Graeme John Finlay

Graeme John Finlay
University of Auckland · Department of Molecular Medicine and Pathology

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100
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Introduction

Publications

Publications (100)
Article
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Glioblastoma is considered the most aggressive and lethal form of brain cancer. Glioblastoma tumours are complex, comprising a spectrum of oncogenically transformed cells displaying distinct phenotypes. These can be generated in culture and are called differentiated-glioblastoma cells and glioblastoma stem cells. These cells are phenotypically and...
Article
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Background Most of the eukaryotic genome is transcribed, yielding a complex network of transcripts including thousands of lncRNAs that generally lack protein coding potential. However, only a small percentage of these molecules has been functionally characterised, and discoveries of specific functions demonstrate layers of complexity. A large perce...
Article
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GRIN2A mutations are frequent in melanoma tumours but their role in disease is not well understood. GRIN2A encodes a modulatory subunit of the N-methyl-d-aspartate receptor (NMDAR). We hypothesized that certain GRIN2A mutations increase NMDAR function and support melanoma growth through oncogenic effects. This hypothesis was tested using 19 low-pas...
Article
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Melanocytes are melanin-producing cells found in skin, hair follicles, eyes, inner ear, bones, heart and brain of humans. They arise from pluripotent neural crest cells and differentiate in response to a complex network of interacting regulatory pathways. Melanins are pigment molecules that are endogenously synthesized by melanocytes. The light abs...
Chapter
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Recent genomic and transcriptomic analysis has revealed that the majority of the human genome is transcribed as nonprotein-coding RNA. These transcripts, known as long noncoding RNA, have structures similar to those of mRNA. Many of these transcripts are now thought to have regulatory roles in different biological pathways which provide cells with...
Chapter
Noncoding RNAs are RNA species that do not encode for proteins, and the majority of the human transcriptome is dominated by ncRNA. Recent extensive genomic and transcriptomic analyses have identified many different classes and sizes of ncRNA. They are now understood to be critical to the overall functioning, growth, development, and differentiation...
Article
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The mammalian target of rapamycin (mTOR), a vital component of signaling pathways involving PI3K/AKT, is an attractive therapeutic target in breast cancer. Everolimus, an allosteric mTOR inhibitor that inhibits the mTOR functional complex mTORC1, is approved for treatment of estrogen receptor positive (ER+) breast cancer. Other mTOR inhibitors show...
Article
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Abstract The development and progression of melanoma have been attributed to independent or combined genetic and epigenetic events. There has been remarkable progress in understanding melanoma pathogenesis in terms of genetic alterations. However, recent studies have revealed a complex involvement of epigenetic mechanisms in the regulation of gene...
Article
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The majority of the human genome is transcribed, even though only 2% of transcripts encode proteins. Non-coding transcripts were originally dismissed as evolutionary junk or transcriptional noise, but with the development of whole genome technologies, these non-coding RNAs (ncRNAs) are emerging as molecules with vital roles in regulating gene expre...
Article
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Cellular signaling pathways involving mTOR, PI3K and ERK have dominated recent studies of breast cancer biology, and inhibitors of these pathways have formed a focus of numerous clinical trials. We have chosen trametinib, a drug targeting MEK in the ERK pathway, to address two questions. Firstly, does inhibition of a signaling pathway, as measured...
Article
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The transcription factor SOX2 is essential for maintaining pluripotency in a variety of stem cells. It has important functions during embryonic development, is involved in cancer stem cell maintenance, and is often deregulated in cancer. The mechanism of SOX2 regulation has yet to be clarified, but the SOX2 gene lies in an intron of a long multi-ex...
Article
SN 28049 is a new DNA-binding topoisomerase II poison identified by its curative activity against the murine colon 38 carcinoma. Previous studies showed activity to be associated with selective drug accumulation and retention in tumour tissue. Retention varied widely among different tumours and was related to antitumour activity. We determined whet...
Article
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The MCF-7 line, derived in 1973 from a malignant pleural effusion, is one of the most commonly used culture models for human breast cancer. Despite its long history, MCF-7 is a surprisingly heterogeneous line. We previously showed that if MCF-7 cells were cultured for a prolonged period either in the absence of estrogen or in the presence of the an...
Article
Full-text available
Previous whole-exome sequencing has demonstrated that melanoma tumors harbor mutations in the GRIN2A gene. GRIN2A encodes the regulatory GluN2A subunit of the glutamate-gated N-methyl-d-aspartate receptor (NMDAR), involvement of which in melanoma remains undefined. Here, we sequenced coding exons of GRIN2A in 19 low-passage melanoma cell lines deri...
Article
A variety of anticancer drugs, including doxorubicin and mitoxantrone, have structures in which a DNA-intercalating chromophore is linked to a positively charged side chain. These drugs generally inhibit tumour growth and survival by poisoning the enzyme DNA topoisomerase II. SN 28049, a benzonaphthyridine derivative with these properties, has cura...
Article
Full-text available
The epithelial–mesenchymal transition (EMT) describes a reversible switch from an epithelial-like to a mesenchymal-like phenotype. It is essential for the development of the normal epithelium and also contributes to the invasive properties of carcinomas. At the molecular level, the EMT transition is characterized by a series of coordinated changes...
Article
Full-text available
The Hippo signaling pathway comprises a series of cytoplasmic tumor suppressor proteins including Merlin and the Lats1/2 and MST1/2 kinases, and is thought to play a critical role in determining the sizes of organs and tissues. The Hippo pathway is regulated upstream by extracellular mechanosensory signaling arising from cell shape and polarity, as...
Article
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The NRAS and BRAF genes are frequently mutated in melanoma, suggesting that the NRAS-BRAF-MEK-ERK signaling pathway is an important target for therapy. Two classes of drugs, one targeting activated BRAF and one targeting MEK, are currently undergoing clinical evaluation. We have analysed the NRAS and BRAF mutational status of a series of 44 early p...
Article
Full-text available
The phosphatidylinositol-3-kinase (PI3K-PKB), mitogen activated protein kinase (MEK-ERK) and the mammalian target of rapamycin (mTOR- p70S6K), are thought to regulate many aspects of tumour cell proliferation and survival. We have examined the utilisation of these three signalling pathways in a number of cell lines derived from patients with metast...
Data
Table S1 PCR primer and sequencing primer sequences used for the study. The Reference sequences (NCBI) for PTEN-NT_030059.12, PIK3CA-NT_000003.11, NRAS-NC_000001.10 and BRAF-NC_000007.13. # The BRAF exon 11 PCR primers were taken from Davies et al. [9]. *The primers for exon 9-13 of PIK3CA were designed to not match a pseudogene on chromosome 22 [5...
Article
SN 28049 (N-[2-(dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide) is a new DNA binding drug that targets topoisomerase II. SN 28049 is curative against the murine Colon 38 adenocarcinoma (CT38) while etoposide, another topoisomerase II-directed drug, shows minimal activity; we investigated the basis for th...
Article
We have examined the cellular action of SN 28049 (N-[2-(dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide), a DNA binding drug with curative activity against the Colon 38 transplantable murine carcinoma, on human tumour cells. Its action has been compared with that of two topoisomerase II-targetted drugs, e...
Article
Correct partitioning of the replicated genome during mitosis is orchestrated by centrosomes, and chromosomal instability is a commonly reported feature of human cancer. Melanomas are notorious for their genetic instability and rapid clonal evolution that may be manifested as aggressive growth and facile generation of therapy-resistant variants. We...
Article
Full-text available
Treatment with anti-estrogens or aromatase inhibitors is commonly used for patients with estrogen receptor-positive (ER+) breast cancers; however resistant disease develops almost inevitably, requiring a choice of secondary therapy. One possibility is to use inhibitors of the PI3K/mTOR pathway and several candidate drugs are in development. We exam...
Article
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ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Article
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Article
Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC ASA404, a Tumor-Vascular Disrupting Agent developed at the Auckland Cancer Society Research Centre, is currently undergoing two Phase III clinical trials (Novartis) against non-small cell lung cancer. Its early effects on tumor tissue include increased tumor vascular per...
Chapter
The organization of normal tissues and organs is thought to be based on stem cells, which are present as a small proportion of the total tissue. Stem cells in turn absolutely require supporting structures to maintain their self-renewal properties and such structures are termed niches. A large amount of evidence now supports the concept that tumors...
Article
SN 28049 (N-[2-(dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide) is a DNA intercalating drug that binds selectively to GC-rich DNA and shows curative activity against the Colon 38 adenocarcinoma in mice. We wished to investigate the roles of topoisomerase (topo) I, topo II and RNA transcription in the act...
Article
A series of mono- and dimeric N-methylquindoline carboxamides were prepared by Friedlander condensation between methyl 2-amino-3-formyl benzoate and 3-acetoxy-1-acetylindoles, followed by exhaustive methylation with methyl iodide to give N-methylquindoline esters. Direct amination of these, or hydrolysis to the acids and amine coupling via intermed...
Article
Symmetrical dimers of lipophilic intercalating chromophores linked by cation-containing chains have recently been shown to have broad-spectrum in vivo anticancer activity. We report the preparation and evaluation of a series of both symmetric and unsymmetric dimers of a variety of intercalating chromophores of varied DNA binding strength, including...
Article
DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride) has high experimental antitumor activity and has completed phase I/II clinical trials. It targets both topoisomerase (topo) I and II, but the roles of each of these enzymes in the antitumour action of DACA are not known. We have used a series of DACA analogues (mainly monosubst...
Article
A series of 7-oxo-7H-dibenz[f,ij]isoquinoline and 7-oxo-7H-benzo[e]perimidines bearing cationic side chains were prepared from aminoanthraquinones. The perimidines were prepared from 1-aminoanthraquinone by initial condensation with urea or dimethylacetamide. A series of 2-, 4-, 8-, and 11-carboxy derivatives of the dibenzisoquinolines were prepare...
Article
A series of 7-oxo-7H-dibenz [f,ij]isoquinoline and 7-oxo-7H-benzo[e] perimidines bearing cationic side chains were prepared from aminoanthraquinones. The perimidines were prepared from 1-aminoanthraquinone by initial condensation with urea or dimethylacetamide. A series of 2-, 4-, 8-, and 11-carboxy derivatives of the dibenzisoquinolines were prepa...
Article
Bis(9-methylphenazine-1-carboxamides) joined by a variety of dicationic (CH(2))(n)()NR(CH(2))(m)NR(CH(2))(n) linkers of varying length (carboxamide N-N distances from 11.0 to 18.4 A) and rigidity were prepared by reaction of 9-methylphenazine-1-carboxylic acid imidazolide with the appropriate polyamines. The compounds were evaluated for growth inhi...
Article
A series of 11-oxo-11H-indeno[1,2-b]quinolines bearing a carboxamide-linked cationic side chain at various positions on the chromophore was studied to determine structure-activity relationships between cytotoxicity and the position of the side chain. The compounds were prepared by Pfitzinger synthesis from an appropriate isatin and 1-indanone, foll...
Article
New substituted indeno[1,2-b]quinoline-6-carboxamides, [1]benzothieno[3,2-b]quinoline-4-carboxamides and 10H-quindoline-4-carboxamides were prepared from methyl 2-amino-3-formylbenzoate by a new Friedlander synthesis. Evaluation of these carboxamides for cytotoxicity in a panel of cell lines showed that small lipophilic substituents in the non-carb...
Article
A series of benzimidazo[2,1-a]isoquinolines with carboxamide side chains at the 1-, 6-, 9- and 11-positions were prepared, in order to study the biological effects of varying the position of the side chain in this tetracyclic series. The 6-, 9- and 11-analogues were obtained by modifications to published chemistry. The 1-carboxamide analogue was ob...
Article
A series of bis(11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides) linked through the 6-carboxamides were prepared by coupling the requisite acid imidazolides with various diamines. Compounds with mono-cationic linker chains were more potent cytotoxins than the corresponding monomer in a panel of rodent and human cell lines, while those with the dic...
Article
Ring-substituted bis(phenazine-1-carboxamides), linked by a -(CH(2))(3)NMe(CH(2))(3)- chain, were prepared from the corresponding substituted phenazine-1-carboxylic acids by reaction of the intermediate imidazolides with bis(3-aminopropyl)methylamine. The compounds were evaluated for growth inhibitory activity in a panel of tumor cell lines, includ...
Article
We set out to measure drug binding to serum proteins. These have been shown to reduce the free plasma concentrations of a number of anticancer drugs, particularly of those of complex organic structure, in both experimental studies and clinical trials. We have used cultures of murine Lewis lung carcinoma cells as sensors of available drug to measure...
Article
A series of ring-substituted analogues of the topoisomerase inhibitor 11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides was prepared and evaluated. The compounds were prepared by Pfitzinger reaction of the appropriate isatin-7-carboxylic acids and 1-indanones, followed by selective thermal decarboxylation of the resulting tetracyclic diacids, subseq...
Article
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 fac...
Article
A series of acridine-substituted bis(acridine-4-carboxamides) linked by a (CH2)3N(Me)(CH2)3 chain have been prepared by reaction of the isolated imidazolides of the substituted acridine-4-carboxylic acids with N,N-bis(3-aminopropyl)methylamine. These dimeric analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-ca...
Article
Methyl N-(4'-(9-acridinylamino)-phenyl)carbamate hydrochloride (AMCA) and methyl N-(4'-(9-acridinylamino)-2-methoxyphenyl)carbamate hydrochloride (mAMCA) are analogues of the topoisomerase II (topo II) poison amsacrine, and are distinguished from amsacrine by their high cytotoxicity towards non-cycling cells. Since mammalian cells contain two forms...
Article
Full-text available
N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA), a DNA intercalating dual topoisomerase I/II poison, has high experimental antitumour activity, is able to overcome several forms of multidrug resistance, and is undergoing clinical trial. We prepared 3H-labelled DACA and investigated its uptake using cultured Lewis lung carcinoma cells (LLTC)...
Article
A series of tricyclic aromatic carboxamides, and their corresponding dimeric analogues, were prepared and their growth-inhibitory properties were evaluated in a series of cell lines. The dimeric compounds were prepared by reaction of the appropriate acids with carbonyl-1,1'-diimidazole, isolating the resulting imidazolides, and reacting these with...
Article
DACA is a DNA-intercalating agent and dual topoisomerase (topo) I/II inhibitor currently in clinical trial as an anticancer drug. Substitutions in the acridine ring of DACA have significant effects on biological activity, with 5-substituted analogues being more potent but relatively less active against cell lines that underexpress topo II, and the...
Article
The action of the anticancer drug amsacrine appears to involve molecular interactions with both DNA and topoisomerase II. It has been shown previously that DNA intercalators can inhibit the action of amsacrine and several other topoisomerase II poisons, presumably as a result of interference with the DNA binding sites for the enzyme. We show here t...
Article
The culture of surgical tumor specimens has long been considered as a potential approach to the tailoring of chemotherapy and radiotherapy to the individual patient, and to the development of improved therapy. Recent work highlighting the importance of cell-cell interactions in the growth and survival of cancer tissue, as well the demonstrated impo...
Article
DACA [N-[2-(dimethylamino)ethyl]acridine-4-carboxamide], an acridine derivative that is highly active against solid tumours in mice, is currently in clinical trial. The ability of DACA to overcome "atypical" (topoisomerase II-mediated) multidrug resistance has been hypothesised to stem from its dual topoisomerase I/II specificity. We investigated t...
Article
The acridine derivative m-AMCA (methyl-N-[4-(9-acridinylamino)-2-methoxyphenyl]carbamate hydrochloride), a carbamate analogue of the topoisomerase II poison amsacrine, is distinguished by its high cytotoxicity against non-cycling tumour cells. We compared the response of cultured Lewis lung carcinoma cells to m-AMCA, amsacrine and the topoisomerase...
Article
A series of tetracyclic quinoline- and quinoxalinecarboxamides were prepared, and their cytotoxicities were evaluated in a series of murine human tumor cell lines. Most of the quinoline derivatives were prepared by an adaptation of the Pfitzinger synthesis, followed by thermal decarboxylation and coupling with N,N-dimethylethylenediamine via a mixe...
Article
The mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is currently in clinical trial as an anticancer drug. A series of acridine-substituted analogues were prepared, using a new synthetic route to substituted acridine-4-carboxylic acids (conversion of substituted diphenylamine diacid monoesters to the corres...
Article
AMCA (methyl N-[4-(9-acridinylamino)-2-methoxyphenyl]carbamate hydrochloride), an amsacrine analogue containing a methylcarbamate rather than a methylsulphonamide side chain, contrasts with amsacrine, doxorubicin and etoposide in its relatively high cytotoxicity against non-cycling tumour cells. AMCA bound DNA more tightly than amsacrine, but the D...
Article
Aclarubicin and doxorubicin are DNA binding anthracycline antibiotics of related chemical structure but differing cytotoxic action. Although doxorubicin mediates its cytotoxicity by poisoning the enzyme topoisomerase II, aclarubicin has been hypothesized to inhibit the catalytic action of topoisomerase II. We show here that aclarubicin, in contrast...
Article
A number of acridine derivatives, including the clinical antileukaemia agent amsacrine and the experimental agent DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide), target the enzyme topoisomerase II. We demonstrate here that DACA induces DNA cleavage in the presence of topoisomerase I as well as of topoisomerase II. We also investigate a ser...
Article
Paclitaxel, a drug which stabilises microtubules, demonstrates marked activity against ovarian cancer. We investigated the sensitivity to paclitaxel of tumour cells from disaggregated solid tumours or tumour-bearing ascites from 7 ovarian cancer patients, and 21 established tumour cell lines (ovarian, melanoma and lung). Response was quantitated by...
Article
1. The solid tumour has various properties which tend to minimize the effects of a cytotoxic agent; the low vascular density of tumours, in particular, limits the diffusion of many anti-tumour drugs. 2. This applies particularly to two general classes of anti-cancer drugs which already play an important role in chemotherapy: mitotic poisons and top...
Article
1. The solid tumour has various properties which tend to minimize the effects of a cytotoxic agent; the low vascular density of tumours, in particular, limits the diffusion of many anti-tumour drugs. 2. This applies particularly to two general classes of anti-cancer drugs which already play an important role in chemotherapy: mitotic poisons and top...
Article
The cytotoxicity of a class of compounds related to the topoisomerase-II poison amsacrine was investigated against plateau-phase murine Lewis lung carcinoma cells (LLTC), HCT-8 human colon carcinoma cells and other cell lines. MethylN-[4-(9-acridinylamino)-2-methoxy-phenyl]carbamate hydrochloride and the corresponding demethoxy compound, which cont...
Article
The cytotoxicity of a class of compounds related to the topoisomerase-II poison amsacrine was investigated against plateau-phase murine Lewis lung carcinoma cells (LLTC), HCT-8 human colon carcinoma cells and other cell lines. Methyl N-[4-(9-acridinylamino)-2-methoxy-phenyl]carbamate hydrochloride and the corresponding demethoxy compound, which con...
Article
Seven new low-passage melanoma lines were developed in this laboratory from clinical melanoma specimens and characterised for chromosome complement, DNA ploidy and S-phase content. The radiosensitivity of these lines was compared with that of eight established melanoma cell lines, FME, MM-96, SK-MEL-5, SK-MEL-28, SK-MEL-2, MALME-3M, M19-MEL and LOX...
Article
Genistein is an inhibitor of the enzymes protein tyrosine kinase and topoisomerase-II. It induces G2-phase arrest in human Jurkat and murine P388 leukemia cells at concentrations at which it is also cytotoxic. The effects of genistein have been investigated on Jurkat and P388 leukemia sublines that manifest multidrug resistance. Cells that possess...
Article
Colorectal cancer (CRC) develops through several histologically well-defined stages, reflecting the sequential acquisition of genetic alterations. Several frequently mutated genes have been identified which probably contribute to the development of both hereditary and sporadic cancer (reviewed in Bishop and Thomas, 1990; Fearon and Vogelstein, 1990...
Article
The successful treatment of cancer requires the identification of new drugs with novel actions. N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride (DACA) is a topoisomerase II-targeted antitumour drug with curative activity against murine Lewis lung carcinoma. DACA was assessed for novel patterns of growth inhibition using normal and...
Article
N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride (DACA) is a topoisomerase II-directed DNA intercalator with high experimental solid-tumour activity. The effect of DACA on the cytokinetics of cultured Lewis lung adenocarcinoma cells was compared with those of two clinical drugs of this class, doxorubicin and amsacrine. Cells were ex...
Article
Metastatic melanoma is notable for its resistance to chemotherapy, and methods for determining resistance in cultures would be advantageous. We investigated the chemosensitivities of seven newly derived low passage lines and eight established melanoma lines. A 96-well microculture system utilising [3H]-thymidine incorporation was used to determine...
Article
We have compared the effects of a number of inhibitors including aphidicolin, 2,4-dinitrophenol (DNP) and novobiocin on the in vitro cytotoxicity of several topoisomerase II (topo II)-directed agents, using cultured murine Lewis lung carcinoma cells. These agents comprised amsacrine, CI-921 (9-[(2-methoxy-4-methylsulfonylamino)phenylamino]-N,5-dime...
Article
We have compared the effectiveness of three short-term proliferative assays [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction, methylene blue staining, and [3H]-thymidine incorporation] in predicting the results of clonogenic assay of radiosensitivity in five mammalian cell lines (SCCVII, AA8, V3, FME, and MM-96). Cells w...
Article
The culture of cancer cells has many applications in chemosensitivity testing and new drug development. Our goal was to adapt simple semiautomated microculture methods for testing the chemosensitivity of melanoma cells freshly recovered from patients' tumors. Cells were cultured on a substrate of agarose and exposed continuously to cytotoxic drugs,...
Article
The cytotoxicity of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601,316), a new experimental DNA-intercalating antitumor drug, against a cultured Lewis lung adenocarcinoma cell line was compared with that of the DNA-intercalating antitumor drug amsacrine. In contrast to amsacrine, AC demonstrated self-inhibition of cytotoxicity follow...
Article
The sensitivity of three Lewis lung carcinoma sublines, which grow in culture and in vivo, and vary in in vivo drug sensitivity, have been compared using topoisomerase II poisons amsacrine, amsacrine analogue CI-921, doxorubicin and etoposide. D10 (drug concentration for 10% clonogenic survival) values were determined in vitro for low and high dens...
Article
A survey is presented of two types of resistance to drugs acting on cellular topoisomerase enzymes, that occurring by altered drug transport and that occurring by altered target interaction. Particular attention is paid to the use of pairs of diagnostic drugs, one susceptible and one refractory to a particular resistance mechanism, in the determina...
Chapter
Once a cancer has metastasized widely, chemotherapy would be expected to offer the best hope for control. However, there are few agents with a high degree of efficacy against the common cancers, and continued drug discovery remains a priority in cancer research. The development of new methods for testing anticancer drugs constitutes a rapidly evolv...
Article
Xanthenone-4-acetic acid (XAA) resembles flavone acetic acid (FAA) in its effects on solid tumours in mice. The activity of methyl-substituted XAA derivatives in vitro was determined using 18 h 51Cr-release assays, continuous exposure growth inhibition assays and stimulation of tumouricidal activity of cultured murine resident peritoneal macrophage...
Article
The antileukemia drug amsacrine and seven analogues were tested for in vitro activity against five multidrug-resistant human leukemia cell sublines (two derived from each of two Jurkat parent lines and one from the K562 line) and the corresponding parent lines (Jurkat, K562, and P388 leukemia). Resistant cell lines were derived by exposure to eithe...
Article
Human and mouse bone marrow cells were cultured for 1 h in the presence of either the antileukaemia drug amsacrine or its 4-methyl,5-[N-methyl]carboxamide disubstituted analogue CI-921, before being plated in methylcellulose medium to determine the survival of granulocyte-macrophage colony forming units (CFU-GM). The drug concentration required for...
Article
Analogues of the phenylbisbenzimidazole dye pibenzimol bind tightly to the minor groove of DNA. A clonogenic assay has been used to investigate the effects of these compounds on the cytotoxicity of the topoisomerase II directed anti-cancer drugs amsacrine, CI-921 (an amsacrine analogue), acridine carboxamide, etoposide and doxorubicin. Although pib...
Article
The effect of three acridine derivatives, 9-aminoacridine (9AA), 4'-(9-acridinylamino)-methanesulphon-O-anisidide (O-AMSA) and quinacrine were compared in their ability to protect against the cytotoxicity of amsacrine, 9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4- acridine-carboxamide (CI-921), N-[2-(dimethylamino)ethyl]acrid...
Chapter
The cytotoxicity of a series of DNA-binding drugs was measured in a number of both mouse and human cell lines and some multidrug resistant sublines. The intercalating drugs used were derivatives of 9-anilinoacridine, including amsacrine. The nonintercalating drugs were phenylbisbenzimidazole derivatives, including the Hoechst dyes H33258 and H33342...
Article
N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601316) is a chemically novel antitumour agent which is thought to interact with DNA topoisomerase II and which has DNA binding properties which are distinct from other acridine derivatives such as amsacrine and its disubstituted analogue CI-921. AC is one of the most active agents, experime...
Article
Flavone-8-acetic acid (FAA), a new antitumor agent currently undergoing clinical trial, fails to inhibit the growth of early stage Lewis lung (LL) tumors growing in the lung. However, the growth of advanced subcutaneous tumors, arising from inoculation of either the original in vivo LL line or a tissue culture-adapted cell line (LLTC) derived from...
Article
Antitumor activity against the Lewis lung carcinoma in mice is reported for the series of 36 acridine-substituted derivatives of the antileukemia agent amsacrine. This series is the one from which the analogue N,5-dimethyl-9-[(2-methoxysulfonylamino)phenylamino]-4-acridinecarboxamide (CI-921), presently in clinical trial, was chosen. The analogues...
Article
A series of derivatives of 9-anilinoacridine related to the anti-leukaemia agent amsacrine have been tested in continuous exposure growth inhibition assays to determine the degree of cross-resistance in the Adriamycin-resistant P/ADR murine leukaemia line. Measured IC50 values for the two cell lines were only poorly correlated (r = 0.51), and cross...
Article
Full-text available
The cytotoxic effects of chemotherapeutic drugs on quiescent and actively proliferating cells of a Lewis lung carcinoma (LLTC) cell line have been examined. The sensitivities of cells in plateau-phase and exponentially growing cultures were compared with those of cells recovered from large subcutaneous tumours both immediately after tumour disaggre...
Article
An established in vitro cell line (LLTC), originally derived from the Lewis lung carcinoma (LL), was found to have lost sensitivity to the C-nucleoside antitumor agent tiazofurin (NSC-286193; 2-beta-D-ribofuranosylthiazole-4-carboxamide) both in vitro and in vivo. A new in vitro cell line (LLAK) was derived from LL and compared to LLTC in its growt...