Is the immunotherapy of metastasis feasible?
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Animals↗
Biomedical subjects
P Frost
Publications and source records attributed to P Frost.
Into the depth.
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Accidents, Occupational↗
Metastatic potential and spontaneous mutation rates: studies with two murine cell lines and their recently induced metastatic variants.
To investigate the hypothesis that increased malignant potential correlates with increased genetic instability, we measured spontaneous mutation rates for the production of ouabain-resistant mutants in two benign (nonmetastatic) murine cell lines and their recently induced metastatic variants. Metastatic variants of the NIH 3T3 and CBA SP-1 cells were induced by transfection with the h-ras oncogene. Metastatic variants were also induced from the CBA SP-1 cell line by treatment with either 2'-deoxy-5-azacytidine or hydroxyurea. Mutation rates for the parent NIH 3T3 cells and their metastatic variants were less than 3 X 10(-8) variants per cell per generation, with no significant differences between them. Rates for the CBA SP-1 line and its variants ranged from 9 X 10(-9) to 8 X 10(-8) variants per cell generation, again without statistically significant differences. We conclude that in the cell lines studied the rate of spontaneous mutation for ouabain resistance was unrelated to the acquisition of the metastatic phenotype. This conclusion was based on the view that the generation of ouabain-resistant mutants is a reflection of the overall stability of the genome. Since the spontaneous mutation rate for ouabain resistance was unchanged in cells that had recently acquired the ability to metastasize, other genetic or epigenetic events were probably responsible for progression to the malignant (metastatic) phenotype.
Animals↗
Venous administration of hypertonic fluids.
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Amino Acids↗
Genetic and epigenetic aspects of tumor progression and tumor heterogeneity.
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Animals↗
Addition of a topically applied corticosteroid to a modified Goeckerman regimen for treatment of psoriasis: effect on duration of remission.
A double-blind parallel group study was undertaken to assess the effect of adding a topically applied corticosteroid cream to a modified Goeckerman regimen to treat patients with psoriasis. Nineteen patients with psoriasis were treated with either this regimen and hydrocortisone valerate cream or the regimen and vehicle cream. Patients were given daily treatments until their skin cleared or until twenty-eight treatments were received. They were then followed up until rebound or relapse occurred or 6 months had passed. The addition of hydrocortisone valerate cream to the modified Goeckerman regimen led to relapse after 5.9 weeks in comparison with 17.9 weeks for the control group.
Administration, Topical↗
Induction of thymidine kinase activity in a spontaneously enzyme-deficient murine tumor cell line by exposure in vivo to the DNA-hypomethylating agent 5-aza-2'-deoxycytidine: implications for mechanisms of tumor progression.
We previously reported that thymidine kinase (TK) activity in a spontaneously TK-deficient (TK-) mouse tumor cell line (called L61-M) could be partially restored by brief exposure of the cells in vitro to the DNA-hypomethylating agent 5-azacytidine. We now show that similar results can be obtained by exposing L61-M cells growing in mice to the DNA-hypomethylating agent 5-aza-2'-deoxycytidine. The frequency of TK+ cells within the TK- L61-M cell population was increased approximately 26,000-fold by the in vitro 5-azacytidine treatment. The frequency of L61-M TK+ cells was increased from between 200- and 1000-fold depending upon the routes of tumor and drug inoculation following the in vivo administration of 5-aza-2'-deoxycytidine. 5-Aza-2'-deoxycytidine treatment increased the proportion of L61-M TK+ cells by the induction of TK activity and not as a result of the selection of any preexisting TK+ cells from within the L61-M tumor cell population. While 5-aza-2'-deoxycytidine treatment increased the frequency of L61-M TK+ cells within the tumor cell population, it had no effect upon the survival times of mice bearing the L61-M tumor line. These results indicate that some anticancer chemotherapeutic drugs may be able to promote the diversification of tumor cell populations in vivo through the activation of previously quiescent genes as a result of alterations in the methylation of DNA.
Animals↗
Antiandrogenic effects of topically applied spironolactone on the hamster flank organ.
The effects of topically applied spironolactone on the sebaceous glands of flank organs in adult male golden hamsters were investigated. Daily treatment with spironolactone (0.3 mg and 3 mg) on one side only significantly reduced the size of the treated flank organs, while the contralateral flank organs remained unchanged. Lower doses of spironolactone and the vehicle had no effect. Cyproterone acetate therapy resulted in the bilateral reduction of flank organ sizes. In vivo measurement of the palpable bulk of the flank organs correlated with flank organ volumes as determined by computer-assisted planimetry of serial histologic sections. Dry weights of seminal vesicles in animals treated with spironolactone did not differ significantly from those of the control group, while topically applied cyproterone acetate significantly reduced seminal vesicle weight. Topically administered spironolactone appears to have only local antiandrogenic effects, as indicated by the lack of changes in the untreated contralateral flank organs and in the weights of seminal vesicles.
Administration, Topical↗
Administering death.
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Attitude to Death↗
Characterization of in vitro immunoselected variants from a highly metastatic murine tumor for alterations in malignant behavior in vivo.
A new Ly-6.2- antigen-loss variant (called L61 -M1) of the highly metastatic DBA/2 mouse (Ly-6.2+) MDAY-D2 tumor has been obtained by means of a monoclonal anti-Ly-6.2 antibody in an in vitro immunoselection technique. Whereas L61 -M1 grew poorly when inoculated subcutaneously into the syngeneic host, it grew and metastasized in a similar way to the parental MDAY-D2 tumor when inoculated into immunosuppressed, athymic nude mice. L61 -M1 as well as another Ly-6.2- variant of the same MDAY-D2 tumor (called L61 ) which is poorly metastatic in the syngeneic host salvaged exogenous fucose into glycoproteins and glycolipids at rates 5.5 and 7.8 times that of the parental MDAY-D2 line. In contrast, the Ly-6.2- variants exhibited a 50-70% decrease in the incorporation of exogenous mannose into glycoproteins and glycolipids. L61 -M1 and L61 also exhibited alterations in the structures of the oligosaccharide moieties linked to the cell surface glycoproteins and/or glycolipids. Thus, the in vitro immunoselection technique can be used to obtain a panel of variants with stable phenotypic alterations in their growth and metastatic capacities. Such mutants may, like previously described lectin-resistant mutants, be useful in studying the contribution of cell surface glycoproteins and glycolipids to tumorigenicity and metastasis.
Animals↗
Selection of strongly immunogenic "tum-" variants from tumors at high frequency using 5-azacytidine.
Highly immunogenic "tum-" (non-tumorigenic in normal syngeneic hosts) clonal variants can be selected from a variety of poorly immunogenic and highly tumorigenic mouse cell lines at very high frequencies (e.g., greater than 80%) after treatment in vitro with chemical mutagens such as ethyl methanesulfonate (EMS) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). We herein demonstrate that the same result can be obtained with the poorly mutagenic cytidine analogue, 5-azacytidine, a strong DNA hypomethylating agent. 5-Azacytidine and EMS were equally and comparably effective, or ineffective, in inducing tum- variants from three different highly tumorigenic mouse cell lines. Like mutagen-induced tum- variants, those obtained after 5-azacytidine treatment generated usually strong cytolytic T lymphocyte (CTL) responses in vitro, and could grow in immunosuppressed (nude mouse) hosts. However, pretreatment of the tumor cell lines with 5-azacytidine did not cause significant increases in mutations at several independent drug-resistant gene loci, whereas EMS did. It is known that treatment of cells with 5-azacytidine can induce transcriptional activation of "silent" genes through a reduction of DNA 5-methylcytosine content, a process that can also be effected by mutagenic DNA alkylating agents such as EMS and MNNG. We therefore hypothesize that an "epigenetic" mechanism (DNA hypomethylation) leading to activation and expression of genes coding for potential tumor antigens is involved in the generation at high frequency of tum- variants after "mutagen" treatment. The implications of these findings to mechanisms of tumor progression and the generation of tumor heterogeneity are discussed.
5-Methylcytosine↗
Regression of chronic generalised lymphadenopathy in a homosexual man after therapy with intravenous acyclovir.
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Acyclovir↗
Relation between osmolality of diet and gastrointestinal side effects in enteral nutrition.
One hundred and eighteen patients with normal gastrointestinal function were randomly allocated to one of three feeding regimens in a double blind study to determine the relation between the tonicity of the diet and gastrointestinal side effects related to the diet and to evaluate the efficacy of "starter" regimens in reducing gastrointestinal side effects during enteral nutrition. Patients received a hypertonic diet with an osmolality of 430 mmol (mosmol)/kg (group 1), the same diet but with the osmolality increasing from 145 to 430 mmol/kg over the first four days (group 2), or an isotonic diet (300 mmol/kg) (group 3). All diets were prepared aseptically and administered by 24 hour nasogastric infusion. The mean daily nitrogen intake in group 1 was significantly greater (p less than 0.05) than that in both groups 2 and 3, and the mean overall daily nitrogen balance was significantly better (p less than 0.05) in group 1 than groups 2 and 3. The incidence of side effects related to the diet was similar in all three groups, but diarrhoea was significantly (p less than 0.001) associated with concurrent treatment with antibiotics. These findings show that undiluted hypertonic diet results in significantly better nitrogen intake and balance, that starter regimens reduce nutrient intake but not symptoms, and that diarrhoea is significantly related to treatment with antibiotics and not to administration of an undiluted hypertonic polymeric diet.
Clinical Trials as Topic↗
Possible epigenetic mechanisms of tumor progression: induction of high-frequency heritable but phenotypically unstable changes in the tumorigenic and metastatic properties of tumor cell populations by 5-azacytidine treatment.
Treatment of a variety of highly tumorigenic mouse lines in vitro with chemical mutagens, such as ethyl methane sulfonate (EMS) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), can result in extraordinarily high frequencies (sometimes in excess of 90%) of strongly immunogenic clones unable to grow progressively in normal syngeneic hosts. These clones will, however, grow in immunosuppressed hosts and gradually regain tumorigenic ability in normal mice if maintained in long-term (several months-1 year) culture, i.e., they are often phenotypically unstable. These features--phenotypic drift and high frequency--make it unlikely that point mutations are the underlying mechanism involved in the generation of the variants. Results presented here demonstrate that these observations can be reproduced on the same tumor lines using 5-azacytidine--an analogue of cytidine which can be incorporated into DNA causing subsequent extensive hypomethylation of cytosine residues in the absence of any significant mutagenic effects. Furthermore, 5-azacytidine treatment of a nonmetastatic mouse mammary tumor led to the emergence of a small number of heritable but unstable tumor clones capable of spontaneous metastatic spread. Because it is known that DNA hypomethylation can lead to transcriptional activation of normally silent genes, that altered methylation patterns can be somatically replicated with a high but not perfect fidelity, and that mutagens can cause DNA hypomethylation, we propose that DNA hypomethylation followed by de novo methylation represents a plausible mechanism to account not only for the induction of the nontumorigenic variants but for a number of aspects of tumor progression and tumor heterogeneity, as well. In particular, we refer to heritable phenotypic alterations in tumor cell populations which occur at very high frequency but which are not necessarily stable over very long periods of time.
Animals↗
5-azacytidine induction of thymidine kinase in a spontaneously enzyme-deficient murine tumor line.
During the course of our studies on murine tumor cell metastases, one of our variant lines (called L61-M) was found to be unable to incorporate [methyl-3H]thymidine into DNA, due to a spontaneous deficiency in thymidine kinase (TK) activity. L61-M cells are unable to proliferate in HAT selection medium and are resistant to bromodeoxyuridine (BrdU). TK activity in L61-M cells is 4.2% of that found in the wild-type parental MDAY-D2 cell line. Treatment of L61-M with 5-azacytidine, a known inducer of DNA hypomethylation, resulted in the expression of TK activity. These observations suggest that the TK deficiency in the L61-M cell line was due in part to an alteration in the methylation pattern of DNA, resulting in the diminished expression of the TK gene. These results demonstrate the ability of 5-azacytidine to induce TK activity in a spontaneously enzyme-deficient murine tumor cell line.
Animals↗
Morphometric studies of the hamster flank organ: an improved model to evaluate pharmacologic effects on sebaceous glands.
The Syrian golden hamster flank organ, composed of clusters of large sebaceous glands, has been used to investigate effects of systemically or topically applied hormones, antiandrogens, and retinoids. Accurate assessments of flank organ sebaceous gland volume and its correlation with in vivo measurements of flank organ size have not been reported. Sixty flank organs were examined. In vivo flank organ size was expressed as the product of the greatest longitudinal (DL) and greatest transverse (DT) diameters of the palpable bulk. Sebaceous gland volumes were calculated from planimetric analyses of serially sectioned specimens of flank organs using a computer-assisted planimetry system. In vivo measurements (DL X DT) were found to correlate with planimetrically determined flank organ volume. Planimetric analysis of every 10th section of a serially sectioned flank organ was almost as sensitive as analysis of every section in determining sebaceous gland volume. Computer-assisted planimetry of serially sectioned flank organs was found to be an accurate and reproducible method for assessing gland volume. In vivo measurements of the palpable bulk are a good indicator of sebaceous gland size and correlate well with planimetrically determined sebaceous gland volumes.
Animals↗
Effect of catheter tunnelling and a nutrition nurse on catheter sepsis during parenteral nutrition. A controlled trial.
In a three-year controlled trial of subcutaneous catheter tunnelling as a method of reducing total parenteral nutrition (TPN) catheter sepsis 99 silicone catheters (52 tunnelled, 47 untunnelled) were inserted into the subclavian (94%) or jugular (6%) veins under aseptic conditions. The influence of a nutrition nurse, who joined the nutrition team after 18 months, on catheter sepsis rate was also documented. Catheter sepsis was confirmed in 13 of 47 (28%) untunnelled catheters and only 6 of 52 (11.5%) tunnelled catheters (p less than 0.05). A nutrition nurse reduced sepsis rate from 33% (tunnelled 6, untunnelled 11) to 4% (0 tunnelled; 2 untunnelled) (p less than 0.001). There was no significant difference between tunnelled and untunnelled catheters in sepsis rates after the arrival of the nutrition nurse. Although 85% patients had concurrent internal sepsis, the pathogens implicated in catheter sepsis came from superficial sites in 16 of 19 cases (p less than 0.01). Rigorous aseptic nursing care is thus the most significant factor in the reduction of TPN catheter sepsis, but tunnelling can reduce sepsis rate when nursing care is suboptimum.
Antisepsis↗
Psoriasis therapy. The effect of UV radiation on sensitization to mechlorethamine.
A study was performed to determine the effect of UV-B radiation on the sensitization of patients to topically applied mechlorethamine hydrochloride. Patients with widespread psoriasis were randomized into two groups. One group was given six daily treatments of one minimal erythemal dose (MErD) prior to starting daily applications of a 0.02% mechlorethamine ointment and, thereafter, one MErD weekly; the other group was given daily applications of mechlorethamine but received no UV-B. The improvement of psoriasis was monitored by a severity score system and patients were treated for 30 days, or until contact dermatitis occurred. The addition of UV-B to topical applications of mechlorethamine reduced the incidence of allergic contact dermatitis to mechlorethamine from 64% to 22%. In those sensitized to mechlorethamine, the time required for sensitization to develop was increased from 14 to 23 days by UV-B therapy.
Administration, Topical↗