Overview Oncologic,Endocrine & Metabolic: Oncologic,Endocrine & Metabolic :Ellipticine and related anticancer agents

Ellipticine (E), 9-methoxyellipticine (9ME) and olivacine are antitumour alkaloids isolated from Ochrosia elliptica and Aspidosperma olivaceum. 9-Hydroxyellipticine (9HE), a metabolite of 9ME, exhibits higher potency than E, but water insolubility has hampered its progression to clinical trials. A number of water soluble derivatives with, for example, a quaternary ammonium ion at position 2 or an amino-alkyl substituent at position 1, have been synthesised to overcome this problem. Elliptinium (2-methyl-9HE), datelliptium (2(diethylamino)ethyl-9HE), retelliptine (1-diethyl-aminopropy-lamino-9ME; BD-84), pazellipticine (1-diethyl-aminopropylamino-9-aza-OL; BD-40), elliprabin (2-arabinosyl-9HE), RPL-6 (carbamate at position 5 of E) and S-16020 (1-diethylaminoethylolivacine) have been extensively studied. Among these, elliptinium and datelliptium have been used for treatment of advanced breast cancer. Ellipticine analogues intercalate with DNA and show inhibition of topoisomerase II, as well as ditercalinium (a bispyridocarbazole derivative) and intoplicine (a 7H-benzo[e]pyrido[4,3-b] indole derivative). 9HE, in addition to inhibiting of topoisomerase II, is able to inhibit kinases which phosphorylate mutant p53 protein, a tumour suppressor gene product. The resulting high amount of dephosphorylated mutant p53 strongly induces expression of an apoptosis-inducing gene, bax. The compounds substituted with quaternary ammonium lose the ability to inhibit phosphorylation of p53. T-215 (9-pentanediolate-ellipticine), a derivative of 9HE, has been developed as the first drug which induces apoptosis of cancer cells selectively, via inhibition of phosphorylation of mutant p53.     

Patent Update Oncologic,Endocrine & Metabolic: Oncologic,Endocrine & Metabolic: Inhibitors of protein farnesylation

In this article, we update the progress reported towards developing an inhibitor of protein farmesyltransferase (PFTase) as a new type of cancer therapy. For the rationale behind this undertaking, please refer to the review published in this journal in December 1995 [1], and other reviews [2,3]. A few experiments bearing on the utility of PFTase inhibitors as antitumour agents are considered first, including biological results obtained with compounds described in our earlier review. Finally, new compounds described in the scientific and patent literature in the past year are reported. As in the previous review, these are grouped according to their kinetic mechanism of inhibition of PFTase.     

Review Oncologic,Endocrine & Metabolic: Recent developments in aromatase inhibitors

Aromatase inhibitors are a structurally diverse family of compounds which are useful for the reduction of serum oestrogen levels. They are reported to have potential in the treatment of several disease states mediated by oestrogen such as endometriosis, uterine fibroids, endometrial cancer and more recently, benign prostatic hyperplasia (BPH). There are currently at least ten drugs undergoing human clinical trials and an additional number of compounds in earlier development stages. Two compounds have recently been approved for the treatment of breast cancer in post menopausal women. This review covers 26 patents on both steroidal and non-steroidal aromatase inhibitors published during the period from January 1993 to March 1995.     

Overview: Oncologic,Endocrine & Metabolic Antisense oligonucleotides for the treatment of cancer

Conventional chemotherapeutic agents which either block enzymatic pathways or randomly interact with DNA irrespective of the cell phenotype, lack specificity for killing neoplastic cells. Growing evidence indicates that antisense oligodeoxynucleotides can be used to control cancer cell growth by specific targeting of cancer-specific genes. The mRNAs of several oncogenes, growth factors or cytokines have been chosen as targets for antisense oligodeoxynucleotides. Discrimination between the protooncogene and the oncogene can be achieved in the case of ras oncogene, of which activation occurs through point mutation in the coding sequence. Targeting at the mRNA of the RIα subunit of cAMP-dependent protein kinase, the positive intracellular regulator of cell growth, with an antisense oligodeoxynucleotide has also shown arrest of cancer cell growth. Synthetic oligonucleotides, thus, provide the potential biological tool for cancer chemotherapy.     

Section Review: Oncologic,Endocrine & Metabolic: Thiazolidinediones

To date, the treatment of Non-Insulin Dependent Diabetes Mellitus (NIDDM) has focused primarily on attempts to correct some of the metabolic abnormalities commonly associated with the disease. Insulin and/or insulin secretagogues, such as sulphonylureas, are frequently used to lower blood sugar; however, there is a significant risk of hypoglycaemia. Moreover, the use of insulin or insulin secretagogues in patients who are already hyperinsulinaemic may accelerate some of the cardiovascular complications of NIDDM, and further aggravate insulin resistance. Other therapeutic strategies have focused on aberrations in glucose metabolism or absorption, including biguanides, such as metformin, or glucosidase inhibitors, such as acarbose. While these agents have been efficacious to a degree, they do not have a direct impact on the underlying pathology of insulin resistance. A novel therapeutic strategy involves the use of insulin-sensitising agents, such as the thiazolidinediones. These compounds appear to improve insulin resistance by enhancing insulin action in skeletal muscle, liver and adipose tissue. Recent preclinical studies have revealed key insights into the potential mechanism of action of the thiazolidinediones. Furthermore, the emerging clinical experience with one of these agents, troglitazone, is substantiating the benefits of these agents in insulin-resistant diseases.     

Drug Evaluation: Oncologic,Endocrine & Metabolic: Toremifene

Toremifene is a triphenylethylene antioestrogenic derivative, chemically and pharmacologically related to tamoxifen. In animals, toremifene blocks the uterotrophic effect of oestradiol and, in intact animals, uterine weights are reduced, demonstrating the antioestrogenic activity of the compound. Such antioestrogenic effects are believed to underlie the antitumour actions of toremifene in breast cancer, i.e., it competes with oestrogen for binding sites in the cancer, thus preventing the growth-stimulating effects of oestrogen. The drug is well absorbed following oral administration and the mean elimination half-life is 5 days. Toremifene is extensively metabolised and the main metabolite in human serum is N-demethyltoremifene. This metabolite has a longer half-life (10 days) than toremifene and its steady state serum concentration is about 2 times higher than that of the parent compound.

Unlike tamoxifen, toremifene is not a genotoxic carcinogen in rodent studies and, similarly, is not associated with endometrial cancers following administration to patients with breast cancer. Phase I studies indicated that toremifene is well-tolerated by post-menopausal volunteers or women with various cancers in doses up to 400 mg/day. Phase II-III studies in patients with locally advanced and advanced breast cancer confirmed that toremifene is well-tolerated and, furthermore, demonstrated similar response rates to tamoxifen. Patients with oestrogen receptor (ER)-positive tumours fared better than those patients with unknown tumour composition. Toremifene's efficacy, excellent tolerability and low toxicity profile render this agent useful for the treatment of patients with locally advanced and advanced breast cancer.     

Section Review Oncologic,Endocrine & Metabolic: Melatonin related to health promotion and biological function

Melatonin is the main hormone secreted by the pineal gland. Bright light inhibits melatonin synthesis, so the amount of hormone present in the blood increases dramatically at night. Due to its sedative effects, melatonin has been linked to quality of sleep and may be used as a sleeping agent. In addition, there seems to be some correlation between melatonin levels and seasonal affective disorder (SAD). In high doses, melatonin is able to suppress ovulation, making it a promising birth control agent. Melatonin had been accepted as a regulator for many systems, including the immune system. For this reason, melatonin is being looked at as a supplement in the treatment of acquired immunodeficiency syndrome (AIDS) and cancer. Melatonin may be helpful to the body because of its antioxidant qualities and may reduce the risk of heart disease.     

Review Oncologic,Endocrine & Metabolic: Multidrug resistance: progress analysis

This review is focused on recent advances in the field of “classical” multidrug resistance mediated by P-glycoprotein, an mdr1 gene product, as well as alternative mechanisms of multidrug resistance. Clinical applications of different molecules associated with the resistance of cancer cells to chemotherapeutic drugs are also discussed.