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D L Dexter

Publications and source records attributed to D L Dexter.

At least 37 records · Page 2Linked to original sources
PubMed1985

Polar solvent-induced changes in membrane lipid lateral diffusion in human colon cancer cells.

Polar organic solvents, such as N-methylformamide (NMF), N,N-dimethylformamide, and dimethyl sulfoxide, have been demonstrated to induce differentiation in a number of neoplastic cell lines, including human colon cancer cells. Although the mechanism of action of these agents is yet unknown, one possibility is that polar solvents induce a change in lateral mobility of membrane lipids, important to the maturational process. To determine the relationship between polar solvent treatment and changes in membranes, we examined the effects of exposure to NMF on membrane fluidity in human colon cancer cells (DLD-1; clone A). Membrane viscosity was assessed by determining lipid lateral diffusion following photobleaching of a fluorescent lipid probe in individual intact cells. Exposure of cells to NMF led to a significant increase in membrane viscosity following 2 days of treatment, with maximal changes occurring after 11 days. NMF induced these effects over a limited concentration range with 1.0% NMF in the medium having the maximal effect, and 0.5% or 1.5% having less or no effect. Growth of cells with N,N-dimethylformamide (0.8%) also led to increases in membrane viscosity. The observed membrane changes correlated well with the effect of NMF on differentiation in these cells as previously reported, as well as with cell growth rate and morphology in the present study. The increase in viscosity caused by prolonged NMF treatment was reversible, with a return to untreated levels by 9-11 days after removal of NMF. Thus, there is a strong correlation between the attainment of more benign, better differentiated phenotype in polar solvent-treated clone A cells and increases in membrane viscosity.

Butyrates↗
PubMed1985

Activity of a novel 4-quinolinecarboxylic acid, NSC 368390 [6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarb oxylic acid sodium salt], against experimental tumors.

A novel, substituted 4-quinolinecarboxylic acid (NSC 339768) demonstrated antitumor activity against L1210 leukemia and B16 melanoma in the National Cancer Institute's Developmental Therapeutics Program. An extensive analogue synthesis program was initiated; over 200 derivatives were synthesized and tested for anticancer activity. One of these compounds, 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid sodium salt, NSC 368390 (DuP-785), was selected for further investigation because of its efficacy against a spectrum of human solid tumors and its water solubility. In initial studies with L1210 leukemia, the compound caused an increase in life span of greater than 80%. The activity was schedule dependent, and the compound was equally efficacious when administered i.p., i.v., s.c., or p.o. In tests against human tumors xenografted under the renal capsule of nude mice, NSC 368390 when injected i.p. in doses of 20-40 mg/kg daily for 9 days inhibited the growth of the MX-1 breast, LX-1 lung, BL/STX-1 stomach, and CX-1 colon carcinomas by greater than 90%. NSC 368390 also inhibited the growth of three distinct human colon carcinomas, the HCT-15, clone A, and DLD-2 tumors, growing s.c. in nude mice. An i.p. dose of 25 mg/kg given daily for 9 days inhibited the growth of the DLD-2 colon cancer by 98%. 1-beta-D-Arabinofuranosylcytosine and Adriamycin were ineffective, and fluorouracil was only moderately effective against these colon tumors. Because of its good activity against human colon tumors and other human carcinomas and its water solubility, NSC 368390 (DuP-785) is being developed as a Phase 1 anticancer agent.

Animals↗
PubMed1985

Disaggregation studies of xenograft solid tumors grown from pure or admixed clonal subpopulations from a heterogeneous human colon adenocarcinoma.

Two clonal tumor subpopulations (designated as A and D) obtained originally from a heterogeneous human colon adenocarcinoma (DLD-1) were used to produce xenograft solid tumors in nude mice. First, disaggregation studies were performed to determine the optimal choice of enzyme and time of dissociation for the pure A and D neoplasms, using cell yield (cells/mg/min) and colony forming efficiency (CFE) assays. The enzymes investigated were: 0.5 or 0.2% trypsin, and two cocktails containing pronase (0.5 or 0.05%), collagenase (0.02%), and DNAse I (0.02%). For the 0.5% trypsin treatments, the cell yield from A and D tumor fragments increased until about 30 min, at which time a plateau in cell yield was reached. A plateau in CFE was also reached at this time. In contrast, the cell yields for the 0.2% trypsin treatment did not reach a plateau within the time of the dissociation (120 min), and the CFEs were lower than with the 0.5% trypsin. Whereas no differences in cell yield or CFE were found between the enzyme cocktail studies (0.5% trypsin vs. 0.05% pronase), the cell yield and the CFE from the clone D carcinomas were significantly less than that found with the 0.5% trypsin (the cell yield and CFE from clone A tumors were identical for 0.5% trypsin or enzyme cocktail). These data indicate that, while these clonal neoplasms have somewhat different responses to enzyme disaggregation, it is possible to select an enzyme treatment and treatment time that is appropriate for use on both A and D tumors (i.e., 0.5% trypsin). After determination of an acceptable enzyme procedure, 'reconstructed' heterogeneous tumors produced from an initial injection bolus of 50% clone A and 50% clone D cells were disaggregated as a function of time (days 12-83 postinjection). Over this period, we found that the cell yield decreased exponentially, with a half-time (T1/2) of 20.5 +/- 7.3 days (95% confidence limits), with a maximum extrapolated cell yield at time zero of about 1.2 X 10(5) cells/mg. The CFE was essentially constant over the duration of the assay period. Moreover, it was found that the percentage of clone A cells appeared to decrease exponentially (T1/2 = 20.5 +/- 11.5 days, 95% confidence limits) until about 40 days postinjection. After this time an equilibrium mixture consisting of about 10% clone A cells and 90% clone D cells was reached.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1984

Characterization of a defect in the pathway for converting 5'-deoxy-5'-methylthioadenosine to methionine in a subline of a cultured heterogeneous human colon carcinoma.

5'-Deoxy-5'-methylthioadenosine (methylthioadenosine) is cleaved to adenine and 5-methylthioribose-1-phosphate (methylthioribose-1-P). Methylthioribose-1-P is converted to 2-keto-4-methylthiobutyrate ( ketomethylthiobutyrate ) which is transaminated to methionine. We report that one subline of a heterogeneous human colon carcinoma, DLD-1 Clone D, only forms methylthioribose-1-P from methylthioadenosine or 5'-deoxy-5'-methylthioinosine (methylthioinosine), a deaminated derivative of methylthioadenosine, whereas Clone A converts methylthioadenosine and methylthioinosine to methionine, as shown by growth studies in culture of Clone A and Clone D cells and radioactive studies utilizing [methyl-14C]methylthioadenosine or [methyl-14C]methylthioinosine in the presence of extracts of these cells lines. To characterize this defect, we utilized three protein fractions isolated from rat liver which together convert methylthioribose-1-P to ketomethylthiobutyrate . Addition of only Fraction A to Clone D sonicates restores its ability to convert methylthioadenosine to methionine. This fraction is responsible for converting methylthioribose-1-P to 5- methylthioribulose -1-phosphate; radioactive studies confirm this observation. Thus, Clone D is deficient in an enzyme contained in Fraction A; this represents a qualitative biochemical difference between the two clones derived from a single human tumor.

Adenosine↗
PubMed1984

Sodium butyrate-induced alteration of growth properties and glycogen levels in cultured human colon carcinoma cells.

The effect of sodium butyrate on three cultured human colon carcinoma cell lines was studied. Exposure to butyrate caused morphological changes and resulted in the alteration of several growth properties. Doubling times of treated cells were increased five-fold and saturation densities and cloning efficiencies were decreased, compared to untreated cells. Histochemical studies using the periodic acid-Schiff reaction in conjunction with diastase digestion showed that butyrate induced increased glycogen levels in all three cell lines. This increase was confirmed by biochemical techniques. These effects of butyrate were reversed when treated cells were subsequently grown in the absence of butyrate. These changes are consistent with findings from several laboratories that butyrate can induce phenotypic changes in cultured tumour cells.

Butyrates↗
PubMed1984

Polar solvent modification of X ray induced potentially lethal damage in heterogeneous human colon tumor cells in vitro.

Two subpopulations of tumor cells (clones A and D) obtained from a human colon adenocarcinoma were examined for their sensitivities to x-irradiation as unfed, early plateau phase cultures. Both the single dose survival curves and the kinetics of potentially lethal damage recovery (PLDR) were determined for the two tumor lines. Also, possible modification of PLDR by N,N-dimethylformamide (DMF), which has previously been shown to enhance the radiosensitivity of exponentially growing tumor cells, was investigated by adding DMF (0.8% v/v) to plateau phase cultures immediately after irradiation, and determining effects on the extent of PLDR. For non-DMF treated cells, the survival curve parameters of the diploid (clone D) and aneuploid (clone A) lines were very similar. The single-hit, multitarget values for n, Do (Gy), and Dq (Gy) were: 7.9, 0.82, and 1.70 for clone D; and 10.6, 0.83, and 1.96 for clone A. Using initial survival levels of 3.5% (clone D) or 5.5% (clone A) to investigate PLDR, it was found that the increase in survival (surviving fraction ratio or SFR) for clone D was 2.2, while the SFR for clone A was 1.6. DMF did not change either the kinetics or extent of PLDR in these two tumor lines when added to cultures immediately after irradiation. Our results indicate that significant heterogeneity in PLDR exists between these closely related tumor subpopulations.

Adenocarcinoma↗
PubMed1984

Polar solvents: a novel class of antineoplastic agents.

It has been known for many decades that certain murine and human cancers can spontaneously mature to benign tissue. These observations have stimulated investigators to attempt to induce a state of more normal or benign differentiation in cancer cells using biologic substances or chemicals. Polar solvents including dimethylsulfoxide, dimethylformamide, and monomethylformamide have proven to be good inducers of maturational events in murine and human cancer cells. Moreover, several laboratories have demonstrated that polar solvents inhibit the growth of human tumor xenografts in nude mice. These findings have resulted in the entry of monomethylformamide into phase I clinical trials in America and Europe. Preclinical work further suggests that polar solvents may be useful agents in combination with conventional treatment modalities. The use of drugs such as monomethylformamide that can convert neoplastic cells to benign cells rather than kill the tumor cells represents an important conceptual departure from standard cytotoxic chemotherapy. The use of maturational-agent therapy should be considered as an important new development in the design of cancer treatment protocols.

Animals↗
PubMed1984

Enhancement by N-methylformamide of the effect of ionizing radiation on a human colon tumor xenografted in nude mice.

Polar solvents, which induce differentiation in murine and human tumor cells, enhance the effect of ionizing radiation on cultured mouse mammary and human colon cancer cells. To determine whether this enhancement occurs in vivo, DLD-2 human colon carcinoma xenografts in nude mice were treated with combinations of 6 MV photon irradiation, the polar solvent N-methylformamide (NMF), or combinations of the two agents. Nude mice bearing 300-mg s.c. implants of DLD-2 tumors were treated i.p. with 150 mg NMF/kg daily for 19 days. Local tumor irradiations were administered as graded single doses or as fractionated doses, daily for 4 days, following the third NMF injection. The growth-inhibiting effect of the radiation treatment for both single dose and fractionation protocols was enhanced by the polar solvent. NMF alone increased the time required for a doubling of initial tumor volume by 1.7 days, compared to control tumors. Initial tumor volume doubling times compared to untreated controls were increased by 3.6 and 7.6 days by photon doses of 10.0 and 13.75 Gy, respectively, whereas NMF plus 10.0 or 13.75 Gy increased the DLD-2 regrowth delay time by 7.5 or 12.9 days. NMF caused essentially equivalent enhancements, whether split-dose schedules of 2.5 Gy daily for 4 days, and 3.44 Gy daily for 4 days, or single doses of 10.0 and 13.75 Gy were used; therefore, radiation enhancement was not due to effects on sublethal damage repair. The results support the use of NMF, currently in Phase 1-Phase 2 clinical trials, with radiation in the therapy of selected human neoplasms.

Animals↗
PubMed1984

Intrinsic and extrinsic heterogeneity in the responses of parent and clonal human colon carcinoma xenografts to photon irradiation.

Responses to photon irradiation of xenografted human colon tumors derived from the heterogeneous DLD-1 line or its derivative A and D subpopulations were determined using excision assay and tumor regrowth delay assays. Differential responses among the three xenografted carcinomas were demonstrated. Clone A tumors treated with up to 17.5 Gy showed no actual regression below pretreatment volume. In contrast, clone D tumors were sensitive to doses as low as 3.5 Gy, and tumor volumes were reduced by 65% with a dose of 17.5 Gy. The responses of DLD-1 tumors were intermediate between the clone A and clone D tumor responses. The survival parameters obtained in the excision assay studies for the DLD-1, clone A, and clone D tumors were, respectively: n = 3.3, 1.4, and 1.0; D0 (Gy) = 2.1, 2.2, and 2.7; and DQ (Gy) = 2.6, 0.6, and 0.0. These data indicate that the DLD-1 tumors were the most resistant, with clone A of intermediate sensitivity, clone D being the most sensitive tumor. In addition to the interclonal diversity among xenograft lines, intraclonal variation was also observed with clone A (but not clone D or DLD-1) tumors. A biphasic survival curve of cells from clone A xenografts irradiated in air-breathing hosts clearly indicated a minority (approximately 3%) subpopulation of hypoxic cells. Similar results indicating a small percentage of hypoxic cells in clone A solid tumors were obtained from the tumor regrowth delay studies. Also, excision assay data from experiments in which the heterografted carcinomas were irradiated under anoxic conditions support the interpretation that clone A tumors contain a small fraction of hypoxic cells. This study indicates that: (a) heterogeneity in vivo to ionizing radiation exists in the DLD-1 system; and (b) intraclonal variation occurs in vivo due to extrinsic (e.g., environmental hypoxia) factors, such that the intrinsic radioresistance of a subpopulation (clone A) of a heterogeneous human tumor can be further increased.

Animals↗
PubMed1983

5'-deoxy-5'-methylthioadenosine phosphorylase--II. Role of the enzyme in the metabolism and antineoplastic action of adenine-substituted analogs of 5'-deoxy-5'-methylthioadenosine.

The biological activities of several previously synthesized [J. A. Montgomery et al., J. med. Chem. 17, 1197 (1974)] adenine-substituted analogs of 5'-deoxy-5'-methylthio- or 5'-deoxy-5'-ethyl-thioadenosine, including the 2-fluoroadenine, 2-chloroadenine, 2,6-diaminopurine, 8-azaadenine, and 4-aminopyrazolo [3,4-d]pyrimidine-containing derivatives, have been reexamined. It is demonstrated that many of these analogs are cleaved to their respective free base analogs by 5'-deoxy-5'-methyl-thioadenosine phosphorylase (MTAPase), an enzyme associated with polyamine biosynthesis, and that this reaction is necessary for the cytotoxic action of these MTA analogs to be fully expressed. Evidence to support this includes: (1) the growth of two MTAPase-containing human colon carcinoma cell lines (the HCT-15 and DLD-1 lines) was inhibited by these analogs, whereas an MTAPase-deficient cell line, the CCRF-CEM human T-cell leukemia, was relatively insensitive to their cytotoxic action; (2) extracts of the MTAPase-containing colon carcinoma cell lines were able to cleave these analogs to their respective free base analogs; in contrast, extracts of MTAPase-deficient CCRF-CEM cells were unable to cleave these analogs; (3) intact colon carcinoma cells converted these MTA analogs to their corresponding 5'-phosphorylated analog nucleotides, whereas CCRF-CEM cells did not, at least to detectable levels; and (4) the MTA analog, 5'-deoxy-5'-ethylthio-4-aminopyrazolo [3,4-d]pyrimidine ribonucleoside, which is not a substrate of MTAPase, did not form analog nucleotides and was essentially noncytotoxic to all cell lines tested, whereas the corresponding adenine analog, 4-aminopyrazolo [3,4-d]pyrimidine, readily formed analog nucleotides and was highly cytotoxic to all the lines. It is postulated that the corresponding adenine analog 5'-phosphorylated nucleotides are the primary active metabolites of these MTA analogs, having been formed by the cleavage of these nucleosides to free adenine analogs by MTAPase, followed by the conversion of these base analogs to analog nucleotides by adenine phosphoribosyltransferase and the enzymes of adenine nucleotide phosphorylation. This pathway represents a novel drug-activation system for the synthesis of analog nucleotides and has the potential to be exploited chemotherapeutically.

Adenosine↗
PubMed1983

Response of a human colon adenocarcinoma (DLD-1) to X irradiation and mitomycin C in vivo.

Mice hosting a heterogeneous human colon xenograft tumor produced by subcutaneous injection of the DLD-1 tumor cell line were treated either with x irradiation alone, with mitomycin C alone (4 mg/kg), or with x irradiation given two hours after intraperitoneal injection of mitomycin C (4 mg/kg). Radiation alone produced a dose dependent delay in the time needed for tumors to regrow to twice their size at the time of irradiation, and in the mice receiving mitomycin C plus x irradiation, an additional growth delay equivalent to that produced by 3-3.5 Gy of X rays was seen at all X ray dose levels. As the DLD-1 tumor xenografts do not appear to possess a significant hypoxic fraction, we conclude that the two agents are acting in a simple additive cytotoxic manner by the killing of oxic tumor cells.

Adenocarcinoma↗
PubMed1983

Survival responses of cell subpopulations isolated from a heterogeneous human colon tumour after combinations of hyperthermia and X-irradiation.

In summary, this research has investigated the effects of combined modality treatment (i.e., low linear energy transfer ionizing radiation and hyperthermia at 42.5 degrees C) on the survival responses of two tumour subpopulations (designated clones A and D) obtained from a heterogeneous human colon adenocarcinoma. A constant hyperthermic exposure (2 hours at 42.5 degrees C) was given either 3 min before or 3 min after graded exposure to X-rays. An isobologram analysis (Steel and Peckham 1979) of the clonogenic survival responses of the two tumour subpopulations showed that the clone A responses were within the envelope of additivity for either sequence of application. In contrast, the responses of the clone D tumour subpopulation exhibited a supra-additive response to the combined treatments with the sequence of heat followed by X-irradiation being somewhat more effective than the sequence of X-irradiation followed by heat. These data indicate that the responses of tumour subpopulations obtained from heterogeneous solid tumours to combined modality treatments may vary in an, at present, unpredictable manner.

Cell Survival↗
PubMed1983

Human tumor cell heterogeneity and metastasis.

Heterogeneity within malignant neoplasms, although described for many years by pathologists, has only recently been extensively studied in the laboratory. It is now accepted that most tumors are composed of subpopulations of cells that differ in many phenotypic characteristics including the ability to form a metastasis. Cells with the capacity to metastasize are the ones most likely to prove lethal to the patient since clinicians can often control the primary neoplasm with surgery or radiotherapy. In this report the process of metastasis is discussed, those aspects of tumor cell heterogeneity that are relevant to this process are reviewed, intrapatient tumor heterogeneity is explored, and future preclinical studies are evaluated that may be useful in designing treatment strategies for patients with disseminated malignancies.

Animals↗
PubMed1983

Conversion of 5'-deoxy-5'-methylthioadenosine and 5'-deoxy-5'-methylthioinosine to methionine in cultured human leukemic cells.

5'-Deoxy-5'-methylthioadenosine and 5'-deoxy-5'-methylthioinosine, which are metabolized to the methionine precursor, 5-methylthioribose-1-phosphate, by 5'-deoxy-5'-methylthioadenosine phosphorylase and purine nucleoside phosphorylase, respectively, can serve as sources of methionine for cultured HL-60 promyelocytic leukemia cells. CCRF-CEM T-cell leukemia cells, which lack 5'-deoxy-5'-methylthioadenosine phosphorylase, convert 5'-deoxy-5'-methylthioinosine (but not 5'-deoxy-5'-methylthioadenosine) to methionine; this conversion is blocked by purine nucleoside phosphorylase inhibitors. Therefore, the pathway for the conversion of 5-methylthioribose-1-phosphate to methionine is present in both human leukemic lines.

Adenosine↗
PubMed1983

Differential expression of tumor-associated antigens in human colon carcinomas xenografted into nude mice.

The tumor-associated antigen profile of a number of different human colon carcinomas xenografted into inbred Swiss nude mice was examined to determine whether the tumors could serve as useful models for antigen purification, radioimmunodetection, and immunotherapy. Extreme heterogeneity was observed both by radioimmunoassay and immunohistochemical procedures for the expression of carcinoembryonic antigen (CEA), colon-specific antigens (CSAp), and colonic mucin antigen (CMA) within the tumors. Four of 10 tumors (DLD-2, DLD-3, DLD-5, and HCT-10) were high producers of CEA (greater than 75 micrograms/g wet tissue wt). Two of these (DLD-2 and HCT-10) correlated with a high production of CSAp and CMA, whereas the other 2 produced low quantities of these antigens. Another tumor, HCT-14-OM1, produced large amounts of CMA yet produced moderate amounts of CEA and low quantities of CSAp. Immunohistochemical analyses of CEA gave a mostly diffuse cellular and cell surface staining for all of the tumors. Staining for CSAp was very focal, as in DLD-5 where only a few of the tumor cells were stained. Staining of CMA was limited; however, DLD-2, HCT-10, and HCT-14-OM1 showed intense cystoplasmic and intraluminal staining. A determination of the tumor antigen profile may be useful in characterization and classification of the tumor as well as enabling the selection of the proper antibody or antibodies for immunodetection and immunotherapy.

Animals↗
PubMed1983

Nude mouse model of the melanosis syndrome.

The occurrence of diffuse hyperpigmentation secondary to a xenografted human malignant melanoma was observed in nude mice. The patient from whom this cell line was established developed cutaneous hyperpigmentation after his disease became disseminated. Light and electron microscopy studies were performed on skin and organ biopsy specimens from the hyperpigmented mice. These studies indicated that this melanoma-associated melanosis was secondary to the release of pigment granules from the xenografted tumors and to the uptake of these granules by macrophages throughout the body, including those located in the dermis.

Adult↗
PubMed1983

Biochemical pharmacology and toxicology of formycin alone and in combination with 2'-deoxycoformycin (pentostatin).

The toxicology and pharmacology of formycin both as a single agent and combined with the adenosine deaminase inhibitor 2'-deoxycoformycin (dCF) were examined in outbred Swiss mice heterozygous for the nude gene (nu/+). The LD10 for formycin alone given on a daily x 5 schedule was 21 mg/kg. When the animals were pretreated with 1 mg/kg of dCF 1 hour prior to each dose of formycin, toxicity was approximately doubled, ie, LD10 was reduced to 10 mg/kg. Death was associated with hepatic toxicity in both treatment regimens; suppression of leukocyte counts was mild except at doses greater than the LD10. Formycin nucleotides were detected by high-performance liquid chromatography in the livers of mice treated with formycin either alone or combined with dCF. When isolated rat hepatocytes were incubated for 2 hours with either formycin or dCF plus formycin, analog nucleotides accumulated in the cells. Cellular ATP decreased to below the limits of detection, whereas a large peak corresponding to formycin-5'-triphosphate was present. This replacement of cellular ATP by formycin-5'-triphosphate may help explain the hepatic toxicity observed.

Adenosine Deaminase Inhibitors↗