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At least 343 records · Page 19Linked to original sources
PubMed1988

Treatment-induced changes in sensitivity in a multiclonal human tumor mixture model in vitro.

An in vitro model has been devised so that mixtures of human tumor cells can be grown together for studies related to drug-induced or -selected changes in sensitivity. In the studies reported here, two human astrocytoma clones, one sensitive and one resistant to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU), were carefully matched for doubling times, cell cycle phase distributions, and colony-forming efficiencies. The clones were mixed and grown together, and after only three weekly treatments with MeCCNU (10 micrograms/ml for 1 h each week) the sensitive cells in the mixture were killed, leaving behind a population that was almost 100% resistant to further exposures to MeCCNU. The loss of the sensitive cells from the mixture each week was easily detected by visual observation of flow microfluorometry histograms since the clones had different DNA indices. Repeated weekly exposures of the unmixed resistant clone (AST 1-1) to MeCCNU caused very little accumulated cell kill. Similar exposures of the unmixed sensitive clone (AST 3-4) produced a linear decrease in survival over the first three weekly treatments with 10 micrograms MeCCNU/ml, but after that time these cells became progressively more resistant to MeCCNU. It is unlikely that the change to resistance in the AST 3-4 clone occurred because of contamination with the resistant AST 1-1 cells, because their DNA index remained stable. These data show that repeated treatments with a single agent can cause a tumor cell population to become more resistant. It remains to be tested whether this resistance was the result of cellular interactions, drug-induced changes in sensitivity, or selection for resistant cells already present in the populations. This mixture model may be useful in studies on how cellular interactions influence growth and drug sensitivity in tumor and normal cell populations.

Astrocytoma↗
PubMedDate not supplied

The effect of high doses of methyl-CCNU on male and female fertility in SJL/J mice.

Single IP injection of high dose (LD 10) of methyl-CCNU administered to sexually mature male mice resulted in severe inhibition of spermatogenesis and reduction in testicular wet weight, without significant changes in plasma testosterone levels, and with hyperplasia of the interstitum, including Leydig cells, in the testis. These effects were temporary, spermatogenesis and testiculer weight recovered 50 days after treatment. Mating of the treated males with normal females demonstrated absolute sterility at 20 days and full recovery at 50 days after treatment. Administration of a single lethal dose (38 mg/kg, LD70) of methyl-CCNU to immature (25 day-old) male mice also caused severe but temporary inhibition of spermatogenesis, and mating of mice which survived the treatment and reached sexual maturity, with normal females, resulted in 80 to 100% pregnancies at 40 and 70 days after treatment, respectively. Three repeated injections of 30 mg/kg (at 10 day intervals) of methyl-CCNU to 15 day-old male mice resulted in inhibition of spermatogenesis without alteration in plasma testosterone. Ninety days after this treatment, only 40% of matings with normal females resulted in pregnancies. Female mice treated once with 20 mg/kg of methyl-CCNU, 3 days before or 7 days after mating with normal males, showed complete failure to complete pregnancy-resorption of the embryos was demonstrated in those female mice treated 7 days after mating. After a second mating trial with these two treated groups, performed 40 to 55 and 42 days after the first trial, respectively, 80 and 86% of the females delivered offspring. However, average litter size was reduced to 4 in the second group, as compared to 8 in untreated mice. There were no apparent birth defects in the offspring of methyl-CCNU treated male or female mice.

Animals↗
PubMed1978

Simultaneous assay by six methods of the effect on haemopoietic precursor cells of adriamycin, methyl CCNU, 60Co gamma-rays, vinblastine, and cytosine arabinoside.

The spleen colony assay, three agar colony assays and two repopulating assays have been employed to measure the effect of single doses of adriamycin, methyl CCNU, 60CO gamma-rays, vinblastine and repeated injection of cytosine arabinoside on early haemopoietic precursors. The results show that there is no consistent correlation between the effect of these agents on the six assays, and the differences in proliferation rate of the cells contributing to the various assays could not be demonstrated by the phase specific agents vinblastine and cytosine arabinoside. The relatively high survival of granulocyte repopulating ability after adriamycin and methyl CCNU indicates that the capacity for differentiation and maturation can be influenced by cytotoxic agents so that colony assays while estimating the number of progenitor cells surviving do not necessarily provide a reliable guide to the capacity of the cells for restoring haemopoiesis. Comparison of colony formation by normal bone marrow cells with the three agar colony assays showed that the agar diffusion chamber method gave three times as many colonies and a much smaller variation between experiments compared to the in vitro agar assay with endotoxin mouse serum as colony stimulating factor. The thin layer feeder cell method gave an intermediate number of colonies.

Animals↗
PubMed1978

Phase II trial of ftorafur with mitomycin C versus ftorafur with methyl-CCNU in untreated colorectal cancer.

In an attempt to substitute ftorafur for burdensome 5-fluorouracil (5-FU) infusions, 52 previously untreated patients were randomized to receive ftorafur with either mitomycin C or methyl-CCNU. Ftorafur was administered monthly as a 2-hour infusion daily x 5 days. Mitomycin C and methyl-CCNU were repeated every 8 weeks. A response rate of 27% (seven responses among 26 patients) was demonstrated on the mitomycin C arm compared to a response rate of 15% (four responses among 26 patients) on the methyl-CCNU arm (P = 0.25). There was no significant difference in the median survival between treatment arms. Central nervous system toxicity occurred in greater than 30% of the patients and appeared to be the limiting factor with ftorafur administration. Alternate schedules of ftorafur should be explored since there appears to be little advantage of a daily ftorafur schedule over conventional 5-FU infusions.

Adenocarcinoma↗
PubMed1978

Phase II study of vinblastine, methyl-CCNU, and medroxyprogesterone in advanced renal cell cancer.

One hundred and sixty-five patients with advanced renal cell cancer were evaluable for combination or single-agent therapy with methyl-CCNU, vinblastine, and medroxyprogesterone. A low order or response was observed, and these agents were not proven effective as treatment for metastatic renal cell cancer. Performance status and a relatively long symptom-free interval from primary tumor to metastatic disease were found to be the most prognostically significant factors for survival.

Adenocarcinoma↗
PubMed1978

5-fluorouracil, methyl-CCNU, adriamycin, and mitomycin C in the treatment of advanced gastric cancer.

Eighteen previously untreated patients with advanced nonresectable adenocarcinoma of the stomach were treated with a four-drug regimen consisting of 5-fluorouracil, methyl-CCNU, adriamycin, and mitomycin C. Objective responses occurred in only two patients (11%); the majority of patients had stable disease for greater than or equal to 8 weeks (61%). The median survival of 27 weeks was similar to that reported in other combination chemotherapy trials. Numerous staging and restaging procedures and strict response criteria were utilized and each was evaluated for its effectiveness in following responses. None of these parameters was useful for evaluating response of intra-abdominal tumor. We conclude that this four-drug combination is no better than previously described two-drug regimens.

Adenocarcinoma↗
PubMed1986

Drug sensitivity of methylnitrosourea- and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea-resistant L1210 lines.

Drug sensitivity of methylnitrosourea (MNU)- and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU)-resistant L1210 lines have been compared. In the production of the MeCCNU-resistant line full resistance to MeCCNU was obtained after 15 generations with a gradual increase of the treatment dose. Treatment of L1210 with MNU (40 mg/kg i.p. on days 1, 3, and 5) produced after five or more treatment generations a MNU-resistant subline with reduced tumor growth in the untreated controls. Therapeutic responses of L1210, L1210-MeCCNU and L1210-MNU to MeCCNU, MNU, cyclophosphamide, 2,2'-dichloro-N-methyldiethylamine hydrochloride, 1-beta-D-arabinofuranosylcytosine, methotrexate, and 6-mercaptopurine were compared in both non-and X-irradiated (400 R) mice. The L1210 and L1210-MeCCNU lines reacted similarly except that L1210-MeCCNU was resistant to Me-CCNU and MNU. However, the L1210-MNU line differed greatly from the parent line. The survival times in nonirradiated mice were increased in all except the MNU- and MeCCNU-treated groups, and in irradiated mice they were less than 30 days and only cyclophosphamide and 2,2'-dichloro-N-methyldiethylamine hydrochloride caused long-term survivors. The different behavior of L1210-MNU and L1210-MeCCNU is apparently due to the fact that at maximum tolerated doses the monofunctional alkylating agent MNU is more mutagenic than the bifunctional MeCCNU. Antigenic change and loss of growth potential presumably are the reasons for the different sensitivity of L1210-MNU as indicated by tests in X-irradiated and nude mice. Apparently this host-related sensitivity is not directly related to the development of drug resistance.

Alkylating Agents↗
PubMed1986

Cytogenetic effects of Me-CCNU on sister chromatid exchange frequency, cellular kinetics and chromosome aberrations.

1-(2-Chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (Me-CCNU) was tested for its in vitro effects on sister chromatid exchanges (SCE), cellular kinetics and chromosome aberrations in CHO cells. There was a relationship between the inhibitory activity of the drug and the cytogenetic damage, which was dose dependent. Increase in SCE values were highly significant (p less than 0.001) for all the four concentrations used. It also delayed the cell cycle progression. Inhibition of DNA synthesis results in increased frequency of chromosomal aberrations, which was highly significant for the higher concentrations, i.e. 5 micrograms and 10 micrograms Me-CCNU/ml.

Animals↗
PubMedDate not supplied

Phase II-III chemotherapy studies in advanced gastric cancer. Eastern Cooperative Oncology Group.

In this study, 139 eligible and evaluable patients with advanced gastric cancer, measurable disease, and no prior chemotherapy were randomized between treatment with Adriamycin alone, 5-fluorouracil (5-FU) plus mitomycin C, and 5-FU plus methyl-CCNU. Objective responses were seen in eight of 37 patients (22%) receiving Adriamycin, in 17 of 53 (32%) receiving 5-FU plus mitomycin C, and in 12 of 49 (24%) receiving 5-FU plus methyl-CCNU. Median durations of response were 4, 3 1/2, and 8 1/2 months, respectively. Sixty-one patients were treated after previous failure to other chemotherapy regimens. Response rates were seen in seven of 47 patients (15%) receiving Adriamycin, in two of nine receiving 5-FU plus mitomycin C, and in one of five receiving 5-FU plus methyl-CCNU. Complete responses were observed more frequently with Adriamycin and with 5-FU plus methyl-CCNU than with 5-FU plus mitomycin C. Although 5-FU plus methyl-CCNU had a slight advantage in interval to disease progression, this was not statistically significant. Median survival for all previously untreated patients was slightly greater than 17 weeks, and there was no meaningful or significant survival difference between the three treatment groups.

Adenocarcinoma↗
PubMedDate not supplied

Phase II-III chemotherapy studies in advanced gastric cancer. The Gastrointestinal Tumor Study Group.

In this multi-institutional study of advanced gastric cancer, 141 eligible and evaluable patients were treated with either (a) Adriamycin alone, (b) a combination of 5-fluorouracil, Adriamycin, and methyl-CCNU (FAMe), or (c) a combination of 5-fluorouracil, mitomycin C, and cytosine arabinoside (FMC). In patients with measurable disease and no prior chemotherapy, objective responses were seen in four of 17 patients (24%) receiving Adriamycin alone, in seven of 15 (47%) receiving FAMe, and in three of 18 (17%) receiving FMC. In previously treated patients with measurable disease, objective responses were seen in three of 17 patients (18%) receiving Adriamycin alone and in one of 11 (9%) receiving FMC. In previously untreated patients with both measurable and nonmeasurable disease, FAMe showed a significant advantage over both Adriamycin alone and FMC with regard to interval to disease progression and survival. In comparing Adriamycin alone with FMC in previously treated patients, intervals to disease progression and survival were essentially identical.

Adenocarcinoma↗