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Biomedical subjects

S C Barranco

Publications and source records attributed to S C Barranco.

At least 37 records · Page 2Linked to original sources
PubMed1988

Changes in drug sensitivity of a human astrocytoma clone previously treated with 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea in vitro.

We have shown in earlier studies that repeated weekly exposures of a human astrocytoma clone (AST 3-4) to MeCCNU (10 micrograms/ml for 1 h per week) produced a linear decrease in survival over the first 3 weekly treatments. But, after that time these cells became progressively more resistant to the 10 micrograms/ml concentration of the agent. In the studies reported here we show that these previously treated cells were also less responsive to other doses ranging from 1 to 30 micrograms MeCCNU/ml. This change in sensitivity to MeCCNU was accompanied by collateral changes in response to other agents: resistance to BCNU and Galactitol, increased sensitivity to Adriamycin, and no change to ionizing radiation. These experiments suggest that once repeated treatments with a single agent cause a tumor cell population to become more resistant, sensitivity to other agents may also change unpredictably.

Astrocytoma↗
PubMed1988

Polyamine levels and gastrin receptors in colon cancers.

Polyamines and gastrin receptors (GR) were studied in samples of colon cancer and mucosa from 40 patients and in control mucosa from 11 patients without cancer. Polyamines (i.e., putrescine, spermidine, spermine) are essential for growth and differentiation. The concentration of polyamines is elevated in rapidly proliferating normal tissues and in some cancers. The presence of GR in human colon cancers has been previously reported. The purpose of the present study was twofold: (1) to determine whether polyamine levels are elevated in colon cancers and in adjacent normal colon mucosa compared to colon mucosa from patients without cancer; and (2) to examine the relationship between polyamine levels and GR in colon cancers. Polyamine levels in colon cancers were significantly higher than in the normal colon mucosa from the same patients. The polyamines, spermidine and spermine, were significantly higher in colon mucosa from patients with cancer compared to patients without cancer. Spermidine and the spermidine:spermine ratio, an index of cell proliferation, were increased in colon cancers with GR compared to cancers without GR. There were no significant correlations between polyamine levels and the following: patient age, CEA level, site of cancer, stage, or differentiation. Because polyamine levels are increased in colon mucosa from patients with cancer, measurement of polyamines may detect patients at risk for subsequent development of colon cancer. Increased levels of polyamines in colon cancers with GR is evidence that gastrin may play a trophic role in human colon cancers.

Carcinoma↗
PubMed1988

Mechanisms of the trophic actions of bombesin on the pancreas.

Bombesin has both direct and indirect effects [mediated through release of cholecystokinin (CCK)] on pancreatic secretion. Polyamine biosynthesis, essential for DNA synthesis, is increased in the pancreas after CCK stimulation. The purpose of this study was to examine the trophic effects of bombesin and to determine whether the mechanism of bombesin-induced pancreatic growth is mediated through synthesis of polyamines. The time course of bombesin-stimulated polyamine biosynthesis was defined. Rats were studied in groups of six and received intraperitoneal (i.p.) injections every 8 h of either saline, bombesin (10 micrograms/kg), CR1409 (2.5 mg/kg) (a CCK-receptor antagonist), or both to define the effects on pancreatic growth and polyamine biosynthesis. Rats were killed at 14 days and the pancreas was excised, weighed, and analyzed for protein, RNA, and DNA content. We found that bombesin produced significant pancreatic hyperplasia (increased pancreatic weight, protein, and DNA content) after 14 days. CR1409 inhibited only bombesin-stimulated DNA content. Bombesin stimulated polyamine biosynthesis as early as 2 h after administration of bombesin, but CR1409 had no effect. The trophic actions of bombesin are both direct and indirect (mediated through CCK), and the direct effects of bombesin are mediated by polyamine biosynthesis.

Animals↗
PubMed1987

Effects of cyclosporine and alpha-difluoromethylornithine on the growth of mouse colon cancer in vitro.

The growth and survival of mouse (MC-26) colon carcinoma in vitro and in vivo are significantly reduced by inhibitors of polyamine biosynthesis. alpha-Difluoromethylornithine (DFMO), is a specific and irreversible inhibitor of ornithine decarboxylase (ODC); the rate-limiting enzyme in polyamine biosynthesis. DFMO treatment inhibits the growth of MC-26 colon cancer cells and decreases MC-26 cell survival both in vitro and in vivo. In the present study, we examined the effects of cyclosporine (CsA) on growth, survival, and polyamine levels in MC-26 colon cancer in vitro. CsA had inhibitory effects on MC-26 colon cancer growth which were similar to DFMO; these effects were blocked by the addition of the polyamine, putrescine. The combination of CsA (8.3 X 10(-4) mM) and DFMO (0.5 mM or 1.0 mM) inhibited MC-26 cell survival to a greater extent than either agent alone. These results suggest that CsA given in combination with other agents which inhibit polyamine synthesis may be useful for the treatment of colon cancer.

Adenocarcinoma↗
PubMed1987

Cyclosporine and alpha-difluoromethylornithine exhibit differential effects on colon and pancreatic cancer in vitro.

alpha-Difluoromethylornithine (DFMO) is a known irreversible inhibitor of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis. Cyclosporine (CsA) has been reported to inhibit ODC activity in vitro. In the present study, we compared the effects of DFMO and CsA on growth, survival, and polyamine levels in mouse colon cancer (MC-26) and hamster pancreatic cancer (H2T) cells in vitro. The growth and survival of MC-26 and H2T cells were inhibited by both DFMO and CsA. However, H2T cells were observed to be significantly more sensitive than MC-26 cells to both CsA and DFMO. The inhibitory effects of CsA were blocked by the addition of the polyamine, putrescine, in both MC-26 and H2T cells. Polyamine levels were altered significantly in both MC-26 and H2T cells treated with CsA and DFMO. However, the profile of these alterations differed between MC-26 and H2T cell lines. Putrescine and spermidine levels in MC-26 cells were more sensitive to DFMO inhibition than were H2T cells. Spermine levels were consistently elevated in MC-26 cells exposed to CsA or DFMO, while the level of spermine in H2T cells decreased significantly in response to the same drugs. These results suggest that CsA and DFMO exhibit different effects on colon and pancreatic cancer growth in vitro. In addition, the differences in the sensitivity of pancreatic and colon cancer to CsA and DFMO indicate potentially important differences in polyamine metabolism between the two cell lines.

Animals↗
PubMed1987

Treatment of hamster pancreatic cancer with alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis.

Polyamines are essential for cell division and growth. Inhibition of polyamine biosynthesis by alpha-difluoromethylornithine (DFMO) on the growth of hamster H2T pancreatic cancer was investigated both in vitro and in vivo. Cell-doubling time (TD) and survival fraction were determined after a single treatment with DFMO (5 mM). We examined the ability of putrescine to reverse the growth-inhibitory effect of DFMO. The TD for cells treated with DFMO in vitro was 49.6 +/- 5.7 versus 25.4 +/- 2.6 hours for control. The addition of putrescine to DFMO-treated H2T cells showed a reversal of the growth-inhibitory effect of DFMO. Cytotoxicity in vitro increased with prolonged treatment; the survival fraction after 24 hours of treatment was 32%; after 48 hours, 19%; after 72 hours, 13%; and after 92 hours, 8%. We performed two separate animal experiments. In experiment I, H2T cells were injected into the cheek pouch of male Syrian golden hamsters; controls did not receive DFMO. Continuous treatment with 3% DFMO in the drinking water was begun 7 days before, on the day of, or 7 days after tumor cell injection. In experiment II, 4 groups were treated identically to those in experiment I. An additional group of 10 hamsters received 3% DFMO and no tumor, and another additional group of 10 hamsters were housed individually with 3% DFMO begun 7 days after tumor cell injection. Tumor size, body weight, water, and food intake were measured. DFMO treatment in vivo significantly inhibited tumor size and inhibited growth of pancreatic cancer by as much as 50% of control. Our results demonstrate a significant antiproliferative effect of DFMO on the growth of pancreatic adenocarcinoma both in vitro and in vivo.

Adenocarcinoma↗
PubMed1986

Heterogeneous survival responses of human gastric cancer clones to alpha difluoromethylornithine in vitro.

The effects of alpha Difluoromethylornithine (DFMO)2 on survival of human gastric cancer clones were studied in vitro. The responses were dose and time dependent. Treatments which lasted for less than 12 h were cytotoxic at only the highest doses used. The greatest effects on survival were observed only when cells were treated for 48 and 72 h. The effects on the clones produced by such prolonged treatment durations were heterogeneous, with survival values differing by as much as 460%. By contrast, the clonal survival responses to short DFMO treatments (12 h) were very uniform (dose differential of only 19%); however, this uniformity in response could be achieved only by using non-pharmacological doses of DFMO. The heterogeneity in survival responses in the clones might be slightly associated with their levels of intracellular spermidine. Clones with the smallest amounts of intracellular spermidine at the start of treatment were most sensitive to DFMO. However, this association may not hold up with further testing in other gastric cancer clones or when studied in other cancer lines in vitro.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Cell cycle kinetics responses of human stomach cancer cells to reduction in polyamine levels by treatment with alpha difluoromethylornithine in vitro.

Treatment of human gastric cancer clones in vitro with low doses of DFMO (5 mM) produced elongation of the cell population doubling times and lowering of the saturation densities. By contrast, DFMO treatment of normal human skin fibroblasts altered only the saturation density. The lack of an effect of 5 mM DFMO on the doubling time of normal fibroblasts may be directly related to baseline intracellular putrescine levels, which were about 2.5 times higher than in the cancer cells. The same dose of DFMO caused a rapid decrease in intracellular polyamine levels in the tumor clones. The effects on the doubling time and saturation density were almost totally abolished by the addition of 50 microM putrescine to the growth medium during the first 24 h of treatment with DFMO. Exposure to 5 mM DFMO for 24 h caused the human gastric cancer cells to become blocked in G1 phase only, and this led to a reduction in the fraction of cells in S phase. The G1 block was reversible and this cohort of cells eventually passed through S phase and then through G2 and M. A higher 100 mM dose of DFMO and longer exposure times for both doses produced cell cycle changes and death of more than 90% of the cell population. These data suggest that cell kinetics changes observed under these experimental conditions may reflect polyamine-related alterations in the biochemical events of cell cycle progression kinetics; but may also be the result of DFMO-induced loss of cell viability.

Cell Cycle↗
PubMed1986

Differential response to gamma radiation of human stomach cancer cells in vitro.

In vitro effects of radiation were studied in two permanent cell lines (AGS and SII) from two patients with adenocarcinoma of the stomach and three permanent sublines from each cell line. Radiation survival parameters for AGS and SII parent cell lines and sublines were determined after in vitro irradiation of their cells with 0.5 to 10 Gy of 60Co gamma rays. The AGS and SII cell lines had different growth properties, DNA contents and radiation survival curves. Surviving fractions of SII parent cells (76 chromosomes) after 2.0 and 10 Gy were 1.22 and 17.8 times greater, respectively, than values for AGS parent cells (47 chromosomes). Sensitivities (D0) were 1.08 and 1.45 Gy for AGS and SII parent lines, respectively. The D0 values for AGS parent cells and sublines were similar (1.01 to 1.08 Gy), but SII parent cells and sublines had D0 values of 1.45, 1.36, 1.37 and 1.12 Gy (for SII-A). Also, the SII parent cells had survival fractions after 2.0 and 10 Gy that were 1.3 and 11.3 times greater, respectively, than values for the SII-A cells. These data show differences in radiation responses among stomach cancer cell lines and sublines that may relate to DNA content, but there was no consistent correlation between radiation response and a particular cell characteristic.

Adenocarcinoma↗
PubMed1986

Loss in cell killing effectiveness of anticancer drugs in human gastric cancer clones due to recovery from potentially lethal damage in vitro.

The ability of human gastric cancer clones to recover from potentially lethal damage was studied. Recovery was greatest following treatments with bleomycin or Adriamycin; the recovery ratios (i.e., survival) increased almost 8-fold during a posttreatment incubation period. Recovery was also possible following treatments with actinomycin D, 1,2:5,6-dianhydrogalactitol, and diaziquone; however, the recovery ratios never increased above 2. No recovery was observed following treatment with 5-fluorouracil. Recovery from potentially lethal damage may be related to the heterogeneity in survival responses observed following treatment with some anticancer drugs. Bleomycin and Adriamycin treatments result in large heterogeneous survival fractions among these human stomach cancer clones, and the potentially lethal damage recovery ratios were larger (and variable). However, actinomycin D, diaziquone, and 1,2:5,6-dianhydrogalacticol produce very uniform killing effects in these cells and the recovery ratios are very much smaller and less variable. Finally the large amount of recovery observed after bleomycin or Adriamycin treatments resulted in the loss of cell killing effectiveness of the agents. Because the survival fractions increased during the recovery period, the net effect on cell killing was reduced to an amount normally obtained with doses that were up to six times smaller.

Antineoplastic Agents↗
PubMed1986

Effects of cyclosporin A and alpha-difluoromethylornithine on the growth of hamster pancreatic cancer in vitro.

The growth and survival of hamster H2T pancreatic ductal adenocarcinoma in vitro are known to be significantly reduced by inhibitors of polyamine biosynthesis. alpha-Difluoromethylornithine (alpha-DFMO) is a specific and irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in polyamine biosynthesis. alpha-DFMO treatment inhibits the growth of H2T pancreatic cancer cells and decreases H2T cell survival in vitro and in vivo. In the present study, the effects of cyclosporin A (CsA) were examined on growth, survival, and polyamine levels in H2T pancreatic ductal adenocarcinoma in vitro. CsA had inhibitory effects on H2T pancreatic cancer growth similar to those of alpha-DFMO; these effects were blocked by the addition of the polyamine putrescine. Polyamine levels were found to be significantly altered in cells treated with CsA and/or alpha-DFMO. The combination of CsA (8.3 X 10(-4) mM) and alpha-DFMO (0.5 mM or 1.0 mM) inhibited H2T cell survival to a greater extent than either agent alone. These results suggest that CsA in combination with other agents that inhibit polyamine synthesis may be useful for the treatment of pancreatic cancer.

Animals↗
PubMed1984

Tumor cell kinetics-directed chemotherapy for advanced squamous carcinoma of the cervix.

Cell cycle phase specific chemotherapeutic agents may be less effective treatment for metastatic or recurrent cervical carcinoma because most solid tumors contain very low cell growth fractions. Maximum therapeutic advantage may be accomplished through the use of a multiple drug protocol whose schedule is based on phase specificity of drug action and tumor cell kinetics. Preliminary data indicate that administration of a synchronizing agent, followed by cell kinetics analysis using flow microfluorometry techniques, allows a second agent to be scheduled at a time in the cell cycle when it would be most effective. These observations are based on the clinical response of 11 patients treated with kinetics-directed regimens (derived from direct kinetics measurements) or kinetics-based protocols (derived from empirical or historical data).

Adult↗
PubMed1983

Several cytokinetic methods for showing circadian variation in normal murine tissue and in a tumor.

Circadian rhythmicity in cell proliferation was studied by several cytokinetic techniques in 8-week-old CD2F1 and Swiss male mice. In separate experiments on four different dates, subgroups of six or seven mice (fed ad libitum and standardized to 8 hours light alternating with 16 hours of darkness) were killed at 3-hour intervals over a period of 24-48 hours. Cosinor analyses were used to determine the parameters of circadian periodicity in the data. Flow cytometric (FCM) analyses of DNA synthesis in tongue and stomach were compared with estimates of tritiated thymidine (3HTdR) incorporation into the DNA in these tissues. Circadian variation in tongue epithelium was reproducible in phasing and in range-of-change (100-140%) in seven 24-hour studies. The proportion of cells in G1 and G2 in tongue epithelium also demonstrated a circadian periodicity. When DNA synthesis in stomach was analyzed by the two methods, the results were entirely different and thus not comparable. The circadian rhythms in 3HTdR uptake agreed with those reported previously, but results of analyses by FCM were less certain, since epithelium of this organ could not be analyzed separately. Circadian rhythms were detected by FCM in G2, S, and G2M in Ehrlich ascites carcinoma (EAC). The mitotic index of this tumor varied with a circadian periodicity similar to that of the FCM-derived rhythm in G2M. This study validates the reliability of older techniques, such as 3HTdR uptake and mitotic indices, and suggests that circadian rhythms can be important in studies of cellular properties using FCM.

Animals↗
PubMed1983

Heterogeneous responses of an in vitro model of human stomach cancer to anticancer drugs.

Four permanent clones of a human adenocarcinoma of the stomach and the parent line from which they were isolated were used as an in vitro model system to evaluate the effects of 8 anticancer agents on cell survival. The drugs tested were actinomycin D (Act-D), Bleomycin (Bleo), adriamycin (adria), melphalan, chlorambucil, 5 Fluorouracil (5FU), 1,2:5,6-Dianhydrogalactitol (DAG), and 1-(2-chloroethyl)-3-(4-methyl cyclohexyl-1-nitrosourea) (MeCCNU). Although the cell lines had similar growth properties, morphologies and modal chromosome numbers, the clones expressed heterogeneous survival responses to each of six drugs tested. A comparison of the doses lethal to 90% of a clonal population (LD90) for each drug indicated large differences between the most sensitive and least sensitive clones. For chlorambucil there was a 160% difference between the LD90 values of the most and least sensitive clones. For MeCCNU the difference was 200%; for adria, 230%; Bleo, 280%; 5FU, 360%; and melphalan, 600%. Despite the heterogeneity in response among the clones to these agents, no particular clone was always the most sensitive or resistant. Of particular interest was the finding that these stomach cancer clones demonstrated uniform responses to both Act-D and DAG. Since the differential drug sensitivities expressed by heterogeneous tumor populations could be a cause of treatment failure in the patient, the demonstration of uniform sensitivities to Act-D and DAG are encouraging and suggest that other anticancer drugs which produce uniform cell killing may be identified and tested. Act-D and adria were the most effective of the drugs tested when compared on a dose for dose basis. Both agents killed more than 99.9% of the parent cell line with doses below 3 micrograms/ml (1-h treatments). The cells were least sensitive to 5FU, with only 30% of the cells killed at 100 micrograms/ml. The studies reported here indicate that this human stomach cancer model can provide valuable insight into the design of clinical protocols for treatment of gastric carcinoma in man.

Adenocarcinoma↗
PubMed1983

In vitro cellular characteristics and survival responses of human astrocytoma clones to chloroethyl-nitrosoureas and dianhydrogalactitol.

Three permanent clones were derived from a single astrocytoma cell line and were characterized for in vitro cell kinetics, chromosomal properties and for their responses to the anticancer drugs: 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU); 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU); 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl-1-nitrosourea) (PCNU); and 1,2:5,6-dianhydrogalactitol (GAL); all of which have been shown to cross the blood brain barrier. The clones showed different population doubling times, saturation densities, plating efficiencies, chromosome counts, ploidy, cell cycle phase distributions and DNA indices. The only positive correlation among these parameters was between the population doubling times and the modal chromosome numbers; the lower the chromosome number, the shorter the doubling time. No correlation was observable between any of the cellular properties and responses to the four drugs. The clones showed a differential sensitivity to the nitrosoureas, seen maximally as a 600-fold difference in survival between two of the clones treated with the same dose of BCNU. In contrast, the clones exhibited almost identical and uniform sensitivities to galactitol, suggesting that this agent exerted its cytotoxic effects by similar mechanisms in each of the clones. By comparison BCNU (at the tested doses and duration of drug exposure used in this study) was found to be the most effective of the agents tested.

Astrocytoma↗
PubMed1983

Survival and cell cycle kinetics responses of Chinese hamster ovary cells, and clones of human adenocarcinoma of the stomach and astrocytoma to diaziquone (AZQ) in vitro.

The anticancer agent 1,4-cyclohexadiene-1,4-dicarbonic acid, 2,5-bis(aziridinyl)-3,6-dioxo-, diethyl ester (AZQ) (NSC 182986) was studied in vitro to determine survival, cell cycle stage sensitivity, and cell cycle kinetics effects. One hour treatments with AZQ doses ranging from 1 micrograms/ml to 25 micrograms/ml revealed that human stomach tumor clones were most sensitive of three cell types studied to to the killing effects of AZQ; this sensitivity was followed in order by human astrocytomas and Chinese hamster ovary (CHO) cells. Depending on the AZQ dose, nondividing CHO cells were 10 to 180 times more sensitive than dividing CHO cells. Synchronized CHO cells were most sensitive to AZQ's killing effects when treated at the late S/G2 phase boundary, with the overall order of sensitivity being late S/G2, G2, mid-S, and G1 phase. Mitotic cells were neither killed by doses used in these studies, nor were they inhibited in their progression from mitosis into the G1 phase. Synchronized CHO cells treated in all other phases of the cell cycle were either blocked completely or delayed for up to 2 hours in their progression through the cell cycle. Flow microfluorometry (FMF) studies on exponentially growing CHO cells demonstrated that even at noncytotoxic doses (1 microgram/ml), AZQ caused very large, but reversible enrichments of cells in the S and G2 phases of the cell cycle. Since AZQ has already been shown to be effective against a variety of animal and human tumors (especially brain tumors) the data reported here may be useful in designing more effective treatment schedules and drug combination regimens.

Adenocarcinoma↗