Targeted NF1 cancer therapeutics with multiple modes of action: small molecule hormone-like agents resembling the natural anticancer metabolite, 2-methoxyoestradiol.

BACKGROUND: Both the number and size of tumours in NF1 patients increase in response to the rise in steroid hormones seen at puberty and during pregnancy. The size of tumours decreases after delivery, suggesting that hormone-targeting therapy might provide a viable new NF1 treatment approach. Our earlier studies demonstrated that human NF1 tumour cell lines either went through apoptosis or ceased growth in the presence of 2-methoxyoestradiol (2ME2), a naturally occurring anticancer metabolite of 17-ß estradiol. Previous reports of treatment with sulfamoylated steroidal and non-steroidal derivatives of 2ME2 showed promising reductions in tumour burden in hormone-responsive cancers other than NF1. Here we present the first studies indicating that 2ME2 derivatives could also provide an avenue for treating NF1, for which few treatment options are available. METHODS: STX3451, (2-(3-Bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline), a non-steroidal sulphamate analogue of 2ME2, was tested in dose-dependent studies of malignant and benign NF1 human tumour cell lines and cell lines with variable controlled neurofibromin expression. The mechanisms of action of STX3451 were also analysed. RESULTS: We found that STX3451-induced apoptosis in human malignant peripheral nerve sheath tumour (MPNST) cell lines, even in the presence of elevated oestrogen and progesterone. It inhibits both PI3 kinase and mTOR signalling pathways. It disrupts actin- and microtubule-based cytoskeletal structures in cell lines derived from human MPNSTs and in cells derived from benign plexiform neurofibromas. STX3451 selectively kills MPNST-derived cells, but also halts growth of other tumour-derived NF1 cell lines. CONCLUSION: STX3451 provides a new approach for inducing cell death and lowering tumour burden in NF1 and other hormone-responsive cancers with limited treatment options.

Synthesis and in vivo brain distribution of carbon-11-labeled δ-opioid receptor agonists.

Three new radiolabeled compounds, [(11)C]SNC80 ((+)-4-[(αR)-α-{(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl}-3-[(11)C]methoxybenzyl-N,N-diethylbenzamide), N,N-diethyl-4-[3-methoxyphenyl-1-[(11)C]methylpiperidin-4-ylidenemethyl)benzamide and N,N-diethyl-4-[(1-[(11)C]methylpiperidin-4-ylidene)phenylmethyl]benzamide, were prepared as potential in vivo radiotracers for the δ-opioid receptor. Each compound was synthesized by alkylation of the appropriate desmethyl compounds using [(11)C]methyl triflate. In vivo biodistribution studies in mice showed very low initial brain uptake of all three compounds and no regional specific binding for [(11)C]SNC80. A monkey positron emission tomography study of [(11)C]SNC80 confirmed low brain permeability and uniform regional distribution of this class of opioid agonists in a higher species. Opioid receptor ligands of this structural class are thus unlikely to succeed as in vivo radiotracers, likely due to efficient exclusion from the brain by the P-glycoprotein efflux transporter.

In vivo evaluation of new carfentanil-based radioligands for the mu opiate receptor.

Eight derivatives of [(11)C]carfentanil were evaluated as alternative mu opioid receptor radioligands with the potential for lower pharmacological activity, faster pharmacokinetics, and/or lower non-specific binding. Derivatives with aryl ring substituents or alkyl group substitutions were prepared in carbon-11 labeled form and examined for initial brain uptake and regional brain tissue pharmacokinetics in mouse brain. Promising derivatives with chloro, methoxy and methyl substituents on one aryl ring were then evaluated for specific binding in an equilibrium infusion rat model of regional brain distributions. Although no derivatives were identified with improved pharmacokinetics or lower non-specific binding, several derivatives show acceptable in vivo specific binding properties and may deserve further evaluation as less potent and thus safer compounds for in vivo imaging studies.

mu-opioid receptor-mediated antinociceptive responses differ in men and women.

Sex differences in the experience of clinical and experimental pain have been reported. However, the neurobiological sources underlying the variability in pain responses between sexes have not been adequately explored, especially in humans. The endogenous opioid neurotransmitters and mu-opioid receptors are centrally implicated in responses to stress, in the suppression of pain, and in the action of opiate analgesic drugs. Here we examined sex differences in the activation of the mu-opioid system in response to an intensity-controlled sustained deep-tissue pain challenge with positron emission tomography and a mu-opioid receptor-selective radiotracer. Twenty-eight young healthy volunteers (14 men and 14 women) were studied during saline control and pain conditions using a double-blind, randomized, and counterbalanced design. Women were scanned during the early follicular phase of their menstrual cycles after ovulatory cycles. Significant sex differences in the regional activation of the mu-opioid system in response to sustained pain were detected compared with saline controls. Men demonstrated larger magnitudes of mu-opioid system activation than women in the anterior thalamus, ventral basal ganglia, and amygdala. Conversely, women demonstrated reductions in the basal state of activation of the mu-opioid system during pain in the nucleus accumbens, an area previously associated with hyperalgesic responses to the blockade of opioid receptors in experimental animals. These data demonstrate that at matched levels of pain intensity, men and women during their follicular phase differ in the magnitude and direction of response of the mu-opioid system in distinct brain nuclei.