Biomedical subjects

L R Kelland

Publications and source records attributed to L R Kelland.

At least 19 recordsLinked to original sources

PubMed2005

Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026.

In this study we investigated the in vitro time dependence of radiosensitisation, pharmacokinetics and metabolism of NU7026, a novel inhibitor of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). At a dose of 10 muM, which is nontoxic to cells per se, a minimum NU7026 exposure of 4 h in combination with 3 Gy radiation is required for a significant radiosensitisation effect in CH1 human ovarian cancer cells. Following intravenous administration to mice at 5 mg kg(-1), NU7026 underwent rapid plasma clearance (0.108 l h(-1)) and this was largely attributed to extensive metabolism. Bioavailability following interperitoneal (i.p.) and p.o. administration at 20 mg kg(-1) was 20 and 15%, respectively. Investigation of NU7026 metabolism profiles in plasma and urine indicated that the compound undergoes multiple hydroxylations. A glucuronide conjugate of a bis-hydroxylated metabolite represented the major excretion product in urine. Identification of the major oxidation site as C-2 of the morpholine ring was confirmed by the fact that the plasma clearance of NU7107 (an analogue of NU7026 methylated at C-2 and C-6 of the morpholine ring) was four-fold slower than that of NU7026. The pharmacokinetic simulations performed predict that NU7026 will have to be administered four times per day at 100 mg kg(-1) i.p. in order to obtain the drug exposure required for radiosensitisation.

Animals↗

PubMed2004

Variation in RNA expression and genomic DNA content acquired during cell culture.

Specific chromosomal abnormalities are increasingly recognised to be associated with particular tumour subtypes. These cytogenetic abnormalities define the sites of specific genes, the alteration of which is implicated in the neoplastic process. We used comparative genomic hybridisation (CGH) to examine DNA from different breast and ovarian cancer cell lines for variations in DNA sequence copy number compared with the same normal control. We also compared different sources of the MCF7 breast line by both CGH and cDNA expression arrays. Some of the differences between the subcultures were extensive and involved large regions of the chromosome. Differences between the four subcultures were observed for gains of 2q, 5p, 5q, 6q, 7p, 7q, 9q, 10p, 11q, 13q, 14q, 16q, 18p and 20p, and losses of 4q, 5p, 5q, 6q, 7q, 8p, 11p, 11q, 12q, 13q, 15q, 19p, 19q, 20p, 21q, 22q and Xp. However, few variations were found between two subcultures examined, 5 months apart, from the same initial source. The RNA arrays also demonstrated considerable variation between the three different subcultures, with only 43% of genes expressed at the same levels in all three. Moreover, the patterns of the expressed genes did not always reflect our observed CGH aberrations. These results demonstrate extensive genomic instability and variation in RNA expression during subculture and provide supportive data for evidence that cell lines do evolve in culture, thereby weakening the direct relevance of such cultures as models of human cancer. This work also reinforces the concern that comparisons of published analyses of cultures of the same name may be dangerous.

Breast Neoplasms↗

PubMed2004

Of mice and men: values and liabilities of the athymic nude mouse model in anticancer drug development.

Human tumour xenografts implanted subcutaneously (s.c.) into immunosuppressed mice have played a significant role in preclinical anticancer drug development for the past 25 years. Their use as a predictive indicator of probable clinical activity has been validated for cytotoxics. A retrospective analysis for 39 compounds where both extensive xenograft testing and Phase II clinical data were available, performed by the National Cancer Institute (NCI), has shown that 15/33 agents (45%) with activity in more than one-third of xenografts showed clinical activity (P=0.04). However, with the exception of non-small cell lung cancer, activity within a particular histological type of the xenograft generally did not predict for clinical activity in the same tumour. Today, the question (largely unanswered) is how useful is the xenograft model (particularly the traditional s.c. model) in contemporary cancer drug discovery? There are many variables when conducting xenograft experiments which impact on outcome; viz, site of implantation, growth properties of the xenograft and size when treatment is initiated, agent formulation, scheduling, route of administration and dose and the selected endpoint for assessing activity. The xenograft model remains of value in current preclinical cancer drug development, especially when such studies give due consideration to the above variables and are based on sound mechanistic (e.g. status of the selected target in the chosen model) and pharmacological (e.g. use of formulated agent) principles. Dependent upon the drug target, a slowing of xenograft tumour growth (cytostatic effect) rather than tumour shrinkage might be the major observed effect. Human tumour xenografts are also particularly useful in determining pharmacodynamic markers of response for subsequent clinical application. Nevertheless, it needs to be kept in mind that the use of xenografts is relatively time-consuming and expensive, raises animal ethical issues and there are instances where the model is inappropriate as a likely predictor of clinical outcome (e.g. inhibitors of the metastatic process and anti-angiogenic strategies as the vasculature is of murine origin).

Animals↗

PubMed2003

Increased tumour extracellular pH induced by Bafilomycin A1 inhibits tumour growth and mitosis in vivo and alters 5-fluorouracil pharmacokinetics.

The aim was to determine if a specific inhibitor of vacuolar H(+)-ATPases (V-ATPases), Bafilomycin A1 (BFM), could increase the low extracellular pH (pHe) typical of solid tumours and thus inhibit their growth in vivo. BFM inhibited the proliferation of various human cells and rat pituitary GH3 tumour cells in vitro (IC50: 2.5-19.2 nM), and flow cytometry on GH3 cells showed a marked increase in S and G2M phases after 16-48 h, but no evidence of increased apoptosis. BFM caused significant inhibition of GH3 xenograft growth, and histomorphometry showed a 30% decrease in mitosis but no change in apoptosis. 31P-magnetic resonance spectroscopy (MRS) in vivo of GH3 xenografts showed that BFM increased pHe, but did not affect pHi, resulting in a decrease in the negative pH gradient (-delta pH). BFM decreased lactate formation suggesting a reduction in glycolysis. We suggest that BFM reduces extracellular H(+)-transport by inhibition of V-ATPases leading to an increase in pHe and decreased glycolysis, and thus reduced tumour cell proliferation. 19F-MRS in vivo showed that a smaller -delta pH was associated with decreased retention of 5-fluorouracil (5FU) which was consistent with our previous data in vivo implying the -delta pH controls tumour retention of 5 FU.

Animals↗

PubMed2002

Sequence-dependent synergism between the new generation platinum agent ZD0473 and paclitaxel in cisplatin-sensitive and -resistant human ovarian carcinoma cell lines.

ZD0473 is a new generation hindered platinum agent currently undergoing worldwide Phase II clinical studies. The in vitro cytotoxicity of ZD0473 either alone or in combination with the anticancer drugs paclitaxel, gemcitabine, vinorelbine, topotecan and doxorubicin was determined using four human ovarian carcinoma cell lines and by the sulphorhodamine B assay (SRB). The lines included one model of acquired cisplatin resistance and one isogenic pair differing only in their p53 status. Notably, the simultaneous exposure to ZD0473 and paclitaxel for 96 h resulted in synergy (as defined by a median effect analysis) in all four cell lines (i.e. independent of cisplatin resistance and p53 status). In addition, synergy was observed in 3/4 lines and 2/4 lines following concomitant exposure to topotecan or gemcitabine, respectively. Sequencing studies with ZD0473 and paclitaxel revealed that, for three of the four cell lines, the combination of ZD0473 administered for 24 h prior to paclitaxel for 24 h conferred a greater growth inhibitory effect than the reverse sequential combination. This scheduling effect was particularly marked for the acquired cisplatin-resistant A2780CisR cell line; synergy being observed with ZD0473/paclitaxel, but antagonism with paclitaxel/ZD0473. This effect did not appear to be correlated with changes in drug-induced cell cycle checkpoints. These data suggest that ZD0473 may be usefully combined with various cytotoxics in the clinic, including paclitaxel, topotecan and gemcitabine.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

Retention of activity by the new generation platinum agent AMD0473 in four human tumour cell lines possessing acquired resistance to oxaliplatin.

Four models of acquired resistance to the clinically-used platinum drug, oxaliplatin, have been established using human tumour cell lines in vitro; two colon (HCT116 and HT29) and two ovarian (A2780 and CH1). Levels of acquired resistance ranged from 3.0- to 15.8-fold with levels of resistance higher in the colon relative to the ovarian carcinoma cell lines. Notably, the platinum analogue, AMD0473, currently undergoing clinical evaluation, exhibited superior circumvention of acquired oxaliplatin resistance in comparison to either cisplatin or the trinuclear platinum BBR3464. Resistance in the two colon cell lines was unique to oxaliplatin itself among the platinum drugs studied. Acquired oxaliplatin resistance was not due to either reduced drug membrane transport or increased levels of glutathione in any of the four resistant lines. Following exposure to oxaliplatin, a lower level of platinum-DNA adducts was present in acquired oxaliplatin-resistant HT29 cells. In the remaining resistant lines, there was no change in the levels of platinum-DNA adducts relative to the parent lines. There was no change in hMLH1 DNA mismatch repair gene status in any of the four cell line pairs. However, in an A2780 subline where loss of hMLH1 and a p53phe172 mutation occurred, 5-fold resistance to cisplatin was observed, but only 1.7-fold resistance to oxaliplatin and no resistance to AMD0473 were observed. Re-introduction of hMLH1 into these cells caused no significant change in the sensitivity to cisplatin, oxaliplatin or AMD0473. These data show that acquired resistance to oxaliplatin may occur in cell lines (and therefore probably in the clinic) and in the four independent cell lines studied this was circumvented by AMD0473. Alongside previously described models of acquired resistance to cisplatin, these oxaliplatin-resistant cell line models may be useful in the evaluation of further novel platinum agents.

Antineoplastic Agents↗

PubMed2001

High levels of the MDM2 oncogene in paediatric rhabdomyosarcoma cell lines may confer multidrug resistance.

The MDM2 protein is known to be overexpressed in some sarcomas including rhabdomyosarcoma. However, the extent to which the MDM2 protein influences sensitivity to chemotherapeutic drugs is unclear. We have analysed this further using stable transfection of the mdm2 gene into 4 well-characterised human paediatric rhabdomyosarcoma cell lines. Transfection with the mdm2 gene resulted in increased levels of the MDM2 protein in all the cell lines. In 2 of the lines, SCMC and RD, the mdm2 gene caused between 2-fold and 61-fold increase in resistance to vincristine, etoposide and doxorubicin but not to cisplatin. In these lines there was an increase in expression of the mdr-1 gene which encodes P-glycoprotein, but not the mrp1 gene which encodes the multidrug resistance protein (MRP). The resistance was reversible using the MDR modulator PSC833, confirming the presence of P-glycoprotein. We conclude that MDM2 overexpression may be a mechanism by which multidrug resistance is regulated in some rhabdomyosarcomas.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Novel approaches to polynuclear platinum pro-drugs. Selective release of cytotoxic platinum-spermidine species through hydrolytic cleavage of carbamates.

BBR3464 is a novel trinuclear platinum drug currently in Phase II clinical trials. Polyamine-bridged dinuclear platinum compounds as represented by [[trans-Pt(NH(3))(2)Cl](2)-mu-spermidine-N(1),N(8)]Cl(3) (1) are highly interesting second-generation analogues of BBR3464 because the hydrogen-bonding and electrostatic contributions of the central platinum-amine group in BBR3464 are replicated by the free, noncoordinated "central" quaternary nitrogens of the linear polyamine linker while the presence of two separate Pt-Cl bonds maintains the bifunctional binding mode on the DNA adducts. Preclinical investigations confirm the potency of these species with cytotoxicity in the nanomolar range. This remarkable potency results in a relatively narrow therapeutic index. To enhance the therapeutic index of these drugs, we investigated the potential for "pro-drug" delivery of less toxic and better tolerated derivatives such as the compounds [[trans-Pt(NH(3))(2)Cl](2)-mu-N(4)-R-spermidine-N(1),N(8)]Cl(2) where N(4)-R represents BOC (tert-butyl), CBz (benzyl), and Fmoc (fluorenylmethyl) carbamate blocking groups, 2-4, respectively. The bulky Fmoc derivative showed evidence for conformational isomers by (1)H NMR spectroscopy due to the inequivalence of the two n-propyl and n-butyl side chains of the spermidine moiety. The rate constants for hydrolysis and release of 1 were calculated. Release of cytotoxic 1 at physiologically relevant pH followed the order 4 > 2 > 3. The calculated values for 4 (pH 5, 6.0(+/-3.9) x 10(-10) s(-1); pH 6, 6.5(+/-0.2) x 10(-9) s(-1); pH 7, 6.0(+/-0.2) x 10(-8) s(-1); pH 8, 1.6(+/-0.1) x 10(-7) s(-1)) show a more pronounced pH dependence compared to 2 (pH 5, 4.6(+/-0.1) x 10(-8) s(-1); pH 6, 4.2(+/-0.1) x 10(-8) s(-1); pH 7, 3.2(+/-0.1) x 10(-8) s(-1)). Preliminary biological assays of cellular uptake and cytotoxicity confirm the utility of the pro-drug concept. While blocked-polyamine compounds such as 2-4 are, in general, 2-3 orders of magnitude less cytotoxic than 1, there is significant cell type variability. Specifically, the Fmoc derivative 4 showed significantly enhanced cytotoxicity warranting further study of the pro-drug concept for greater selectivity and/or oral delivery.

Animals↗

PubMed2001

Synthesis of the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine dimer.

We report the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer 16 synthesised through a new and efficient route, thus establishing that C2-C3-endo unsaturation enhances both cytotoxicity and DNA-binding affinity in A-Ring-linked PBD dimers but to a lesser extent than C2/C2'-exo-unsaturation. This new route has allowed the preparation of multi-gram quantities of the related clinical candidate 1 and should lead to more structurally diverse PBD dimer analogues.

Azepines↗

PubMed2001

Short tandem repeat profiling provides an international reference standard for human cell lines.

Cross-contamination between cell lines is a longstanding and frequent cause of scientific misrepresentation. Estimates from national testing services indicate that up to 36% of cell lines are of a different origin or species to that claimed. To test a standard method of cell line authentication, 253 human cell lines from banks and research institutes worldwide were analyzed by short tandem repeat profiling. The short tandem repeat profile is a simple numerical code that is reproducible between laboratories, is inexpensive, and can provide an international reference standard for every cell line. If DNA profiling of cell lines is accepted and demanded internationally, scientific misrepresentation because of cross-contamination can be largely eliminated.

Cell Line↗

PubMed2001

Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors.

The telomerase enzyme is a potential therapeutic target in many human cancers. A series of potent inhibitors has been designed by computer modeling, which exploit the unique structural features of quadruplex DNA. These 3,6,9-trisubstituted acridine inhibitors are predicted to interact selectively with the human DNA quadruplex structure, as a means of specifically inhibiting the action of human telomerase in extending the length of single-stranded telomeric DNA. The anilino substituent at the 9-position of the acridine chromophore is predicted to lie in a third groove of the quadruplex. Calculated relative binding energies predict enhanced selectivity compared with earlier 3,6-disubstituted compounds, as a result of this substituent. The ranking order of energies is in accord with equilibrium binding constants for quadruplex measured by surface plasmon resonance techniques, which also show reduced duplex binding compared with the disubstituted compounds. The 3,6,9-trisubstututed acridines have potent in vitro inhibitory activity against human telomerase, with EC(50) values of up to 60 nM.

Acridines↗

PubMed2001

Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity.

A novel sequence-selective pyrrolobenzodiazepine (PBD) dimer 5 (SJG-136) has been developed that comprises two C2-exo-methylene-substituted DC-81 (3) subunits tethered through their C8 positions via an inert propanedioxy linker. This symmetric molecule is a highly efficient minor groove interstrand DNA cross-linking agent (XL(50) = 0.045 microM) that is 440-fold more potent than melphalan. Thermal denaturation studies show that, after 18 h incubation with calf thymus DNA at a 5:1 DNA/ligand ratio, it increases the T(m) value by 33.6 degrees C, the highest value so far recorded in this assay. The analogous dimer 4 (DSB-120) that lacks substitution/unsaturation at the C2 position elevates melting by only 15.1 degrees C under the same conditions, illustrating the effect of introducing C2-exo-unsaturation which serves to flatten the C-rings and achieve a superior isohelical fit within the DNA minor groove. This behavior is supported by molecular modeling studies which indicate that (i) the PBD units are covalently bonded to guanines on opposite strands to form a cross-link, (ii) 5 has a greater binding energy compared to 4, and (iii) 4 and 5 have equivalent binding sites that span six base pairs. Dimer 5 is significantly more cytotoxic than 4 in a number of human ovarian cancer cell lines (e.g., IC(50) values of 0.0225 nM vs 7.2 nM, respectively, in A2780 cells). Furthermore, it retains full potency in the cisplatin-resistant cell line A2780cisR (0.024 nM), whereas 4 loses activity (0.21 microM) with a resistance factor of 29.2. This may be due to a lower level of inactivation of 5 by intracellular thiol-containing molecules. A dilactam analogue (21) of 5 that lacks the electrophilic N10-C11/N10'-C11' imine moieties has also been synthesized and evaluated. Although unable to interact covalently with DNA, 21 still stabilizes the helix (Delta T(m) = 0.78 degrees C) and has significant cytotoxicity in some cell lines (i.e., IC(50) = 0.57 microM in CH1 cells), presumably exerting its effect through noncovalent interaction with DNA.

Antineoplastic Agents↗

PubMed2001

A new class of symmetric bisbenzimidazole-based DNA minor groove-binding agents showing antitumor activity.

The synthesis and evaluation of the novel head-to-head bisbenzimidazole compound 2,2-bis[4'-(3' '-dimethylamino-1' '-propyloxy)phenyl]-5,5-bi-1H-benzimidazole is described. An X-ray crystallographic study of a complex with the DNA dodecanucleotide sequence d(CGCGAATTCGCG) shows the compound bound in the A/T minor groove region of a B-DNA duplex and that the head-to-head bisbenzimidazole motif hydrogen-bonds to the edges of all four consecutive A:T base pairs. The compound showed potent growth inhibition with a mean IC(50) across an ovarian carcinoma cell line panel of 0.31 microM, with no significant cross-resistance in two acquired cisplatin-resistant cell lines and a low level of cross-resistance in the P-glycoprotein overexpressing acquired doxorubicin-resistant cell line. Studies with the hollow fiber assay and in vivo tumor xenografts showed some evidence of antitumor activity.

Animals↗

PubMed2001

Synthesis and antitumour activity of platinum(II) and platinum(IV) complexes containing ethylenediamine-derived ligands having alcohol, carboxylic acid and acetate substituents. Crystal and molecular structure of [PtL4CL2].H20 where L4 is ethylenediamine-N,N'-diacetate.

Several cisplatin analogues of ethylenediamine-derived ligands containing alcohol, carboxylic acid and acetate substituents have been prepared and characterised. Oxidation of some of these square planar platinum(II) complexes using aqueous hydrogen peroxide gave octahedral platinum(IV) complexes, containing trans hydroxo ligands. Acetylation of the hydroxo ligands was achieved by reaction with acetic anhydride, giving complexes which are analogues of the antitumour drug, JM-216. Oxidation of the complex [Pt(H2L4)Cl2], where H2L4 is ethylenediamine-N,N'-diacetic acid, with H2O2 gave the platinum(IV) complex [PtL4Cl2].H2O in which L4 is tetradentate as shown by a crystal and molecular structure. This complex was previously reported to be [Pt(HL4)(OH)Cl2] in which HL4 is tridentate. Several of the complexes were tested for antitumour activity against five human ovarian carcinoma cell lines. IC50 values range from 4.0 microM for cis,trans-PtCl2(OH)2(NH2CH2CH2NHCH2CH2OH) against the CH1 cell line to >25 microM indicating moderate to low activity relative to other platinum complexes.

Antineoplastic Agents↗

PubMed2001

Telomerase: biology and phase I trials.

In normal somatic cells, the ends of chromosomes (the telomeres) shorten with each cell division. By contrast, in tumour cells, telomere length is maintained, generally through the reactivation of the reverse transcriptase enzyme, telomerase. At least three applications relating to telomeres and telomerase have been proposed: in cancer diagnosis and prognosis (especially through measurements of the catalytic component of telomerase, hTERT) and as a means of monitoring tumour response to therapy; as an aid to tissue engineering; and inhibition as a cancer therapeutic strategy. Mouse knockout, hTERT dominant negative, and antisense experiments suggest that telomerase inhibitors will confer anticancer activity, especially in tumours with short telomeres. Inhibitory strategies have focused on antisense molecules, inhibitors of reverse transcriptases, and small molecules able to interact with and stabilise four-stranded (G-quadruplex) structures formed by telomeres. Clinical trials involving telomerase inhibitors require careful consideration compared to those looking at conventional anticancer cytotoxic drugs.

Clinical Trials, Phase I as Topic↗

PubMed2001

Characterization of a human colorectal carcinoma cell line with acquired resistance to flavopiridol.

Flavopiridol is a broad-spectrum inhibitor of cyclin-dependent kinases (cdks) and represents the first in this anticancer class to enter clinical trials. In anticipation of the likelihood that, as with other cancer drugs, acquired resistance may limit the drug's efficacy, an acquired resistance model has been established by in vitro drug exposure of the human colon carcinoma cell line HCT116. This stably resistant line, possessing 8-fold resistance to flavopiridol, showed a lack of cross-resistance to the anticancer agents etoposide, doxorubicin, paclitaxel, topotecan, and cisplatin, and notably to other chemical classes of cdk inhibitors: the aminopurines roscovitine and purvalanol A, 9-nitropaullone, and hymenialdisine. Resistance did not seem to be related to differences in the levels of multidrug resistance drug efflux proteins, P-glycoprotein, and MRP1. Moreover, there were no changes in overall drug accumulation between the resistant and sensitive cell lines. Flavopiridol induced cell cycle arrest, apoptosis, and inhibition of retinoblastoma gene product phosphorylation on serine 780 in both parental and resistant lines, but the latter required 8-fold higher concentrations to achieve these effects. Cyclin E protein levels and cyclin E-associated kinase activity were increased in the resistant line, suggesting that overexpression of cyclin E may be the mechanism of resistance to flavopiridol. However, transfection of cyclin E to increase expression of this protein did not result in an increase in resistance to flavopiridol. Thus, up-regulation of cyclin E alone does not seem to cause resistance to this cdk inhibitor.

Antineoplastic Agents↗

PubMed2001

Potent inhibition of telomerase by small-molecule pentacyclic acridines capable of interacting with G-quadruplexes.

A novel pentacyclic acridine, 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4), has been identified as a potent inhibitor of telomerase in the cell-free telomeric repeat amplification protocol (TRAP). Modeling and biophysical studies suggest that RHPS4 inhibits telomerase through stabilization of four-stranded G-quadruplex structures formed by single-stranded telomeric DNA. In contrast to G-quadruplex interactive telomerase inhibitors described previously, RHPS4 inhibited telomerase at submicromolar levels (50% inhibition in the TRAP assay at 0.33 +/- 0.13 microM). Moreover, RHPS4 exhibited a wide differential between this potent inhibition of telomerase and acute cellular cytotoxicity (mean IC(50) value of 7.02 microM in 4-day growth inhibition assay). RHPS4, when added to 21NT breast cancer cells at nonacute cytotoxic concentrations (200 nM) every 3 to 4 days, induced a marked cessation in cell growth after 15 days. Similar effects were observed using another cell line possessing relatively short telomeres, A431 human vulval carcinoma cells, but not in a human ovarian carcinoma cell line (SKOV-3) possessing relatively long telomeres. In 21NT cells, growth cessation was accompanied by an increase in cells in the G(2)/M phase of the cell cycle, a reduction in cellular telomerase activity, and a lower expression of the hTERT gene. These effects occurred in the absence of a detectable reduction in telomere length as measured by slot blotting. RHPS4 also induced a cessation of growth of GM847 cells that maintain telomeres by a nontelomerase alternative mechanism for lengthening telomeres (ALT) after 15 days. RHPS4 represents a promising G-quadruplex interactive small molecule that is a potent cell-free inhibitor of human telomerase and induces growth inhibitory effects in human tumor cell lines after prolonged (2-week) exposure to nonacute cytotoxic drug concentrations.

DNA↗

PubMed2001

Farnesyl transferase inhibitors--a novel therapy for breast cancer.

Inhibitors of the enzyme farnesyl protein transferase prevent a key step in the post-translational processing of the Ras protein, and were developed initially as a therapeutic strategy to inhibit cell signalling in ras-transformed cells. As more has been learnt about the biological effects of farnesyl transferase inhibitors (FTIs) on cancer cells, it is clear that tumours without oncogenic ras mutations such as breast cancer may also be targets for FTI therapy. This article reviews the rationale for the development of FTIs, focussing on early preclinical data in breast cancer models together with preliminary results from the first phase II study of an FTI in advanced breast cancer.

Alkyl and Aryl Transferases↗