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.     

Section Review Oncologic,Endocrine & Metabolic: Farnesyl-protein transferase inhibitors in early development

Over the last decade the underlying mechanisms that cause tu-mourigenesis are progressively being elucidated. One potential mechanism includes the participation of farnesyl-protein transferase in promoting the effects of oncogenic forms of ras. Membrane localisation of Ras is essential for ras-induced tumour formation. Farnesyl-protein transferase catalyses the attachment of farnesyl to the carboxyl terminal cysteine residue of Ras. Genetic evidence indicates that unprenylated oncogenic Ras is soluble, cannot promote tumourigenesis and is apparently not deleterious to the cell. Several inhibitors of farnesyl-protein transferase are currently being tested in animal models of tumourigenesis. This review will focus on compounds that are presently being developed by Eisai, Banyu, Bristol-Myers Squibb, Merck, Roche/Genentech/University of Texas, Schering-Plough and the University of Pittsburgh.     

Section Review: Oncologic,Endocrine & Metabolic: Future directions for the treatment of human pancreatic carcinoma

Pancreatic cancer is the fifth leading cause of death from malignant disease in the Western world. The majority of patients with carcinoma of the exocrine pancreas haveunresectable, incurable disease at the time of diagnosis. At present, no medical treatment can be considered as standard therapy in advanced or locally unresectable pancreatic carcinoma. Since no chemotherapeutic regimen has been demonstrated to offer a clear survival benefit for these patients, future clinical trials should be designed to evaluate quality of life and palliation of symptoms, such as recent observations with gemcitabine, a novel nucleoside analogue. In this review, recent developments in our understanding of the biology and pathogenesis of pancreatic carcinoma are described. Future progress in the cellular and molecular aspects of this disease may lead to potential new remedies.     

Section Review: Oncologic,Endocrine & Metabolic: Liposomal chemotherapy for AIDS-related Kaposi's sarcoma

Drug encapsulation within a liposome offers a potential therapeutic advantage by preventing interaction of the drug with plasma components and extending the duration of exposure of the target to the drug. Previous liposomal studies have been hindered by the rapid clearance of the liposome by cells of the reticuloendothelial system. Developments in membrane technology and production standards have allowed development of a range of new liposomal agents which show activity without the problems of previous generations of the drugs. Kaposi's sarcoma has been used as a trial neoplasm for two types of liposomal anthracycline. DaunoXome, a liposomal preparation of daunorubicin, shows high response rates with minimal toxicity when used for advanced systemic AIDS-related KS. Dox-SL, a liposomal preparation of doxorubicin, shows similar activity but with a differing range of toxicity. Liposomal membranes differ for both drugs and are predominantly responsible for the differences in toxicity. Phase I and II studies show that the drugs are active with toxicity less than would be expected with conventional combination chemotherapy for AIDS-related KS. The results of Phase III studies are awaited and the roles of such drugs in commoner, solid malignancies are being explored.     

Section Review: Oncologic,Endocrine & Metabolic: Gastrin antagonists and gastrointestinal tumours

The role of gastrin in the growth of gastrointestinal tumours is complex, involving both endocrine and autocrine/paracrine pathways. Receptor subtypes, distinct from the classical gastrin/CCK-B receptors which mediate the normal physiological functions of gastrin, are now being identified. These appear to have potential roles in gastrin-associated proliferative pathways in malignant cells. Due to the recent expansion of knowledge in this area, the role of the classical anti-gastrin agents remains unclear. This is especially so for the gastrin/CCK-B receptor antagonists, due to the multiple receptor types now in evidence. However, certain agents may potentially overcome the problem of the different gastrin-mediated mitogenic pathways and the receptor isoforms involved. Although agents which block gastrin secretion, such as somatostatin analogues, might have been expected to be successful at targeting the autocrine/paracrine pathway, clinically, in gastrointestinal adenocarcinomas, they have proven disappointing. This may possibly be due to low tumour expression of the relevant somatostatin receptor subtypes. Antibody neutralisation of mitogenic forms of gastrin by use of gastrin immunogens may have therapeutic potential in the clinic but has so far only been evaluated in a pre-clinical setting.

CCK-A receptor antagonists have low affinity for gastrin receptors and information on CCK-A receptor antagonists and Gl cancers is scarce. Consequently, this review concentrates on the effects of gastrin/CCK-B receptor antagonists in Gl cancers.     

Section Review Oncologic,Endocrine & Metabolic: Recent developments with novel anthracyclines for the treatment of haematological malignancies

This review discusses recent developments with novel anthracyclines for the treatment of haematological malignancies. The acquisition of the active 13-hydroxy (-OH) derivatives of anthracyclines is fascinating, as their derivatives are persistent in blood, whilst those of daunorubicin and doxorubicin are inactive. Chemical modification of daunorubicin led to the newly developed anthracycline, idarubicin, whose 13-OH derivative, idarubicinol, is active in vivo. Idarubicin is superior to daunorubicin in the treatment of acute myelogenous leukaemia. Amrubicin (SM-5887), another newly synthesised anthracycline, has a unique structure with an amino residue introduced at the C-9 position. The most characteristic feature is that amrubicin itself is a depot form of its active 13-OH derivative. Amrubicin is less cardiotoxic than doxorubicin in the chronic rabbit model. This may be due, in part, to the fact that cardiotoxicity depends on the C_max of the drug, since the 13-OH derivative maintains a relatively low plasma level persistently. Amrubicin is expected to be effective against non-Hodgkin's lymphoma. In addition, the development of orally active drugs, predominantly to allow out-patient treatment of lymphoma and myeloma, is described. Menogaril, an analogue of nogalamycin, is one such novel anthracycline. It can be administered orally and its bioavailability is estimated to be 32 ± 12%. Although the clinical outcome following iv. administration was disappointing, oral treatment with menogaril is expected to be useful for patients with lymphoma and breast cancer. Further studies are required to clarify the effectiveness of these drugs.     

Section Review Oncologic,Endocrine & Metabolic: Angiogenesis inhibition as a drug target for disease: an update

Angiogenesis is required for the development of many proliferative diseases, including granulomatous disease, such as rheumatoid arthritis, psoriasis and neoplasia, as well as diabetic retinopathy. A substantial effort is being made to develop inhibitors of angiogenesis for the treatment of these diseases. This article is an update of a previous review [Colville-Nash & Seed, Curr. Opin. Invest. Drugs (1993) 2:763-813], and reviews the recent developments in the use of: angiostatic steroids, fumagillol derivatives, somatostatin analogues, matrix metalloproteinase (MMP) inhibitors, modulators of vascular endothelial cell growth factor (VEGF), fibroblast growth factor (FGF), angiostatin, endostatin, platelet factor-4 (PF4), thrombospondin-1 (TSP-1), cell adhesion molecules (integrins and selectins), urokinase plasminogen receptor antagonists, cyclo-oxygenase (COX) and non-steroidal anti-inflammatory drugs (NSAIDs), nitric oxide synthase (NOS), cytokine-suppressing anti-inflammatory drugs (CSAIDs), and drug combinations. Most of these approaches have been shown to be effective in inhibiting tumour growth in vivo, and many in models of inflammation. The field has, therefore, a very wide range of effective drug targets which are being exploited. Many areas are still limited by their reliance on high molecular weight molecular technologies, antibodies and constructs; however, low molecular weight compounds are now being sought in areas such as cytokine suppression, VEGF, MMPs, COX, NOS, and adhesion molecules. Angiostatic therapy is a rapidly advancing, therapeutically viable and exciting field.     

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.     

Section Review: Oncologic,Endocrine & Metabolic: The vacuolar H+-ATPase: A potential target for drug development in bone diseases

Osteoporosis and other skeletal or joint disorders involve an increased bone resorption by osteoclasts. Acidification of the bone resorbing compartment, which underlies osteoclasts at their site of attachment to the bone matrix, is of critical importance and results from the activity of vacuolar proton ATPases present in the osteo-clast's plasma membrane. In this review, we discuss the possibilities of therapeutic intervention by drugs targeted toward these proton transport systems, potentially resulting in decreased bone resorption in vitro and in vivo. The mechanisms of action of various inhibitors of the osteoclast vacuolar proton pump are discussed in the context of the current structural and functional knowledge of vacuolar-type proton ATPases.     

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.     

Section Review: Oncologic,Endocrine & Metabolic: Immunoneuroendocrine therapy for endocrine tumours: recent developments

Immunoneuroendocrine therapy for endocrine tumours represents a therapeutic strategy capable of inhibiting endocrine cancer growth by acting simultaneously on both endocrine and immune mechanisms. This strategy is realised by the administration of cytokines able to induce both endocrine and immune effects and/or neurohor-mones with immunomodulating properties in addition to their neuroendocrine activity. In terms of their effects on endocrine tumours, interferon-α (IFNα) and interleukin-2 (IL-2) are the most investigated cytokines; the long-acting somatostatin analogue, octreotide, and the pineal hormone, melatonin (MLT), are the correspondingly most interesting neurohormones. At present, there are clinical data concerning the efficacy of IFN alone and octreotide alone, whereas only Imited data are available concerning the effects of IL-2 alone or IL-2 plus MLT. IFN alone and octreotide alone seem to be the most effective drugs in the control of the cell proliferation and clinical symptomatology, respectively, of gastroenteropancreatic (GEP) endocrine tumours. Moreover, their association would be expected to improve treatment efficacy further. On the contrary, the efficacy of IFN or octreotide in endocrine neoplasms other than GEP tumours, such as medullary thyroid carcinoma, phaeochromocytoma and adrenal cancers, remains to be established. IL-2 in association with MLT has been proven to induce objective tumour regressions in endocrine neoplasms previously unresponsive to standard therapies. IL-2 alone seems to be less effective. Future advances in the knowledge of immunoneuroendocrine interactions will allow us to improve the clinical results of immunoneuroendocrine therapy for endocrine tumours.     

Section Review Oncologic,Endocrine & Metabolic: Bleomycin antibiotics and their role in cancer chemotherapy

The bleomycins are a group of glycopeptide anticancer cytotoxic agents which have been used in the clinical treatment of several human malignancies as single or combination chemotherapy for over two decades. However, the risk of dose-dependent pulmonary toxicity, which ultimately results in pulmonary fibrosis, limits the scale of application. Meanwhile, the unique mechanism of the antitumour effects of bleomycins has also attracted considerable interest from biologists. Extensive studies at the molecular level have provided a guide to attempts to obviate the pulmonary toxicity. Recent progress made in the areas of drug delivery, electropermeabilisation and conjugate synthesis has provided valuable additional information to improve bleomycin chemotherapy. The patents and publications discussed in this review are selected from those covering the period from 1992 to date based on a Chemical Abstracts search.     

Section Review: Oncologic,Endocrine & Metabolic: Treatments,topics, and trends in ovarian cancer

Long-term survival is now a reality for patients diagnosed with advanced ovarian cancer. Although cisplatin-based chemotherapy has been the standard therapy for the 1990s, new data suggest that combination chemotherapy, including initial treatment with pacli-taxel, is superior to cisplatin/cyclophosphamide. Other areas of progress include the use of the tumour marker, CA125, the recognition of prognostic factors, the impact of dose, intraperitoneal treatment, the role of surgery, and new drugs. However, many questions are unresolved. For example, what is the best dose and scheduling of paclitaxel? Is it better to treat recurrent disease as soon as possible or to wait until symptoms occur? What will be the new standard chemotherapy in the next decade? What is the best end-point for future clinical trials? These are questions that can only partly be answered from the literature; the final answer will come from performing the necessary trials. A number of new agents with activity during platinum therapy in patients with progressive disease have recently become available, including docetaxel, 2′,2′-difluorodeoxy-cytidine, topoisomerase I inhibitors, and lobaplatin. The results of studies with these drugs will certainly have an impact on future clinical practice and research.     

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.