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G J Finlay

Publications and source records attributed to G J Finlay.

67 records · Page 4Linked to original sources
PubMed1986

Comparison of in vitro activity of cytotoxic drugs towards human carcinoma and leukaemia cell lines.

Eight human haematopoietic cell lines and four human carcinoma lines were used to compare the activity of a number of cytotoxic drugs including amsacrine, the amsacrine analogue CI-921, methotrexate, nitracrine, doxorubicin, daunorubicin and 5-fluorouracil. Activity was assessed by means of semiautomated microculture growth inhibition assays. Cell density of the non-adherent cell lines was measured using the technique of Mosmann (J Immunol Methods 1983, 65, 55-63), in which the dye thiazolyl blue (MTT) is metabolised to a dark blue formazan product. This technique gives similar results to those obtained by direct cell counting in an electronic cell counter, and when applied to some adherent cell lines gives similar results to those obtained by the methylene blue staining technique previously developed (Anal Biochem 1984, 139, 272-277). Both methylene blue and MTT methods were used to investigate cytotoxicity in conjunction with semi-automated 96-well microculture plate techniques. The results show that the three T-cell leukaemia lines (CCRF-CEM, Jurkat and MOLT-4) are more sensitive to DNA-binding drugs (excluding nitracrine) than are the colon carcinoma lines (HCT-8, HT-29, SW480 and SW620). The more resistant haematopoietic lines are intermediate in drug sensitivity between the T cell leukaemia and carcinoma lines. The DNA binding drugs show remarkably similar patterns of differential activity against the different cell lines.

Aminoacridines↗
PubMed1986

Potential antitumor agents. 47. 3'-Methylamino analogues of amsacrine with in vivo solid tumor activity.

Replacement of the 3'-methoxy group of the clinical antileukemic agent amsacrine with a 3'-methylamino group provides a compound (3) with a broader spectrum of action, including in vivo activity against experimental solid tumors. The synthesis, physicochemical properties, and biological activity of a series of acridine-substituted analogues of 3 are described. The compounds show higher levels of DNA binding, water solubility, and in vivo solid tumor activity (lewis lung carcinoma) than their amsacrine counterparts. However, the structure-activity relationships for acridine substitution are different, with 3,5-disubstituted 3'-methylamino compounds showing the highest activity (compared to 4,5-disubstituted amsacrine analogues).

Acridines↗
PubMed1985

Human tumor cells in culture stimulate glycosaminoglycan synthesis by human skin fibroblasts.

The human tumor cell lines, MM-96, FME, HCT-8, HT-29, MCF-7 and T-47D, in culture produced a factor or factors able to stimulate glycosaminoglycan (GAG) synthesis in human skin fibroblasts (HF). Conditioned growth media from the melanoma MM-96 and the colon carcinoma HT-29 produced a 10- and 8-fold stimulation of HF GAG synthesis, respectively, with an even larger stimulation of hyaluronic acid. Conditioned media from the melanoma FME and the breast carcinomas MCF-7 and T-47D stimulated GAG synthesis 2-fold, whereas media from the colon carcinoma HCT-8 gave a variable response often with no effect on GAG levels. Conditioned media from HF cultures had no effect on tumor cell GAG synthesis. Coculture of tumor cells and HF also resulted in increased GAG synthesis, and the degree of stimulation was similar to that with the conditioned media. Tumor cell-conditioned media were also effective in stimulating GAG synthesis by porcine smooth muscle cells and by chick embryo fibroblasts in culture, although the increase in GAG synthesis was much less than with HF cultures. These findings support the concept that the stromal desmoplasia characteristic of many growing and invasive tumors in vivo arises by tumor cell modulation of GAG synthesis by surrounding normal connective tissue cells.

Cell Communication↗
PubMed1984

A semiautomated microculture method for investigating growth inhibitory effects of cytotoxic compounds on exponentially growing carcinoma cells.

A method is described by which the growth inhibitory effects of cytotoxic compounds on exponentially growing adherent cell lines can be quantitated. Cultures are established in microtiter plates and the cytotoxic compounds to be tested are added after 2 days. Dilution series are constructed within the microcultures using 8-channel micropipets designed for use with microtiter plates. To measure growth after several days of drug exposure, adherent cell layers are fixed, stained, and the plates washed in water to remove excess stain. After stained cells are air-dried and solubilized, absorbance is determined using spectrophotometers designed for reading of microtiter trays. This method is reproducible and offers the advantage that any adherent cell line can be utilized without the need for tedious cell-counting procedures.

Adenocarcinoma↗
PubMed1984

The use of human cancer cell lines as a primary screening system for antineoplastic compounds.

Exponentially growing cells of human cancer lines have been utilized to investigate the cytotoxic activity of antineoplastic agents. Different cancer cell lines differ greatly in their responsiveness to both clinical and experimental cytotoxic drugs. For example, sensitivities to 5-fluorouracil and cytosine arabinoside ranged over 15- and 30-fold respectively. Cell lines derived from carcinomas were more sensitive to 5-fluorouracil and less sensitive to cytosine arabinoside than was a leukaemic cell line. In general, colon carcinoma lines were most resistant to DNA-intercalating drugs, and a breast carcinoma and leukaemia line most sensitive. In a congeneric series of amsacrine analogues, in vitro patterns of activity against different lines were shown to correlate with activity against the Lewis lung mouse carcinoma in vivo. Results suggest that established cell lines manifest responsiveness to anticancer drugs consistent with that expected from their tumours of origin. This assay is economical, reproducible and convenient, and could be used to complement the human tumour stem cell assay in drug development studies.

Antineoplastic Agents↗
PubMed1984

Potential antitumor agents. 43. Synthesis and biological activity of dibasic 9-aminoacridine-4-carboxamides, a new class of antitumor agent.

The synthesis and biological activities of representatives of a new class of antitumor agent, the N-[2-(dialkylamino)ethyl ]-9-aminoacridine-4-carboxamides, are reported. Members of this class are stable and very water soluble with high levels of in vitro and in vivo antitumor activity. The compounds bind tightly to double-stranded DNA by intercalation, but the requirements for antitumor activity are more restrictive. They depend critically on the separation distance, positioning, and pKa values of the two cationic centers. For in vivo activity, significant bulk tolerance exists for lipophilic but not hydrophilic groups about the C-9 acridine position and for both lipophilic and hydrophilic groups on the side-chain cationic moiety. Significant attenuation of the pKa of the side-chain cationic center abolishes activity, as does alteration of either the disposition or separation distance of the side-chain charge with respect to the chromophore.

Adenocarcinoma↗
PubMed1984

Synthesis, antitumor activity, and DNA binding properties of a new derivative of amsacrine, N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino) phenylamino]-4-acridinecarboxamide.

The 4-(N-methylcarboxamido)-5-methyl derivative of amsacrine (NSC 249 992) has been synthesized as part of a program aimed at optimizing solid tumor activity in this series. Physicochemical studies of this analogue (N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino) phenylamino]-4-acridinecarboxamide; NSC 343 499) indicate a slightly increased lipophilicity (estimated log p = 1.10), a decreased acridine base strength (pKa 6.40), and a 16-fold-higher association constant for double-stranded calf thymus DNA (Ka 2.1 X 10(6) M-1 at 0.01 ionic strength). Like amsacrine, the drug binds to DNA by intercalation. Inhibition of cell growth has been monitored by continuous drug exposure assays with a variety of rodent and human cell lines. The concentration for 50% inhibition varied from 6.7 nM (T-47D, a human breast carcinoma line) to 800 nM (P388/ADR, a murine cell line resistant to Adriamycin). N-5-Dimethyl-9-[(2-methoxy-4-methylsulfonylamino) phenylamino]-4-acridinecarboxamide was cytotoxic at growth-inhibitory concentrations and also induced cell cycle arrest in the G2 phase. It was active against P388 leukemia following administration by p.o., i.v., or i.p. routes, and it was superior to amsacrine, daunorubicin, and Adriamycin. It was curative towards i.v.-injected Lewis lung tumor in a proportion of animals when treatment was started on Day 1 or Day 5 after tumor inoculation. It also produced highly significant life extensions against advanced tumors (treatment starting Day 9 after i.v. inoculation or on Day 8 after s.c. inoculation) and was comparable to cyclophosphamide in its effectiveness. It is a candidate drug for clinical trial.

Aminoacridines↗
PubMed1983

Insulin receptor regulation in cultured human tumor cells.

Insulin binding to monolayer cell cultures of human fibroblasts, human colon carcinoma (HCT-8, HT-29), human breast carcinoma (MCF-7, T-47D), and melanoma (MM-96) was measured using 125I-insulin. Binding was time and temperature dependent in all cell lines, and only one cell line (MM-96) degraded 125I-insulin. High-affinity insulin-binding sites (Kd = 1.4 X 10(-9) M to 0.4 X 10(-10) M) were detected in all cell lines, and insulin-binding capacity ranged from 0.6 to 14 fmol/10(6) cells. Receptor down-regulation was studied by exposing cells to increasing concentrations of unlabeled insulin, dissociating surface-bound insulin and measuring residual receptors by 125I-insulin uptake. Exposure of tumor cells to greater than 10(-6) M insulin for 2 hr at 37 degrees led to a decrease in the number of insulin binding sites in MM-96 and colon cell lines only, with maximum down-regulation ranging from 58% (MM-96) to 88% (HCT-8) receptor loss. The decrease in insulin binding was due to a decreased number of receptors per cell with no change in affinity. Monolayers exposed to 1.7 X 10(-5) M unlabeled insulin for 7 hr at 37 degrees invariably showed greater than 50% receptor loss. However, monolayers exposed to 1.7 X 10(-8) M unlabeled insulin for 7 hr at 37 degrees showed less marked (0 to 39%) down-regulation. In comparison, human fibroblasts showed 57% receptor loss after exposure to 3.5 X 10(-9) M unlabeled insulin for 7 hr. Thus, markedly supraphysiological concentrations of insulin are required to down-regulate insulin receptors in tumor cell lines compared with normal cells. This suggests a tumor-associated resistance to receptor down-regulation.

Blood↗
PubMed1979

Antibody responses of human lymphocytes in vitro. Specificity and physical properties of plaque-forming cell precursors.

When human tonsillar lymphocytes are cultured with pokeweed mitogen they generate a larger number of antibody-secreting cells. A substantial number of the plaque-forming cells generated have specificity for sheep erythrocytes but very few are specific for either bovine or horse erythrocytes. We have investigated the physical properties of sheep erythrocyte-specific precursors and have found that they have the characteristics of larger lymphocytes and are heterogeneous with respect to density. Our results support the concept that the percursors which can be induced by pokeweed mitogen to develop into plaque-forming cells belong to a pre-activated sub-population of lymphocytes.

Animals↗
PubMed1979

Antibody responses of human lymphocytes in vitro. Enhancing effects of hydrocortisone.

Cultures of human tonsillar lymphocytes stimulated by pokeweed mitogen in the presence of hydrocortisone succinate generate more sheep red blood cell-specific plaque-forming cells than when the hydrocortisone is absent. Such enhancement is even more marked when sheep red blood cells and pokeweed mitogen are present in cultures. This contrasts with the inability of sheep red blood cells to enhance pokeweed mitogen-stimulated response in cultures lacking hydrocortisone. Hydrocortisone causes greater enhancement when the concentration of cells in culture is high than when it is low. These data are consistent with hydrocortisone inhibiting the activity of suppressor cells which would otherwise mask helper effects.

Animals↗
PubMed1977

Interferon-induced antibody suppression: a selective effect on high density, late responding precursor cells.

Mouse spleen cells have been fractionated into three subpopulations by density gradient centrifugation and the effect of interferon on the ability of each fraction to generate an antibody response in vitro has been examined. The results show that only the antibody-forming cell precursors (AFCP) of the high density, late responding fraction are suppressed by interferon. The presence of interferon had no effect on either the number or the mean size of clones of antibody-forming cells in cultures of the low and medium density fractions. Interferon-mediated suppression of the response of high density precursors was due to a decrease in the number but not the size of responding clones. These results suggest that interferon suppresses antibody responses by affecting the degree to which high density AFCP can becoming activated rather than the degree to which precursors proliferate.

Animals↗
PubMedDate not supplied

Cytotoxicity of salicylaldehyde benzoylhydrazone analogs and their transition metal complexes: quantitative structure-activity relationships.

A series of salicylaldehyde benzoylhydrazone derivatives, their copper(II) complexes and a range of transition metal complexes of the unsubstituted ligand has been synthesized and evaluated for cytotoxicity against a human adenocarcinoma cell line. A QSAR analysis revealed ligand cytotoxicity is strongly correlated with electronic and transport factors and can be modeled by treating each 'half' of the molecule as an isolated unit. Activity increases when substituents in the benzoyl ring were electron withdrawing whereas, for the salicylaldehyde ring, electron donation was required. The cytotoxicity of the Cu(II) complexes was greater than, and paralleled the ligands. Activity for the transition metal complexes of the unsubstituted ligand mirrored charge density on the metal.

Benzaldehydes↗