followed by MISO treatment in hypoxia) protocol was adopted. Utilizing this treatment scheme, it was possible to significantly enhance CCNU toxicity by post-treating with MISO immediately after exposure to CCNU. Enhanced cross-link formation detected by alkaline elution, at this time, correlated well with the magnitude of cell-kill enhancement, thereby implicating enhanced cross-link formation in the mechanism of potentiation. However, if the cells were allowed to incubate for various intervals between CCNU and MISO treatments, the magnitude of potentiation progressively diminished. Beyond approximately 8-10 hours (corresponding to the time required for maximal cross-link formation after CCNU treatment), treatment with MISO was ineffective at potentiating CCNU cytotoxicity. These experiments suggest that chemopotentiation can be produced by treating with MISO after treatment with CCNU (post-incubation) and that enhanced cross-link formation is involved in the mechanism of MISO chemopotentiation of CCNU activity. The kinetic studies, using the post-incubation protocol, further suggest that the chemopotentiating effect of MISO is exerted subsequent to monoadduct formation and probably does not involve inhibition of DNA-DNA cross-link repair.

Animals↗
PubMed1986

A phase II study of CCNU with benznidazole for metastatic malignant melanoma.

The response of 18 patients with metastatic malignant melanoma to the combination of CCNU (130 mg/m2) preceded 3-4 hr earlier by 20 mg/kg of the 2-nitroimidazole benznidazole has been studied. There were four partial and no complete responses in 16 patients evaluable after 1-6 courses. The median response duration was 14 wk (range 5-33) and for static disease 24 wk (range 10-54). Evidence for chemosensitization is equivocal.

Drug Evaluation↗
PubMed1986

Neurologic dysfunction in patients treated for small cell carcinoma of the lung: a clinical and radiological study.

The neurologic dysfunction in 7 patients treated for small cell carcinoma (SCC) of the lung by combination chemotherapy and prophylactic brain irradiation was evaluated. The disease appeared to be a diffuse encephalopathy frequently affecting the higher cortical functions. Five out of seven patients had progressive dysfunction leading to death in 1 to 26 months; one patient had stabilization of symptoms followed by death in 21 months, probably from the neurologic disease as well as SCC; one patient's symptoms improved. The clinical course of the neurologic disorder seemed different from the known reactions to brain irradiation and from the other neurologic syndromes associated with lung cancer. The relative contributions of cranial irradiation and treatment with chemotherapeutic agents in producing the neurotoxicity are not known. Computed tomographic (CT) brain scans done after the onset of symptoms did not show any focal signs or necrosis. However, there was a suggestion of progressive increase in intracranial fluid volume on the scans. The incidence of the disorder, 10.2% among a group of 49 patients, suggests the need for prospective studies to evaluate the problem.

Adult↗
PubMed1988

Combined modality treatment of localized unresectable adenocarcinoma of the pancreas.

Since 1978, 86 patients with unresectable localized adenocarcinoma of the pancreas have been treated with a combined modality program using radioactive iodine 125-Implantation, external beam radiation, and systemic chemotherapy. Three treatment approaches were used with sequential modifications of the technique based on the course of disease and patterns of failure. Group 1 was comprised of 13 patients treated with a combination of implantation followed by a planned external radiation dose of 5000 to 6000 cGy delivered in 6 weeks. Group 2 included patients treated as in Group 1 followed by adjuvant chemotherapy. The most recent group of 54 patients, Group 3, has been treated since 1981 with implantation into the tumor of radioactive Iodine 125 seeds (12000 cGy minimal peripheral dose), perioperative chemotherapy (5-FU, Mito-C), and external beam irradiation (5000-5500 cGy) followed by further chemotherapy. Incidence of perioperative mortality has been reduced from 31% (10/32) in Groups 1 & 2 to 7% (4/54) in Group 3. Clinical local control of tumor has been excellent in all three groups (84%). Analysis of the Group 3 results indicate that the problem of distant metastasis, in spite of adjuvant chemotherapy, still remains overwhelming (64%)--especially to the liver--and requires development of more effective regimens. Median survival in the three groups of patients is 5.5, 11.3, and 12.5 months. The 2-year survival is 0, 15, and 22%, retrospectively in the three groups.

Adenocarcinoma↗
PubMed1988

Potentiation of combination chemotherapy by nitroheterocyclics.

The effect of including a nitroimidazole in a treatment regimen combining two alkylating chemotherapeutic agents was evaluated in a mouse tumor model. KHT sarcoma-bearing female C3H/HeJ mice were treated with a single dose of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) either alone or in combination with the radiosensitizer misonidazole (MISO) prior to a range of cyclophosphamide (CY) doses. CCNU (5 mg/kg) preceded CY treatment by 3 hr. MISO (1 mmol/kg) was given 1 hr after CCNU (2 hr prior to CY). Tumor response was assessed using either an in vitro to in vivo clonogenic cell survival assay 22-24 hr after treatment or an in situ delay of tumor regrowth assay. The results demonstrated that the inclusion of MISO at a dose of 1.0 mmol/kg increased tumor cell kill resulting from the combination of CCNU-CY by a factor of 1.4-1.5 compared to that seen in the absence of the nitroimidazole. Normal tissue toxicity resulting from the CCNU-CY or CCNU-MISO-CY combinations was determined by measuring bone marrow stem cell (CFU-S or CFU-GM) toxicity. Compared to CCNU-CY alone, the addition of MISO did not enhance this normal tissue toxicity. These findings indicate that the inclusion of MISO in a combination chemotherapy protocol may yield a significant therapeutic benefit.

Animals↗
PubMed1988

Effects of changes in oxygen tension, pH, and glucose concentration on the response to CCNU of EMT6 mouse tumor monolayer cells and multicellular spheroids.

We have studied the effect of individually changing medium glucose content, pH and oxygen tension upon the response to CCNU (1-(2-chloroethyl)3-cyclohexyl-1-nitrosourea) of EMT6/Ca/VJAC cells grown as early plateau phase monolayer cultures or small (200 microns diameter) spheroids. The effect of changing all three factors together has also been studied in the spheroid model. All the changes in medium conditions (except for 4 hr hypoxia) were maintained for 24 hr prior to drug exposure. Plating efficiency (PE) of monolayer cells was decreased by reduced medium pH (below 6.5) or oxygen tension while no change in PE was brought about by reduced medium glucose content. In small spheroids reduction in PE caused by low pH was similar to that seen in monolayer, there was again no effect of reduced glucose, and the effect of hypoxia was clearly less than in monolayer. Combination treatment of spheroids (pH 6.5, 120 mg/l glucose and hypoxia) reduced the PE of spheroid cells to 50% of control. Reducing medium glucose content from 920 to 0 mg/l, or oxygen tension from 20% to near zero (for either 4 or 24 hr) reduced the sensitivity of monolayer cells to CCNU. A similar pattern was seen for reducing medium pH from 7.2 to 6.1 during the 24 hr pre-incubation period and 1 hr drug exposure period. A reverse trend was, however, seen if medium pH during the drug exposure period was maintained at 7.2 following reduced pH pre-incubation. Reduced sensitivity to CCNU was seen for cells within small spheroids pre-incubated in medium at low pH (for both schedules) or under hypoxia (for either 4 or 24 hr) whereas reduced medium glucose content appeared to have no such effect. Cells in small spheroids after 24 hr combination treatment were also less sensitive to CCNU than cells from control spheroids.

Anaerobiosis↗
PubMed1989

A randomized study of CCNU with and without benznidazole in the treatment of recurrent grades 3 and 4 astrocytoma. Report to the Medical Research Council by the Brain Tumor Working Party.

In a randomized, double-blind study, 44 patients with recurrent high grade malignant glioma were allocated to chemotherapy of CCNU, with or without benznidazole (BENZO). Of 42 eligible patients, 23 received CCNU alone, and 19 CCNU received BENZO. Only 8 patients received the full 6 courses of treatment. The mean number of courses given was 2.8 for placebo and 3.4 for benznidazole patients. Progressive disease caused termination of treatment early for the majority of patients. There was no evidence of increased toxicity-leucopenia, anemia or thrombocytopenia-in the BENZO group, and only one patient in each treatment group had chemotherapy terminated because of toxicity. The BENZO group did not demonstrate any survival advantage: median survival time was 25 weeks in the BENZO group and 30 weeks in the placebo group. The confidence interval for the treatment difference is wide but excludes a BENZO-related addition of more than 7 months to the median survival time.

Adolescent↗
PubMed1989

The chemosensitizing and cytotoxic effects of RSU 1164 and RSU 1165 in a murine tumor model.

RSU 1069, the lead compound in a series of nitroimidazoles containing an alkylating aziridine function, has been shown to be a potent radiosensitizer and chemopotentiator both in vitro and in vivo. However, this agent also demonstrates significant in situ toxicity. Recently it has been shown that less toxic analogues of RSU 1069 can be produced by the introduction of alkyl substituents to moderate the reactivity of the aziridine function. The present investigations were undertaken to evaluate the in vivo cytotoxicity and chemosensitizing efficacy of two such analogues, RSU 1164 and RSU 1165. All experiments were performed with KHT sarcomas grown intra-muscularly. In the cytotoxicity studies, a range of sensitizer doses was utilized whereas in the chemopotentiation investigations a fixed sensitizer exposure was combined simultaneously with a range of doses of the nitrosourea CCNU. In both studies, tumor cell survival was determined 22-24 hr after treatment using a soft agar clonogenic assay. Normal tissue toxicity in the chemopotentiation studies was assessed by bone marrow CFU-S assay. Both analogues were found to be significantly less cytotoxic to KHT sarcoma cells than RSU 1169 (a factor of 4-6 in dose at 50% cell survival). Combining a 1.0 to 2.0 mmol/kg dose of RSU 1164 or RSU 1165 with a range of doses of CCNU increased tumor cell killing by a factor of 1.5-1.6 but did not enhance bone marrow stem cell toxicity. The addition of either sensitizer to CCNU treatment therefore led to a significant therapeutic benefit.

Animals↗
PubMed1990

Chemosensitization of the nitrosoureas by 2-nitroimidazoles in the subcutaneous 9L tumor model: pharmacokinetic and structure-activity considerations.

Alterations of the pharmacokinetics and cytotoxic effects of the nitrosoureas, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-(cyclohexyl)-1-nitrosourea (CCNU) by the 2-nitroimidazoles, misonidazole (MISO) and SR-2508 were investigated using the subcutaneous (sc) 9L tumor model in male Fisher 344 rats. When 50 mg/kg of CCNU was given i.p., the peak plasma concentration of CCNU was about 3 micrograms/ml. CCNU was eliminated with biphasic kinetics that had a terminal half-time (T1/2) of approximately 47 min. When 2.5 mmole/kg of MISO was given i.p. 150 min before CCNU, the peak plasma concentration of CCNU was increased by approximately 63% with no change in the elimination kinetics. Clamping did not change the pharmacokinetics of CCNU in either plasma or tumors. MISO pretreatment increased the peak CCNU concentration in unclamped tumors by 3-fold, but had no effect on the CCNU pharmacokinetics in clamped tumors. With the exception of a decrease in the peak BCNU concentration in tumors similar to that observed with MISO, SR-2508 (3.75 mmole/kg, i.p.) did not change the pharmacokinetics of BCNU or CCNU in plasma and tumors. CCNU had no effect on the MISO concentration in plasma and unclamped tumors. However, in the clamped tumors, CCNU delayed the return of the MISO concentration to the unclamped tumor level by about an additional 60 min after the clamp was released. SR-2508 was eliminated from the plasma with biphasic kinetics having an initial and terminal T1/2 of approximately 11 and approximately 76 min, respectively. SR-2508 reached a peak tumor concentration of about 500 micrograms/ml in 30 min. The elimination T1/2 for SR-2508 in unclamped and clamped tumors was approximately 81 and approximately 42 min, respectively. When the clamp was released, the SR-2508 concentration returned to the level found in the unclamped tumors approximately 90 min after it reached its nadir; BCNU and CCNU had no effect on the kinetics of this process. MISO significantly potentiated the cytotoxicity of BCNU in clamped tumors at surviving fractions less than or equal to 0.5. MISO did not potentiate the cytotoxicity of CCNU until the surviving fraction reached 0.05. SR-2508 did not potentiate the cytotoxicity of either BCNU or CCNU.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Evaluation of bromodeoxyuridine in glioblastoma multiforme: a Northern California Cancer Center Phase II study.

In a study activated in 1983 and closed in 1987, the Brain Tumor Research Center of the University of California and the Northern California Cancer Center evaluated the effect of bromodeoxyuridine in the treatment of glioblastoma multiforme. A total of 160 patients were evaluable of 173 entered. Patients were to receive a bromodeoxyuridine infusion of 0.8 g/m2 daily over 24 hours for 4 days of each of 6 weeks of radiotherapy directed to the tumor plus a margin delivering a total of 60 Gy. Eligibility requirements included Karnofsky performance status greater than or equal to 70, biopsy or resection and central pathology review by one of the authors. Following radiotherapy patients were to receive chemotherapy with procarbazine, CCNU, and vincristine for 1 year. Median survival was 55.7 weeks and time to failure, 34.5 weeks for the evaluable group of 160 patients. In a univariate analysis the variables that influence survival and time to failure were: age, Karnofsky performance status, bromodeoxyuridine dose and the delivery of at least one procarbazine, CCNU, and vincristine cycle following radiotherapy. In multivariate analysis, age, Karnofsky performance status, and bromodeoxyuridine dose remain significant for time to failure; age and Karnofsky performance status remain significant for survival.

Adult↗
PubMed1992

Long-term results of combined modality treatment with I-125 implantation for carcinoma of the pancreas.

From 1981 to 1987, 81 patients with localized, unresectable carcinoma of the pancreas were treated at Thomas Jefferson University Hospital with a combination of intraoperative Iodine-125 implantation, external beam radiation, and peri-operative systemic chemotherapy. Fifty patients had Stage II disease and 31 patients had Stage III disease. Radioactive Iodine-125 seeds were implanted intraoperatively into the tumor to deliver a minimum peripheral dose of 12,000 cGy over one year. This was followed by external beam radiation (50-55 Gy) and systemic chemotherapy (5-FU, Mitomycin-C +/- CCNU). Incidence of peri-operative mortality was 5% (4/81). Early morbidity was observed in 34% of patients and late complications in 32%. A median survival of 12 months and 2- and 5-year survival rates of 21% and 7% were observed. The determinate 2- and 5-year survival rates were 28% and 13%, respectively. The overall 2- and 5-year survival rates with Stage II disease were 27% and 8% and for Stage III disease, 13% and 3%, respectively (p less than 0.05). The determinate 2- and 5-year survival rates were 34% and 19% for Stage II and 19% and 5% for Stage III disease, respectively (p = 0.08). Local control of disease was achieved in 71% of patients. This combined modality approach appears to have achieved satisfactory local control of primary cancer and long term survival of selected patients.

Adenocarcinoma↗
PubMed1994

In vitro cytotoxicity and chemosensitizing activity of the dual function nitroimidazole RB 6145.

PURPOSE: To determine the cytotoxicity and chemosensitizing potential of RG 6145 in mouse KHT/iv and human A549 tumor cells. METHODS AND MATERIALS: RSU 1069, the lead compound in a series of nitroimidazoles containing an alkylating aziridine function, has been shown to possess a high degree of selective cytotoxicity for hypoxic cells in addition to being a potent sensitizer of radiation and chemotherapy. Unfortunately, preliminary clinical studies have revealed a dose-limiting gastrointestinal toxicity for RSU 1069. Recently RB 6145, the ring-opened analogue of RSU 1069, has been found to be less emetic than RSU 1069. In the present studies, we assessed both the differential hypoxic cell cytotoxicity of RB 6145 and its chemosensitizing potential when combined concomitantly with variable doses of the activated form of cyclophosphamide (4-hydroperoxy-cyclophosphamide, 4-OOH-CP) or the nitrosourea CCNU. RESULTS: As we had observed previously for RSU 1069, RB 6145 was found to be less cytotoxic to human than rodent tumor cells. In addition, the degree of selective cytotoxicity toward hypoxic cells was (a) less in A549 than in KHT/iv cells (factor of 9 vs. 80) but (b) comparable to that seen with RSU 1069. For both cell lines, inclusion of the sensitizer enhanced the cell killing of the chemotherapeutic agent 4-OOH-CP by a factor of approximately 1.5-1.7-fold. When combined with CCNU, RB 6145 increased the killing of A549 cells approximately 1.8-fold. Similar hypoxic cell preferential cytotoxicity and enhancement in anti-tumor treatment efficacy were seen when A549 cells were exposed to the R enantiomer of RB 6145 (PD 144872) either alone or in combination with CCNU. CONCLUSION: These data support the notion that further consideration should be given to the clinical application of these bioreductive agents.

Animals↗