Current Pharmaceutical Design - Volume 7, Issue 16, 2001

Background: The incidence of brain and other central nervous system malignant neoplasias is 6.5 cases per 100,000 inhabitants-years, and appears to increase with increasing age (1.2 percent per year), with the greatest rate of increase in the population over age 70 years. Material and methods: Chemotherapy remains part of the treatment that includes surgery and radiation therapy for the management of malignant gliomas. This article reviews the new drugs that have been introduced in the treatment of these patients in the latest years, their specific cellular targets, the objective response, the TTP and the MST. Results: The most encouraging results to date come from studies of temozolomide, which is one of the most active and best tolerated drugs in recent years, and from clinical trials of CPT11. Conclusions: New approaches to chemotherapy treatment are necessary. Enrollment of patients into rigorous, well conducted, clinical trials, both at tumor diagnosis and recurrence, will generate new information regarding investigational therapies, and may offer improved therapies for patients with malignant gliomas.

Ras is a 21 kDa membrane-localized G protein that is coupled to receptor and non-receptor tyrosine kinase activation of downstream cytoplasmic and nuclear events. Mutated ras genes are common, and occur in a wide variety of human malignancies. These activating mutations result in constitutive signaling, thereby stimulating cell proliferation and inhibiting apoptosis. Preclinically, inhibitors of ras signaling revert ras-dependent cellular transformation, and cause regression of ras-dependent rodent tumor xenografts. The ras signaling pathway has therefore attracted considerable attention as a target for anticancer therapy. In this review, novel therapeutic approaches based on the inhibition of ras-mediated signaling, are described. The discussion will be limited to inhibitors which are currently in human clinical trials, and include inhibitors of ras processing, inhibitors of ras protein synthesis and inhibitors of downstream ras effectors.

The development of drug resistance is considered to be a major cause for the failure of chemotherapy in a number of types of cancer, including ovarian, breast and lung. Most previous research has focused on approaches to reverse drug resistance once it has arisen, that is, on the use of agents which can make drug-resistant tumors more sensitive to chemotherapy. Unfortunately, this approach has thus far met with only limited clinical success. Because of the prevalence of drug resistance in cases of advanced cancer, there exists an urgent need to develop new approaches to dealing with this problem. We have hypothesized the feasibility of an alternative approach: the use of specific agents to prevent the development of resistance before it arises. Our initial studies to examine this hypothesis have focused on ovarian cancer. We have designed both in vitro and in vivo systems in which resistance develops rapidly after exposure of tumor cells or xenografts to melphalan or cisplatin. Using these systems we have shown that two selenium compounds, selenite and selenomethionine are able to prevent the induction of resistance. Furthermore, inclusion of selenite in a chemotherapeutic protocol can result in a significant enhancement of the efficacy of cisplatin in suppressing the growth of human ovarian tumor xenografts. These results have supported the idea that prevention may be a useful new approach to the problem of drug resistance in cancer chemotherapy.

Cancer, only second to heart disease, is a leading cause of death in the United States. Despite many years of cancer research little progress has been made in the treatment of many types of cancer. With the advent of molecular biology and advanced biochemical techniques, we have begun to elucidate the various signaling pathways that account for the transformation of normal cells to malignant cells. Our understanding of cancer cell signaling and cell cycle deregulation has paved the way for the rational design of specific inhibitors. Alas, attempts to specifically and exclusively target treatment to the cancer cell have fallen short of expectations for cure and often result in unfortunate drug side effects. More recently, Folkman proposed neovascularization requirements for tumor expansion and metastasis, and this sparked great interest in both the molecular mechanism of tumor-induced angiogenesis and its potential target for anticancer treatment. In this review, we first describe protein growth factors that have been shown to induce endothelial cell proliferation and angiogenesis. We also discuss the signal transduction cascades that result from growth factor receptor binding in light of drugs that are know to inhibit these cascades. Finally, we discuss the potential use of antagonists of lipid second messengers. In particular BN-50730, a PAF antagonist shows promise in preliminary anti-tumor therapy in vitro and in vivo in athymic nude mice by specifically inhibiting angiogenesis.

Agents that interact with cytoskeletal elements such as tubulin include synthetic spiroketal pyrans (SPIKET), targeting the spongistatin binding site of beeta-tubulin, and monotetrahydrofuran compounds (COBRA compounds), targeting a unique binding cavity on alpha-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P caused tubulin depolymerization and demonstrated potent cytotoxic activity against cancer cells. COBRA-1 inhibited GTP-induced tubulin polymerization. Treatment of human breast cancer and brain tumor cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Other agents that have shown promise for cancer treatment include phorboxazoles, natural products that are extremely cytostatic towards the National Cancer Institute's panel of 60 tumor cell lines. In standard MTT assays, synthetic phorboxazole A exhibited potent cytotoxicity against NALM-6 acute lymphoblastic leukemia cells (IC 50 = 1.7 nM), BT-20 breast cancer cells (IC 50 = 3.4 nM), and U373 glioblastoma cells (IC 50 = 6.7 nM). Structure-activity studies were reported for seven synthetic analogs of phorboxazole A. Out of these, two showed potent anti-cancer activity. Phorboxazole analog 2 was active against NALM-6 cells (IC 50 = 4.8 nM), BT-20 cells (IC 50 = 12.6 nM) and U373 cells (IC 50 = 27.4 nM), as was analog 3 (NALM-6 IC 50 = 5.2 nM, BT-20 IC 50 = 11.3 nM, and U373 IC 50 = 29.2 nM). Anticancer activity of the phorboxazole analogs was correlated to the presence of certain structural moieties such as portions of the macrolide group, the central oxazole group, and the polyene side chain. The requirement of more than one structural element for activity suggested that at least bimodal interactions of the natural product with key cellular components may occur. Promising anti-mitotic agents with pro-apoptotic activity include inhibitors of the tyrosine kinase BTK. The leflunomide metabolite analog LFM-A13 inhibited BTK in leukemia and lymphoma cells. Consistent with the anti-apoptotic function of BTK, treatment of leukemic cells with LFM-A13 enhanced their sensitivity to chemotherapy-induced apoptosis

Despite some interesting pilot experiments more than a century ago, nucleic acid has only recently been added to the list of agents used for the prevention and therapy of cancer. Two distinct features of nucleic acids are used for this purpose: in DNA and RNA vaccines, genetic information for pathogen- or tumor-derived antigens is delivered to the host who then produces the encoded antigen and initiates an immune response. In DNA adjuvants, immunostimulatory sequences (CpG motifs) present in DNA of bacterial origin are used. Such sequences are delivered in the form of oligonucleotides or within the sequence of DNA vaccine. In addition, CpG oligonucleotides by themselves have successfully been used to stimulate the immune system in an antigen-independent manner for the treatment of experimental tumors. DNA and RNA vaccines for the treatment and prevention of cancer and other diseases suffer from two some shortcomings: insufficient immunogenicity and - in the case of RNA - low stability. A variety of strategies are being explored to improve the efficacy of nucleic acid vaccines (genetic vaccines) especially for self-antigens in the case of cancer. Among the most recent improvements are self-replicating RNA vaccines and replicase-based DNA-vaccines in which antigen expression is under the control of an alphaviral replicase. Despite highly promising results in many animal tumor models the efficacy of nucleic acid vaccines and adjuvants in the clinic remains to be seen.

The protein kinase family presents remarkable opportunities for drug discovery and development targeting mainly to the ATP binding cleft. Cyclin-dependent kinases CDKs control the cell division in by controlling its sub phases. The regulation of CDKs is altered in a number of tumor types, and therefore CDKs are a particularly attractive target group of kinases with reference to proliferative disorders including cancer, but also extending to graft stenosis, and autoimmune disorders. Screening of chemical modulators of CDKs that modulate aberrant CDK activity might be beneficial for cancer therapy by directly inhibiting kinase activity, or influencing cell cycle “checkpoint”function, which is mediated through effects of exogenous cellular regulators of CDK activity. In this regard small molecule modulators such as flavopiridol and UCN-01 are in early clinical trials. Other more selective modulators of CDK function are being actively sought, and initial results with flavopiridol analogs, indirubins, paullones, and purine-based inhibitors will be considered.

In 1995, a new cytokine termed TRAIL (tumor necrosis factor - related apoptosis-inducing ligand) was discovered and demonstrated to selectively induce programmed cell death in transformed cell lines. Preclinical cytotoxicity studies in mice and nonhuman primates have produced promising results by demonstrating that TRAIL exerts potent tumoricidal activity but lacks severe toxicity towards normal tissues making it a potentially ideal candidate for cancer therapy. This article reviews aspects of our current understanding of TRAIL signaling pathways and summarizes how this knowledge is currently being translated into TRAIL-based tumor-selective therapeutic strategies