G-quadruplex compounds and cis-platin act synergistically to inhibit cancer cell growth in vitro and in vivo.

The ability of two structurally diverse telomeric G-quadruplex-binding compounds to synergise the action of cis-platin has been investigated in two cancer cell lines. One compound is a trisubstituted acridine compound AS1410, a close analogue of BRACO-19, and the other is a non-polycyclic compound synthesised using click chemistry and containing two triazole rings. Both compounds produce growth arrest at sub-cytotoxic concentrations in the two cell lines (MCF7 and A549), with behaviour consistent with telomere targeting mechanisms.

Amide-based prodrugs of spermidine-bridged dinuclear platinum. Synthesis, DNA binding, and biological activity.

The chemistry and biology of acetyl-protected spermidine-bridged dinuclear platinum complexes [{ trans-PtCl(NH 3) 2] 2-mu-NH 2(CH 2) 3N(COR)(CH 2) 4NH 2]X 2 (R = H, X = Cl (1,1/t,t-spermidine, BBR3571); R = CH 3 , X = Cl ( 2); R = CH 2 Cl, X = ClO 4 ( 3); R = CF 3 , X = Cl ( 4)) are compared with their carbamate analogues. The compounds are potential prodrugs for the parent compound 1, a highly potent antitumor agent. At pH 6-8 hydrolysis of the blocking group with the release of the "parent" protonated species follows the order 4 > 3 >> 2.

Structure-based design of benzylamino-acridine compounds as G-quadruplex DNA telomere targeting agents.

The design, synthesis, biophysical and biochemical evaluation is presented of a new series of benzylamino-substituted acridines as G-quadruplex binding telomerase inhibitors. Replacement of the previously reported anilino substituents by benzylamino groups results in enhanced quadruplex interaction, and for one compound, superior telomerase inhibitory activity.

Evidence for the involvement of p38 MAP kinase in the action of the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA).

Aims: DMXAA (AS1404), a small-molecule vascular disrupting agent that has now completed Phase II clinical trial, induces endothelial cell apoptosis, increased vascular permeability and decreased tumour blood flow in vivo. Its action is incompletely understood and we wished to develop an in vitro system to study its effects.

Methods: Human tumour cell lines developed from aggressive tumours were grown on Matrigel to simulate a tumour microenvironment.

Discovery and development of anticancer aptamers.

Aptamers, also termed as decoys or "chemical antibodies," represent an emerging class of therapeutics. They are short DNA or RNA oligonucleotides or peptides that assume a specific and stable three-dimensional shape in vivo, thereby providing specific tight binding to protein targets. In some cases and as opposed to antisense oligonucleotides, effects can be mediated against extracellular targets, thereby preventing a need for intracellular transportation.

Synthesis and antimelanoma activity of reversed amide analogues of N-acetyl-4-S-cysteaminylphenol.

The melanin biosynthetic pathway from tyrosine is a potential target for combating malignant melanoma. N-Acetyl-4-S-cysteaminylphenol 1 is a previously synthesized analogue of tyrosine that probably acts by this pathway. It interferes with cell growth and proliferation via selective oxidation in melanocytes to an oquinone that can alkylate cellular nucleophiles.

Rat tumor response to the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid as measured by dynamic contrast-enhanced magnetic resonance imaging, plasma 5-hydroxyindoleacetic acid levels, and tumor necrosis.

The dose-dependent effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on rat GH3 prolactinomas were investigated in vivo. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to assess tumor blood flow/permeability pretreatment and 24 hours posttreatment with 0, 100, 200, or 350 mg/kg DMXAA. DCE-MRI data were analyzed using K(trans) and the integrated area under the gadolinium time curve (IAUGC) as response biomarkers.

Enhancement of aqueous solubility and stability employing a trans acetate axis in trans planar amine platinum compounds while maintaining the biological profile.

A general approach to solubilization and possible in vivo activation of the transplatinum geometry is presented. The synthesis and characterization of new water-soluble cytotoxic transplatinum compounds are described. Use of acetate ligands (and carboxylate ligands in general) in trans-[Pt(OAc)(2)(L)(L')] results in significantly enhanced aqueous solubility and chemical stability in comparison to the parent dichlorides.

Synthesis and antimelanoma activity of sterically congested tertiary amide analogues of N-acetyl-4-S-cysteaminylphenol.

Interference with the biosynthetic pathway to melanin may be a useful means for developing new chemotherapeutic drugs to combat malignant melanoma. N-Acetyl-4-S-cysteaminylphenol (1) is an analogue of tyrosine that is involved in the pathway to melanin. It is probably oxidized selectively in melanocytes to an o-quinone that can alkylate thiol groups on important cellular enzymes, resulting in interference with cell growth and proliferation.

In vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202.

Purpose: To investigate pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine, and CYC202 (R-roscovitine; seliciclib) in the HCT116 human colon carcinoma model.

Experimental Design: The in vitro activity of the agents was determined in a human tumor panel using the sulforhodamine B assay. The concentration and time dependence was established in HCT116 cells.

Emerging drugs for ovarian cancer.

Because most patients presenting with advanced ovarian cancer are not curable by surgery alone, chemotherapy represents an essential component of treatment. The disease may be considered as chemosensitive, as in around three-quarters of patients major (complete) responses are seen to initial treatment with the platinum-containing drugs cisplatin and carboplatin either used alone or in combination with the taxane, paclitaxel. However, only 15-20% of patients experience long-term remission as tumours often become resistant.

Tumor dose response to the vascular disrupting agent, 5,6-dimethylxanthenone-4-acetic acid, using in vivo magnetic resonance spectroscopy.

Purpose: To use (31)P and (1)H magnetic resonance spectroscopy (MRS) to assess changes in tumor metabolic profile in vivo in response to 5,6-dimethylxanthenone-4-acetic acid (DMXAA) with a view to identifying biomarkers associated with tumor dose response.

Experimental Design: In vivo (31)P and (1)H MRS measurements of (a) tumor bioenergetics [beta-nucleoside triphosphate/inorganic phosphate (beta-NTP/Pi)], (b) the membrane-associated phosphodiesters and phosphomonoesters (PDE/PME), (c) choline (mmol/L), and (d) lactate/water ratio were made on murine HT29 colon carcinoma xenografts pretreatment and 6 or 24 hours posttreatment with increasing doses of DMXAA. Following in vivo MRS, the tumors were excised and used for high-resolution (31)P and (1)H MRS of extracts to provide validation of the in vivo MRS data, histologic analysis of necrosis, and high-performance liquid chromatography.

Overcoming the immortality of tumour cells by telomere and telomerase based cancer therapeutics--current status and future prospects.

A key property of malignant tumours is their immortality or limitless replicative potential. Cell replication is associated with the maintenance of telomeres and in the great majority of cases, through the reactivation of the reverse transcriptase telomerase. Targeting the telomere/telomerase machinery offers a novel and potentially broad-spectrum anticancer therapeutic strategy since telomerase is constitutively overexpressed in the vast majority of human cancers.

Mechanisms of tumor vascular shutdown induced by 5,6-dimethylxanthenone-4-acetic acid (DMXAA): Increased tumor vascular permeability.

The novel vascular targeting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) has completed phase 1 clinical trial and has shown tumor antivascular activity in both mice and humans. We have investigated its ability to change tumor vascular permeability, relating it to tumor vascular perfusion and other responses. The murine colon 38 adenocarcinoma was grown in C57Bl wild-type mice and mice lacking expression of either tumor necrosis factor receptor-1 (TNFR1(-/-)) or TNF (TNF-/-).

Evaluation of by disubstituted acridone derivatives as telomerase inhibitors: the importance of G-quadruplex binding.

The synthesis and evaluation of a group of 2,6-, 2,7- and 3,6-bis-aminoalkylamido acridones are reported, which show a similar level of activity against telomerase in vitro compared to their acridine counterparts. Computer modelling and calculations of relative binding energies suggest an equivalent binding mode to human intramolecular G-quadruplex DNA, but with significantly reduced affinity, as a result of the limited delocalisation of the acridone chromophore compared to the acridine system. Thermal melting studies on acridone and acridine quadruplex complexes using a FRET approach support these predictions.

A G-quadruplex telomere targeting agent produces p16-associated senescence and chromosomal fusions in human prostate cancer cells.

The trisubstituted acridine derivative BRACO-19 has been designed to interact with and stabilize the quadruplex DNA structures that can be formed by folding of the single-stranded repeats at the 3' end of human telomeres. We suggest that the BRACO-19 complex inhibits the catalytic function of telomerase in human cancer cells and also destabilizes the telomerase-telomere capping complex so that cells enter senescence. Here, we present evidence showing that the inhibition of cell growth caused by BRACO-19 in DU145 prostate cancer cells occurs more rapidly than would be expected solely by the inhibition of the catalytic function of telomerase, and that senescence is accompanied by an initial up-regulation of the cyclin-dependent kinase inhibitor p21, with subsequent increases in p16(INK4a) expression.

SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 1: cellular pharmacology, in vitro and initial in vivo antitumor activity.

SJG-136 (NSC 694501) is a rationally designed pyrrolobenzodiazepine dimer that binds in the minor groove of DNA. It spans 6 bp with a preference for binding to purine-GATC-pyrimidine sequences. The agent has potent activity in the National Cancer Institute (NCI) anticancer drug screen with 50% net growth inhibition conferred by 0.

Synthesis and biological evaluation of novel chloroethylaminoanthraquinones with potent cytotoxic activity against cisplatin-resistant tumor cells.

Novel 1- and 1,4-substituted chloroethylaminoanthraquinones with DNA binding and alkylating properties along with their respective hydroxyethylaminoanthraquinone intermediates were synthesized. Selected chloroethylaminoanthraquinones were shown to cross-link DNA and alkylate guanines (at low nM concentration) with a preference for reaction sites containing 5'-PyG. A compound (Alchemix) with the bis-chloroethyl functionality confined to one side chain alkylated but did not cross-link DNA.

Acquired cellular resistance to flavopiridol in a human colon carcinoma cell line involves up-regulation of the telomerase catalytic subunit and telomere elongation. Sensitivity of resistant cells to combination treatment with a telomerase inhibitor.

Flavopiridol is a broad-spectrum inhibitor of cyclin-dependent kinases and of global transcription via the inhibition of positive transcription elongation factor b (P-TEFb). Although flavopiridol is currently undergoing phase II clinical trials, acquired cellular resistance to the compound during treatment is a potential problem, as it is with almost all current anticancer agents. A HCT116 human colon carcinoma cell line with an acquired 8-fold resistance to flavopiridol has been established.

Trisubstituted acridine derivatives as potent and selective telomerase inhibitors.

The synthesis and evaluation for telomerase-inhibitory and quadruplex DNA binding properties of three related series of rationally designed trisubstituted acridine derivatives are described. These are substituted on the acridine ring at the 2,6,9; 2,7,9; and 3,6,9 positions. The ability of several of the most potent compounds to interact with and stabilize an intramolecular G-quadruplex DNA was evaluated by surface plasmon resonance methods, and affinities were found to correlate with potency in a telomerase assay.

Synthesis and antimelanoma activity of tertiary amide analogues of N-acetyl-4-S-cysteaminylphenol.

The biosynthetic pathway to melanin is a realistic target for therapeutic intervention in the development of new drugs to combat malignant melanoma. N-Acetyl-4-S-cysteaminylphenol (1) is an analogue of a biosynthetic intermediate in the pathway to melanin. It probably acts as a prodrug and is oxidized selectively in melanocytes to an o-quinone, which can alkylate cellular nucleophiles resulting in interference with cell growth and proliferation.

Chemical synthesis and cytotoxicity of dihydroxylated cyclopentenone analogues of neocarzinostatin chromophore.

Compounds containing the naphthoate moiety of Neocarzinostatin chromophore or 2-hydroxynaphthoate have been synthesized and evaluated for cytotoxic activity against a leukemia cell line and a small panel of human-tumor cell lines. Those compounds containing a cyclopentenone moiety were active, with the carbonyl group being essential for biological activity.

Antitumor and cellular pharmacological properties of a novel platinum(IV) complex: trans-[PtCl(2)(OH)(2)(dimethylamine) (isopropylamine)].

The antitumor and cellular pharmacological properties of the trans-Pt(IV) complex, trans-[PtCl(2)(OH)(2)(dimethylamine)(isopropylamine)] (compound 2) has been evaluated in comparison with its corresponding trans-Pt(II) counterpart, trans-[PtCl(2)(dimethylamine)(isopropylamine)] (compound 1). The results reported here indicate that compound 2 markedly circumvents cisplatin resistance in 41McisR and CH1cisR ovarian tumor cell lines endowed with different mechanisms of resistance (decreased platinum accumulation and enhanced DNA repair/tolerance, respectively). However, compound 1 is able to circumvent cisplatin resistance only in CH1cisR cells.

Farnesyl transferase inhibitors in the treatment of breast cancer.

Until recently, the therapeutic treatment of breast cancer has been dominated by endocrine-based drugs (oestrogen receptor antagonists, aromatase inhibitors etc.) and conventional cytotoxics (doxorubicin, cyclophosphamide, 5-fluorouracil etc.).