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At least 415 records · Page 23Linked to original sources
PubMed1982

5-Fluorouracil, 1,3-bis(2-chloroethyl)-1-nitrosourea, and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea: effect on the human granulopoietic system.

The reaction pattern of the normal (nonleukemic) human granulopoietic system to single-agent treatment with 5-fluorouracil (FUra) and to a combination of FUra with two nitrosoureas, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU), was studied serially by morphologic and in vitro culture methods. The granulopoietic toxicity of FUra was acute and rapidly (by day 21) reversible. In contrast, the toxicity of the combination regimens was long lasting. Evidence exists that an early toxicity (that of FUra) and a delayed toxicity (that of the nitrosourea) were overlapping. Toxicity of BCNU and MeCCNU was most pronounced at the level of in vitro colony-forming units of the granulopoietic system (G-CFUc). G-CFUc compartments of bone marrow and peripheral blood continued to be reduced in size at the time of recovery of the peripheral blood granulocyte count from nitrosourea-induced toxicity. This finding may be responsible for the cumulative toxicity to the human hematopoietic system that frequently has been observed after repeated administration of nitrosourea compounds.

Adult↗
PubMed1980

Randomized trial of chlorpromazine, caffeine, and methyl-CCNU in disseminated melanoma.

One hundred and fifty-seven evaluable patients with advanced metastatic malignant melanoma were randomly assigned to receive either methyl-CCNU (MeCCNU) (200 mg/m2 orally every 6 weeks) (82 patients) or a combination of MeCCNU, chlorpromazine (50 mg/m2 im), and caffeine (600 mg/m2 sc) in the periumbilical area (75 patients). The response rate was 12% for the combination (three complete responses and six partial responses) and 11% for MeCCNU alone (two complete responses and seven partial responses). The median survival was 20 weeks and was the same for both treatments. The data support the hypothesis that caffeine and chlorpromazine do not enhance MeCCNU activity in malignant melanoma, unlike the marked enhancement seen for this drug combination in L1210 leukemia in mice.

Caffeine↗
PubMed1980

Comparison of two combination chemotherapy regimens for multiple myeloma: methyl-CCNU, cyclophosphamide, and prednisone versus melphalan and prednisone.

Of 139 evaluable and previously untreated patients with multiple myeloma, 67 received methyl-CCNU-cyclophosphamide-prednisone (group A) and 72 received melphalan-prednisone (group B); 48% and 33% respectively had good responses and the overall response rates (good plus partial) were 75% and 65% for groups A and B respectively. The survival curves for both groups of patients were similar, with a median survival of 32 months. At 36 months, 70% of those patients who obtained good response were alive, 29% of those with partial response were alive, and 13% of those with no response were alive. The clinical staging system described by Durie and Salmon shows a good prognosis for stage I patients, with 80% remaining alive at 48 months, while the survival curves for stage II and III patients were similar, with 33% and 28% respectively remaining alive at 48 months. The combination of methyl-CCNU-cyclophosphamide-prednisone is not more effective in terms of response rate or duration of survival than melphalan-prednisone.

Adult↗
PubMedDate not supplied

Survival response of malignant gliomas to radiotherapy with or without BCNU or methyl-CCNU chemotherapy at the University of Kentucky Medical Center.

A total of 115 patients were randomly assigned to one of six therapeutic groups within 3 weeks from craniotomy as part of the Brain Tumor Study Group protocols. In category A (surgery without radiotherapy) there was no significant difference in survival between supportive care only and chemotherapy (BCNU or methyl-CCNU) groups. More than one half of patients in this category died within 6 months of surgery. In category B the addition of 6000 rad of whole-brain radiation treatment to the surgery increased survival time significantly: the 6-month survival rate was two to three times that observed in category A. More than 50% of patients were alive at 1 year and at least 20% survived 2 years. The best survival rate in this study was obtained in patients who received methyl-CCNU with irradiation. The duration of survival was increased to nearly two times that of the radiotherapy group and to six times that of the surgery only group. Reasons for this are discussed.

Adolescent↗
PubMed1981

Multi-drug chemotherapy with and without radiation for carcinoma of the stomach and pancreas: a prospective randomized trial.

A prospectively randomized trial in advanced gastric and pancreatic carcinoma compared multi-drug chemotherapy, with and without radiotherapy to the local lesion, in terms of median survival and toxicity. Of 29 patients with gastric adenocarcinoma, 14 were randomized to receive 5-FU and Methyl-CCNU, and 15 to receive 5-FU and local radiotherapy to a dose of 4600 rad, and then Methyl-CCNU. Thirty patients with advanced adenocarcinoma of the pancreas were similarly randomized. There was no significant difference between the two arms of the gastric or pancreatic adenocarcinoma groups, with a median survival of 13 months and 11.5 months respectively in gastric carcinoma, and 7.8 months and 7.3 months in pancreatic carcinoma. Complications were minimal in both groups. There was more hematopoietic depression in the radiation-treated patients, but none had radiotherapy discontinued because of toxicity.

Adenocarcinoma↗
PubMed1982

Quantitative dose-response relations for the cytotoxic activity of chloroethylnitrosoureas in cell culture.

A dose-response relation for the cytotoxic activity of chloroethylnitrosourea cancer chemotherapeutic agents in cell culture has been developed. Data for the activity of 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea, and 1-(2-chloroethyl)-3-(piperidine-3,6-dion-3-yl)-1-nitrosourea against 9L rat brain tumor cells are presented. Cytotoxicity resulting from treatment schedules at different initial drug concentrations, exposure periods, and preincubation periods are correlated using a proposed dose function. Equations are presented that incorporate drug concentration, duration of exposure of cells, and the rate constant for conversion of the drug from an active intermediate into a single dose function. When compared in this way, all cell treatment schedules used were found to be equally effective in killing cells in culture. The cytotoxic activity of the four different chloroethyl-nitrosourea analogs were also found to be the same. These data demonstrate the application of quantitative dose-response relations to the activity of chloroethylnitrosoureas in cell culture and provide new insight into the mechanism of action and structure-activity relationships of these compounds.

Animals↗
PubMed1982

Effect of scheduling of combinations of 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea on the Harding-Passey and Cloudman S91 mouse melanomas.

Harding-Passey mouse melanoma (HP) cells (10(6)) were administered i.p. to female BALB/c x DBA/2 F1 (hereafter called CD2F1) mice on Day 0. We showed earlier (H. Z. Hill, et al., Arch Surg., 114: 135-138, 1979) that a single dose of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) administered on Day 0 or on subsequent days was equally effective regardless of the day of administration. We now show that a single dose of 10 mg of 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU) per kg was most effective in prolonging survival of HP-bearing CD2F1 mice when administered on Day 0. There was then a decline in effectiveness to Day 10, at which time the increase in survival of the drug-treated animals was no longer significant. The effect of sequential scheduling of DTIC and MeCCNU on HP was studied. The first drug was given on Day 0 or on Day 10. The second drug followed on the same day or on subsequent days. The greatest enhancement of survival was seen when DTIC was administered on Day 0 and MeCCNU on Day 1. Nine of 10 mice on this schedule were cured. When treatment of HP was started on Day 10, the most enhancement was again seen for DTIC on Day 10 and MeCCNU on the next day. Reversal of the order of the two drugs produced less prolongation of survival and fewer cures. The effect of scheduling two doses of DTIC was also studied using the HP model. The first dose was given on Day 0 or on Day 10. The second dose produced the greatest enhancement of survival when administered 3 to 4 days after the first dose, but the enhancement was less than that seen when DTIC was followed by MeCCNU. For comparison, the two drugs were also studied in female DBA/2 mice carrying the Cloudman S91 melanoma. In combination, on Day 0, in only one of three experiments was survival prolonged beyond the controls. Other schedules were ineffective. The enhancement seen when HP-bearing CD2F1 mice are treated with the best combination of the two drugs is clearly not seen with S91. The results imply that dosage scheduling in the treatment of murine melanomas must be individualized. Extrapolation to the human situation suggests the same conclusion.

Animals↗
PubMed1978

Treatment of advanced colorectal cancer with methyl-CCNU plus 5-day 5-fluorouracil infusion.

Thirty-six patients with advanced colorectal carcinoma who had not received prior chemotherapy and had tumor sites measurable or evaluable for response received methyl-CCNU at a dose of 175 mg/m2 orally on Day 1 plus 5-fluorouracil at a dose of 30 mg/kg/24 hours by continuous iv infusion for 120 hours (Days 1-5). Doses were chosen to approach the maximum which could be administered in combination. The cycle was repeated 6 weeks later. Objective partial responses occurred in six patients (17%), with five responses apparent after the first cycle and one additional response after the second cycle. The response duration ranged from 1.5 to 18+ months (median, 5 months). Dose-limiting toxic effects included mucositis in 18 patients (50%) and dermatitis in nine patients (25%), while leukopenia (less than 4000 cells/mm3) and thrombocytopenia (less than 100,000 platelets/mm3) were observed on at least one occasion during therapy in 52% and 46% of patients, respectively. 5-Fluorouracil administration by infusion avoided overlapping myelosuppression and allowed a higher total dose to be given with methyl-CCNU. However, the response to the combination did not exceed the results anticipated for the use of either drug alone.

Adult↗
PubMed1982

Use of the agar diffusion chamber for the exposure of human tumor cells to drugs.

Human melanoma xenografts in immune-deprived mice have been used to assess the value of the agar diffusion chamber for chemosensitivity testing. Tumor cells were treated with melphalan, Adriamycin, or methyl trans-1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea either as solid tumors growing in mice or as suspensions in agar in i.p. diffusion chambers. Survival of clonogenic human tumor cells was measured by the agar diffusion chamber assay in both cases. Cell survival curves were log-linear for treatment of tumor cells in vivo or in the chambers. For melphalan the slopes of survival curves were significantly greater for treatment in the chambers than as solid tumors in vivo, but for methyl trans-1-(2-chloroethyl(-3-(4-methylcyclohexyl)-1-nitrosourea or Adriamycin, they were indistinguishable. Experiments with [14C]melphalan showed that the levels of drug achieved were less inside the diffusion chambers than in the tumors in vivo so that the sensitivity of tumor cells to melphalan was much greater when they were treated in chambers. The differences in drug exposure and in cellular chemosensitivity between chambers and tumors suggest caution in the interpretation of drug testing using this system, but the log-linear nature of the dose-response curves is an important feature which may be useful in the eventual development of optimal chemosensitivity testing systems.

Agar↗
PubMed1982

Combined actions of 5-fluorouracil and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea on human colonic carcinoma cells in vitro.

Two lines of human colonic carcinoma cells have different sensitivities to 5-fluorouracil and 1-(2-chlorethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (methyl-CCNU). The growth of the BE line is 50% inhibited by 330 microM 5-fluorouracil and 15 microM methyl-CCNU, and the HT-29 line is 50% inhibited by 85 and 140 microM, respectively. On cloning, 50% of BE cells are killed by 500 microM 5-fluorouracil and 6 microM methyl-CCNU, and the HT-29 cells are killed by 250 and 120 microM respectively. When the drugs were combined, there were additive effects which occurred in cell growth of both lines and killing of BE cells. Synergism occurred in killing HT-29 cells when a low concentration of 5-fluorouracil was combined with methyl-CCNU. The synergism did not increase with increasing concentrations of 5-fluorouracil. Both drugs caused growth delay of spheroids (HT-29 cells), an effect that was additive when the drugs were combined. Growth inhibition of both lines in monolayer culture by 5-fluorouracil was more sensitive than was cell killing or inhibition of spheroid growth but, with methyl-CCNU, killing of BE cells was more sensitive than was growth inhibition. HT-29 cells showed similar sensitivity to methyl-CCNU in all three systems. The type and sensitivity of drug effect seen in vitro depends on the particular drug used, the cell line tested, and the parameter measured.

Cell Division↗
PubMed1982

[Enhancement of MeCCNU potency (chemosensitization) by misonidazole in a human melanoma xenograft system].

In addition to the well-known radiosensitizing properties of misonidazole its potential for chemosensitization has been investigated recently. According to results obtained mostly with conventional murine tumor systems, the degree of such chemosensitization depends on the particular tumor system, the type of antineoplastic agent and the dose of misonidazole employed. Our experiments were conducted with a human melanoma transplanted onto (nu/nu) mice. At the dose level of 1 g/kg misonidazole toxicity was enhanced by a factor of about 3, whereas antineoplastic activity was enhanced only by a factor of about 1.8. Therefore, the usefulness of such chemosensitization remains limited, especially since under clinical circumstances this dose of misonidazole would cause unacceptable neurotoxicity. The retention of radiotivity from 14C-MeCCNU is increased in neoplastic as well as in normal tissues by a factor of 1.3.DNA interstrand crosslinks measured 24 hours after drug exposure, however, are increased by a factor of about 2. Despite their nonselective reaction at the level of molecular pharmacology, drugs with sensitizing or protective properties may well constitute a valuable addition to the serial synthesis of chemical congeners in drug development. The use of oxazaphosphorines is quoted as an example where selective protection from urotoxicity is afforded by sodium-2-mercaptoethanesulfonate.

Animals↗
PubMed1981

[Combination chemotherapy of transplanted rat leukemia L 5222 with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and cyclophosphamide (CPA) as well as with methyl-CCNU and CPA (author's transl)].

The acute transplanted rat leukemia L 5222 was used to investigate the two-drug combinations 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and cyclophosphamide (CPA) as well as methyl-CCNU and CPA. A therapeutic synergism could not be demonstrated in either combination. In both combinations the monotherapy with the nitrosourea was superior to the combination as well as to the monotherapy with CPA.

Animals↗
PubMed1981

Immunotherapy of L1210 leukemia using neuraminidase-modified plasma membranes combined with chemotherapy.

Purified L1210 plasma membranes treated with Vibrio cholerae neuraminidase (VCN) were used for active immunotherapy of L1210 tumors in DBA/2J mice. Immunotherapy with VCN-treated membranes was effective only when combined with 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU). Successful therapy was a function of the dose of MeCCNU, the dose of VCN-treated membranes, and the time after MeCCNU treatment when VCN-treated membranes were administered. Optimum conditions for treating animals with tumors initiated with 10(4) cells were MeCCNU (20/kg) given 3 days after tumor inoculation and 0.25 mg VCN-treated membranes given 1 day after chemotherapy. Control membranes, not treated with VCN, that were administered 1 day after MeCCNU were ineffective; when given 4 days after chemotherapy, the caused accelerated mortality, suggesting immunological enhancement of tumor growth. Our results indicate that VCN-treated plasma membranes can be used for active immunotherapy of established tumors and underscore the importance of carefully designing immunotherapy protocols to achieve optimum desirable effects.

Animals↗