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Biomedical subjects

P Frost

Publications and source records attributed to P Frost.

At least 91 records · Page 5Linked to original sources
PubMed1991

Continuous infusion 5-fluorouracil, etoposide and cis-diamminedichloroplatinum in patients with metastatic carcinoma of unknown primary origin.

We conducted a phase II clinical trial of 5-fluorouracil (5 day continuous infusion), cis-diamminedichloroplatinum and etoposide in previously untreated patients with metastatic carcinoma of unknown primary origin. Of the thirty-six evaluable patients (21 adenocarcinoma, 14 undifferentiated carcinoma and 1 squamous cell carcinoma), eight patients responded to this treatment (4 CR, 4 PR). Responses were seen in both soft tissue and visceral disease. Toxicity was significant and included grade III/IV myelosuppression in over 90% of patients treated. Non-hematologic toxicity included nausea/vomiting and stomatitis. Although the remissions obtained in this study appear to be durable (median duration of complete remission greater than 24 months), the regimen does not appear to offer significant advantages over other less toxic and more easily administered cisplatin-based combinations.

Adenocarcinoma↗
PubMed1990

Synergistic cytotoxicity using 2'-deoxy-5-azacytidine and cisplatin or 4-hydroperoxycyclophosphamide with human tumor cells.

The combined use of 2'-deoxy-5-azacytidine with cisplatin or 4-hydroperoxycyclophosphamide in vitro frequently resulted in synergistic cytotoxicity against a panel of six human cell lines. This enhanced cell killing occurred at drug concentrations that are clinically achievable. Synergy was also seen if the sequence of drug administration was altered, implying that a temporal overlap between the drugs was necessary, but that the actual biochemical lesions induced by each agent were probably unique, and interacted in an as yet undefined manner. Of further interest was the observation that at least one of the synergistic pairs was active against five of the six cell lines tested. 2'-Deoxy-5-azacytidine incorporation as assessed by the level of gross genomic DNA methylation did not appear to correlate with the synergistic cytotoxicity observed. Thus, we could not discern a clear relationship between the degree of DNA hypomethylation and the observed synergies, although DNA hypomethylation frequently occurred when synergy was demonstrated. The practical usefulness of these drug combinations has not yet been tested and awaits appropriate clinical trials both to assess the tumoricidal effects and possible increased toxicity.

Antineoplastic Agents↗
PubMed1990

The use of a genotypic marker to demonstrate clonal dominance during the growth and metastasis of a human breast carcinoma in nude mice.

When a mixture of 11 clones of a human breast carcinoma (MDA-MB-435)--each clone transfected with pSV2neo and identified as having a unique insertion site of the gene--was injected into nude mice, the resulting tumors were found to contain only one clone (Neo 24). This clone, identified by the unique restriction fragments on Southern blot analyses, was also found in metastases recovered from the lungs and lymph nodes of the animals. The individual clones showed no differences in in vitro growth, while in vivo the Neo 24 cells produced the largest tumors. Thus, one explanation for the observed clonal dominance in this study could be the more rapid growth in vivo of the Neo 24 cells. This study illustrates how an introduced selectable gene marker can be used in lineage studies of human tumor cell populations.

Animals↗
PubMed1990

Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response.

A poorly immunogenic murine colon cancer was used to investigate mechanisms of antitumor immunity. Injection of tumor cells engineered by gene transfection to secrete IL-2 stimulated an MHC class I-restricted cytolytic T lymphocyte (CTL) response against the parental tumor. The tumor cells secreting IL-2 produced an antitumor response in vivo, even in the absence of CD4+ T cells. Animals immunized with the engineered cells were protected against subsequent challenge with the parental tumor cell line. Similar findings were demonstrated for other tumor types. Thus, provision of a helper lymphokine in a paracrine fashion induced a tumor-specific immune response involving activation of endogenous CTLs and other immune effector cells. These findings demonstrate that the failure of an effective antitumor immune response may be primarily due to a helper arm deficiency of the immune system rather than a paucity of tumor-specific cytotoxic effector cells. Furthermore, they outline a novel strategy for augmenting tumor immunity.

Animals↗
PubMed1990

Transformation injury and the unicellular phenotype of malignant cells.

In 1984, Philippe Shubik wrote in an editorial in the Journal of the National Cancer Institute that: 'In terms of general biology, the multicellular organisms have evolved a complex series of defensive responses to extracellular injury involving various inflammatory reactions and their systemic concomitants. Needless to say, these reactions are by no means always successful from the standpoint of the host and indeed may well be the immediate cause of the obvious ill effects noted. The unicellular organisms, in contrast, react to injury by dividing and moving. In the search for the features that may link chemical, physical, and viral carcinogens apart from their ability to induce neoplasia, only one characteristic in common is obvious, namely, their ability to produce intracellular change or injury while leaving the cell viable. Perhaps the initial and fundamental characteristics of neoplasia is a reversion of the cell to unicellular behavior. Division and invasiveness are the characteristics of the neoplastic cell, and increased motility certainly seems to be the most likely mechanism for invasion'. Dr. Shubik presented these views as a basis for 'further discussion' regarding the nature of the neoplastic response. We hope that this presentation will augment Shubik's plea by reviewing his idea in the context of our current knowledge of tumor development. In addition, we will attempt to integrate the concept of the unicellular behavior of tumor cells with Foulds' and subsequently Nowell's insightful hypothesis concerning tumor progression.

Cell Transformation, Neoplastic↗
PubMed1990

Phase I clinical trial of cisplatin given i.v. with 5-fluorouracil and high-dose folinic acid.

We report the results of a phase I study of intravenously administered cisplatin, 5-fluorouracil and high-dose folinic acid. This trial was designed to exploit potential biochemical interactions between these three agents. The maximum tolerated doses were cisplatin, 75 mg/m2, day 1; 5-fluorouracil, 375 mg/m2, days 1-5 and leucovorin 500 mg/m2, days 1-5. The dose-limiting toxic effect of this regimen was myelosuppression. Mild non-hematologic toxic effects were also observed and included nausea, vomiting, stomatitis, and diarrhea. Phase II trial of this regimen are underway, however randomized studies will eventually be necessary to establish whether cisplatin contributes clinically significant activity to this regimen.

Adult↗
PubMed1990

Nutritional support in hospitals in the United Kingdom: national survey 1988.

The increasing sophistication of enteral and total parenteral nutritional support techniques has resulted in improvements in the clinical practice of such support in recent years. This survey was designed to establish current clinical practice in the management of nutritionally-compromised hospital patients in 206 districts in the United Kingdom. However, despite recent developments in these techniques, the response revealed a wide variation in the practice of clinical nutritional support. The results also indicate that in each district there should be a group of people, with an interest in clinical nutrition, to monitor and advise on nutritional support. It is suggested that, a national multidisciplinary group should be formed, similar to the American and European Societies of Parenteral and Enteral Nutrition. The group would promote the appropriate use of, and research into, nutritional support specifically for the nutritionally compromised patient in the United Kingdom.

Dietary Services↗
PubMed1989

Biochemical analysis of the role of transmethylation in the methionine dependence of tumor cells.

The effects on methionine metabolism of the substitution of homocysteine for methionine in vitro were investigated in normal and tumor cell lines differing in their ability to utilize homocysteine for growth. The major finding of this study was that methionine-independent (Met-Indep) cell lines had much lower basal transmethylation rates than methionine-dependent (Met-Dep) cell lines. This was particularly evident in the parent SP1 cell line and its Met-Indep revertant, SP1-R. SP1-R compensated for a lack of methionine by reducing both its transmethylation and growth rates. An analysis of other potential differences in methionine metabolism between Met-Dep and Met-Indep cell lines failed to demonstrate any consistent abnormalities in all but the absolutely Met-Dep MDAY-D2 cell line. Thus, protein, S-adenosylmethionine, and polyamine synthesis were the same in Met-Dep and Met-Indep cell lines. These results indicate that the major regulatory step in determining the Met-Dep phenotype is an inherent increase in the rate of transmethylation reactions. Cell lines with high basal transmethylation rates cannot compensate for a relative deficiency of methionine and either cease growing (MDAY-D2) or generate revertants (SP1-R) for which the basal rate of transmethylation is considerably reduced.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1989

Immunological characteristics of immunogenic variants induced in the MCA-F murine fibrosarcoma using 1-methyl-3-nitro-1-nitrosoguanidine, 5-aza-2'-deoxycytidine, or ultraviolet radiation.

The purpose of this study was to compare the frequency of generation and in vivo cross-reactivity of highly immunogenic (Imm+) clones induced in a single parental murine fibrosarcoma cell line MCA-F by 4 weekly treatments with either UV-B radiation, 1-methyl-3-nitro-1-nitrosoguanidine, or 5-aza-2'-deoxycytidine. These agents are believed to induce Imm+ variants by different mechanisms. The frequency of Imm+ variant generation was similar for the three different protocols, suggesting that the frequency of Imm+ generation was related more closely to the cell line than the inducing agent used. The strength of the immunogenic phenotype, however, was better correlated to the agent used, since 1-methyl-3-nitro-1-nitrosoguanidine yielded clones with the strongest immunogenicities. Three of four UV-B-induced Imm+ clones grew preferentially in chronically UV-irradiated syngeneic mice, a phenotype associated with UV-induced skin tumors. Cross-reactivity was tested with two Imm+ clones from each treatment group in a modified immunoprotection assay that selectively engendered antivariant, but not antiparental, immunity. Under these conditions each clone, except one, protected against itself. The clones displayed a complex pattern of cross-protection. Intervariant cross-protection was sensitive to the challenge dose, suggesting possible differences in the strengths of the cross-reacting immunities. Conversely, parental cross-protection was observed only with high immunizing multiplicities of Imm+ cells. The clones expressed the Imm+ phenotype in both C3H/HeN and C3H/HeJ mice, suggesting that expression of mammary tumor virus antigens did not account for the strong antitumor immune response. We also investigated whether the level of major histocompatibility complex class 1 or class 2 expression and immunogenic phenotype were correlated. Flow cytofluorography using haplotype-specific anti-Kk and anti-Dk monoclonal antibodies did not reveal a consistent difference in the constitutive or gamma-interferon-induced class 1 expression by Imm+ clones. However, we did observe a significant increase in the constitutive expression of IAk by most of the Imm+ variant clones. Together, these data demonstrate that in this system Imm+ variants engendered by a variety of mechanisms can express a range of cross-reactive tumor rejection neoantigens, independent of parental tumor antigens or major histocompatibility complex antigen expression.

Animals↗
PubMed1989

Unknown primary tumors: establishment of cell lines, identification of chromosomal abnormalities, and implications for a second type of tumor progression.

We describe the establishment of two human unknown primary tumor (UPT) cell lines and a comparison of their cytogenetic properties with two direct harvests from two tumor biopsy specimens. Histopathological analysis of all four tumor specimens revealed them to be undifferentiated adenocarcinomas of unknown origin. The chromosome numbers in these samples vary between 38 and 144. Consistent structural anomalies involving chromosome 1 were observed in all cases. These included a deletion of the short arm (4 of 4), duplication of 1q (3 of 4) and the presence of homogeneously staining region (2 of 4). Several additional chromosomal changes involving chromosomes 7, 8, and 9 were also observed, but these were less consistent and their importance is not yet clear. Abnormalities in chromosome 1 have generally been associated with advanced malignancy. The finding of consistent chromosome 1 changes in UPT supports our hypothesis that these are type 2 progressors in that benign or less malignant stages are not readily identified. In short, UPT are likely malignant soon after transformation occurs, and this is reflected in their rapid acquisition of the metastatic phenotype and abnormalities in chromosome 1. We are therefore characterizing a number of additional UPT cases to determine if chromosome 1 and other cytogenetic changes are consistently associated with this unique subgroup of tumors.

Animals↗
PubMed1989

Systemic immunity against a murine colon tumor (CT-26) produced by immunization with syngeneic cells expressing a transfected viral gene product.

We have previously shown that CT-26 tumor cells expressing the transfected hemagglutination antigen of influenza virus elicit an immune response in syngeneic hosts that is cross-protective against an s.c. challenge with non-transfected parental cells. Since CT-26 is a murine colorectal carcinoma we sought to determine whether the same immuno-protective effect could be achieved after a challenge with parent tumor cells injected into the usual sites of colon tumor growth and metastasis. We now show that the protection afforded by this immunization protocol is systemic and that animals can be protected against tumor growth in the cecum, lymphatics of the mesentery, liver and lung.

Adenocarcinoma↗
PubMed1989

Genotypic and phenotypic evidence of clonal interactions in murine tumor cells.

The stability of mixed tumor cell populations has been described in terms of phenotypic characteristics such as metastatic potential, immunogenicity, and drug resistance. We have extended these analyses to the molecular level in a model that uses transfection of the hemagglutinin antigen (HA) gene of influenza virus into murine CT-26 colorectal carcinoma cells. Transfection was followed by fluorescence-activated cell sorting (FACS) to select a parent population with expression of high levels of HA. We characterized this population (FACS-3) and four derived clones (5, 6, 9, and 18) over time with regard to phenotypic characteristics: immunogenicity and cross-protection against tumor challenge, cell surface expression of HA, evidence of HA gene amplification, and levels of HA mRNA. During 6 months in culture, the FACS-3 parent cells remained stable, but the individual clones varied for all of the parameters assessed. Among the clones, all possible molecular variations occurred, including changes in HA gene copy number (increased in clone 5 and decreased in clone 18), gene rearrangement (clone 5), decrease in HA mRNA (clones 6, 9, and 18), increase in HA mRNA (clone 5), and an abnormality in translational control or a posttranslational error. In all cases, the molecular changes correlated with cell surface HA expression, immunogenicity, and cross-protective potential. We conclude that in vitro clonal interactions play a role in stabilizing heterogeneity in this system. These studies show that even in the absence of selection, clonal interactions may alter the phenotype of tumors by increasing malignant progression or impeding tumor growth.

Animals↗
PubMed1989

Retention of immunogenicity after X-irradiation of mouse colon tumor cells expressing the transfected influenza virus hemagglutinin gene.

We have previously demonstrated that murine colon tumor cells transfected with the gene coding for the hemagglutination antigen (HA) of influenza virus acquire an inherent immunogenicity, fail to grow in syngeneic mice, and demonstrate an ability to cross-protect against a challenge with parental nontransfected cells. In the present study the immunogenic potential of HA-transfected cells correlated with cell-surface HA expression, as measured both by a fluorescence-activated cell sorter and by radio-labeled antibody binding. HA-transfected immunogenic cells had a median lethal dose (LD50) that was 10,000-fold greater than that of nontransfected cells. Most importantly this study demonstrated that HA-transfected cells retained their immunogenicity after X-irradiation with 12,000 rad. This characteristic makes their potential usefulness in treating human neoplasia more plausible.

Animals↗
PubMed1988

Patterns of methionine auxotrophy in normal and neoplastic cells: the methionine independence of lymphocyte mitogenesis and low frequency of the methionine-dependent phenotype in human tumors.

Seven murine and 17 human tumor-derived cell lines were tested for their ability to grow in methionine-free medium containing the methionine precursor homocysteine. Three murine tumors, SP1, MDAY-D2, and L1210, failed to grow in this medium and were therefore methionine dependent (Met-Dep). In contrast, all human tumors, including 8 recently established cell lines, were methionine independent (Met-Indep). Concanavalin A-induced lymphocyte mitogenesis was also Met-Indep but required 3 to 4 times the amount of homocysteine needed for the growth of normal fibroblasts or Met-Indep tumors. In addition, lymphocyte mitogenesis was also supported by exogenous 5'-methylthioadenosine, another methionine precursor formed during polyamine synthesis. In contrast, Met-Dep tumors did not respond to increasing homocysteine concentration, nor was their growth supported by 5'-methylthioadenosine. These findings demonstrate that Met-Dep can occur by varied mechanisms relating to such parameters as homocysteine concentration and the ability of cells to generate Met-Indep revertants or to grow in 5'-methylthioadenosine. In general, we found the Met-Dep phenotype to be more common in murine tumor cells and to occur infrequently in human tumors. This may imply a species difference in methionine metabolism.

Adenosine↗