Carcinogenicity of anticancer agents

Chemotherapeutic treatment for cancer has been successful in prolonging survival but it has also been demonstrated that survivors of cancer patients who had received chemotherapy with alkylating agents have an increased risk of second malignancies, mostly acute non-lymphatic leukemia. The purpose of this paper is to show practical problems pertaining to the development and clinical use of anticancer agents in terms of prevention of second cancers.     

Selective cytostatic and cytotoxic anticancer effects of bisfunctional agents: A strategy for the design of DNA binding agents

Various agents have been synthesized and proved useful for the National Cancer Institute’s anticancer testing as potential new drugs, but most agents suffer side effects from their limited selectivity against cancer cells over healthy ones. Therefore, this paper attempts to describe drugs in terms of the level of tumor cell selectivity which they possess to define the features of molecules that are essential for useful cytotoxicity. Selected cyclic amidinothymine analogues (NSC 697864, NSC 697865, and NSC 697869) have nanomolar inhibitory activities against leukemia cell lines: CCRF-CEM, HL-60(TB), while bisfunctional cancer fighters NSC 702408 and NSC 702409, showing larger numbers of cytostatic and cytotoxic effects, in an extended conformation would probably adopt a similar to NSC 715653 conformation leaving both opposite H-bond donor groups at the same distance to interact with DNA in a similar way. Such specific interactions (cell line selectivity to unique mutated patterns) lower considerably the observed dose-response concentrations. This in vitro selectivity is shown to translate into in vivo efficacy indicated by the inflection in the cumulative testing curve.     

Pharmacokinetic variability of anticancer agents

The translation of advances in cancer biology to drug discovery can be complicated by pharmacokinetic variation between individuals and within individuals, and this can result in unpredictable toxicity and variable antineoplastic effects. Previously unrecognized variables (such as genetic polymorphisms) are now known to have a significant impact on drug disposition. How can the pharmacokinetic variability of anticancer agents be reduced? This will require the understanding of correlations between pharmacokinetics and treatment outcomes, the identification of relevant patient parameters, mathematical modelling of individual and population pharmacokinetics, and the development of algorithms that will tailor doses to the individual patient.     

The main steps in the development of anticancer agents

The development of new anticancer agents is a long-term process, which involves the acquisition of new compounds, screening for antitumor activity, production and formulation, animal toxicology and finally, evaluation of toxicity and antitumor activity of the compound in man (Table I). In this paper, the main steps in the early development of new cytotoxic agents up to phase II clinical studies will be discussed. However, clinical phase III-IV trails, where the efficacy of the drug has been proven, should be dealt with separately.     

Radiation recall with anticancer agents

Radiation recall is an acute inflammatory reaction confined to previously irradiated areas that can be triggered when chemotherapy agents are administered after radiotherapy. It remains a poorly understood phenomenon, but increased awareness may aid early diagnosis and appropriate management. A diverse range of drugs used in the treatment of cancer has been associated with radiation recall. As most data come from case reports, it is not possible to determine the true incidence, but to date the antineoplastic drugs for which radiation recall reactions have been most commonly reported include the anthracycline doxorubicin, the taxanes docetaxel and paclitaxel, and the antimetabolites gemcitabine and capecitabine. Radiation recall is drug-specific for any individual patient; it is not possible to predict which patients will react to which drugs, and rechallenge does not uniformly induce a reaction. There are no identifiable characteristics of drugs that cause radiation recall, and thus, it is a possibility that must be kept in mind with use of any drug after radiotherapy, including those from new drug classes. Although it is not yet possible to design treatment regimens to eliminate the risk of radiation recall, it seems likely that risks can be minimized by prolonging the interval between completion of radiotherapy and initiation of chemotherapy.     

Aurora-kinase inhibitors as anticancer agents

Errors in mitosis can provide a source of the genomic instability that is typically associated with tumorigenesis. Many mitotic regulators are aberrantly expressed in tumour cells. These proteins could therefore make useful therapeutic targets. The kinases Aurora-A, -B and -C represent a family of such targets and several small-molecule inhibitors have been shown to block their function. Not only have these inhibitors advanced our understanding of mitosis, but, importantly, their in vivo antitumour activity has recently been reported. What have these studies taught us about the therapeutic potential of inhibiting this family of kinases?     

Novel antibodies as anticancer agents

In recent years antibodies, whether generated by traditional hybridoma technology or by recombinant DNA strategies, have evolved from Paul Ehrlich's 'magic bullets' to a modern age 'guided missile'. In the recent years of immunologic research, we are witnessing development in the fields of antigen screening and protein engineering in order to create specific anticancer remedies. The developments in the field of recombinant DNA, protein engineering and cancer biology have let us gain insight into many cancer-related mechanisms. Moreover, novel techniques have facilitated tools allowing unique distinction between malignantly transformed cells, and regular ones. This understanding has paved the way for the rational design of a new age of pharmaceuticals: monoclonal antibodies and their fragments. Antibodies can select antigens on both a specific and a high-affinity account, and further implementation of these qualities is used to target cancer cells by specifically identifying exogenous antigens of cancer cell populations. The structure of the antibody provides plasticity resonating from its functional sites. This review will screen some of the many novel antibodies and antibody-based approaches that are being currently developed for clinical applications as the new generation of anticancer agents.     

Cannabinoids: potential anticancer agents

Cannabinoids - the active components of Cannabis sativa and their derivatives - exert palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite. In addition, these compounds have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell-signalling pathways. Cannabinoids are usually well tolerated, and do not produce the generalized toxic effects of conventional chemotherapies. So, could cannabinoids be used to develop new anticancer therapies?     

Arsenic compounds as anticancer agents

In this paper the use of arsenic compounds as anticancer agents in clinical trials and in in vitro investigations is reviewed, including the experience at our institute. Treatment of newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL) with arsenic trioxide (As2O3) has been found to result in complete remission (CR) rates of 85-93% when given by intravenous infusion for 2-3 h at a dose of 10 mg/day diluted in 5% glucose saline solution. Patients exhibit a response in 28-42 days. CR rates after administration of Composite Indigo Naturalis tablets containing arsenic sulfide and of pure tetraarsenic tetrasulfide reached 98% and 84.9%, respectively. At higher concentrations (1-2 microM), arsenic induced apoptosis, while at lower concentrations (0.1-0.5 microM), it triggered cell differentiation in vitro. As2O3-induced apoptosis has been observed in many cancer cell lines, including esophageal carcinoma, gastric cancer, neuroblastoma, lymphoid malignancies, and multiple myeloma. Its effectiveness was confirmed in the treatment of multiple myeloma. Arsenic compounds are effective agents in the treatment of APL and their activity against other types of cancer requires further investigation.     

Drug interactions with anticancer agents

Each anticancer agent has its own pharmacologic activities. Effect of anticancer agent may be influenced by the concomitant administration of another drug. In addition, patients with advanced cancer occasionally require other medications as well. These drugs can alter both the effects and adverse reactions of anticancer agents. Therefore, much attention must be placed on the interaction with anticancer agents. This paper summarizes drug interactions between anticancer agents and other drugs. Furthermore, clinical significance of these interactions will be discussed. It is hoped that this paper will provide more attention for the study of this problem.     

Microtubule-targeted anticancer agents and apoptosis

Over the past decade, significant progress has been made in our understanding of the biology of microtubule (MT) assembly into the mitotic spindle during mitosis and the molecular signaling and execution of the various pathways to apoptosis. In the same period, the microtubule-targeted tubulin-polymerizing agents (MTPAs), notably paclitaxel and taxotere, have come to occupy a central role in the treatment of a variety of human epithelial cancers. Following their binding to B-tubulin, MTPAs inhibit MT dynamic instability, cell cycle G2/M phase transition and mitotic arrest of cancer cells. MTPA-induced anti-MT and cell cycle effects trigger the molecular signaling for the mitochondrial pathway of apoptosis. This triggering is orchestrated through different molecular links and determined by the threshold for apoptosis that is set and controlled diversely in various cancer types. The complexity and regulatory potential of the links and the apoptosis threshold are integral to the transformed biology of the cancer cell. The emerging understanding of this biology and how it is influenced by treatment with MTPAs has highlighted novel strategies to further enhance the antitumor activity and overcome resistance to MTPA-induced apoptosis in cancer cells.     

Pharmacogenetics and pharmacogenomics of anticancer agents

Large interindividual variation is observed in both the response and toxicity associated with anticancer therapy. The etiology of this variation is multifactorial, but is due in part to host genetic variations. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this variation in susceptibility to chemotherapy. This review provides an overview of the progress made in the field of pharmacogenetics and pharmacogenomics using a five‐stage architecture, which includes 1) determining the role of genetics in drug response; 2) screening and identifying genetic markers; 3) validating genetic markers; 4) clinical utility assessment; and 5) pharmacoeconomic impact. Examples are provided to illustrate the identification, validation, utility, and challenges of these pharmacogenetic and pharmacogenomic markers, with the focus on the current application of this knowledge in cancer therapy. With the advance of technology, it becomes feasible to evaluate the human genome in a relatively inexpensive and efficient manner; however, extensive pharmacogenetic research and education are urgently needed to improve the translation of pharmacogenetic concepts from bench to bedside. CA Cancer J Clin 2009;59:42–55. © 2009 American Cancer Society.     

Selective anticancer agents suppress aging in Drosophila

Mutations of the PI3K, TOR, iNOS, and NF-κB genes increase lifespan of model organisms and reduce the risk of some aging-associated diseases. We studied the effects of inhibitors of PI3K (wortmannin), TOR (rapamycin), iNOS (1400W), NF-κB (pyrrolidin dithiocarbamate and QNZ), and the combined effects of inhibitors: PI3K (wortmannin) and TOR (rapamycin), NF-κB (pyrrolidin dithiocarbamates) and PI3K (wortmannin), NF-κB (pyrrolidine dithiocarbamates) and TOR (rapamycin) on Drosophila melanogaster lifespan and quality of life (locomotor activity and fertility). Our data demonstrate that pharmacological inhibition of PI3K, TOR, NF-κB, and iNOS increases lifespan of Drosophila without decreasing quality of life. The greatest lifespan expanding effect was achieved by a combination of rapamycin (5 μM) and wortmannin (5 μM) (by 23.4%). The bioinformatic analysis (KEGG, REACTOME.PATH, DOLite, and GO.BP) showed the greatest aging-suppressor activity of rapamycin, consistent with experimental data.     

Problems in the development of analogs of anticancer drugs

Undoubtedly the progress of cancer chemotherapy is supported by the development of new anticancer drugs. In Japan, there is a tendency to develop anticancer drugs by both chemical modification of the known anticancer drugs (analogues) and finding new structures. However, we have to be cautious to develop analogues of the known anticancer drugs. Before we consider to put these drugs into the clinical trials, several points must be clarified: that is, the new compounds would have any merit or superior points compared to the mother compounds. Especially, we should observe whether or not the new compounds possess any reduction of major toxicities of the mother compounds, how about the situation of cross resistance, anticancer efficacies and particularly the results of toxicology studies. We have limited cancer patients for testing new drugs, and also from ethical view, some easy consideration for developing analogues having minor differences from the mother compounds, must be abandoned.     

Gastrointestinal cancer and oral anticancer agents

5-FU has been very valuable as an anticancer agent since it was first developed by Heidelberger in 1957. For over 40 years it has been used either by itself or in combination therapy for the treatment of patients with all types of malignant tumors. To date, no better anticancer agent has been developed for the treatment of patients with gastrointestinal tract cancer. During administration, consideration for a combined regimen from the standpoints of dose intensity, schedule dependency, and biochemical modulation can improve the antitumor effectiveness of 5-FU. It has been found to be most effective if administered by long term (if possible, 4 weeks or more) intravenous or intraarterial continuous drip infusion. However, there are also negative aspects. The dose-limiting toxicity with drip infusions brings about gastrointestinal disorders such as stomatitis and diarrhea. Furthermore, the possibility of trouble and difficulty in managing a catheter kept in the body over long periods not only greatly reduces the patient's QOL, it is also very inconvenient for the patient and increases medical costs. Since the development of oral FT by Kimura, however, many 5-FU prodrugs and masked compounds have been developed in Japan. The aim has been to see how far the concentration of 5-FU in the blood and cancer tissues could be raised. UFT, 5'-DFUR, and HCFU have been developed as derivatives of 5-FU, and these are widely used clinically either alone or in combination therapy. With the aim of further improving antitumor effectiveness and reducing side effects, these compounds have been improved from the viewpoints of pharmacodynamics and pharmalokinetics, based on biochemical modulation, to create S-1 and Capecitabine. Although these are still currently undergoing clinical trials, sufficient results have already been obtained. Cisplatin and CPT-11 are effective for use in the gastrointestinal tract, and much work is going on now to allow these to be taken orally. Future prospects indeed look bright.     

Farnesyl transferase inhibitors as anticancer agents

Protein farnesylation catalysed by the enzyme farnesyl protein transferase involves the addition of a 15-carbon farnesyl group to conserved amino acid residues at the carboxyl terminus of certain proteins. Protein substrates of farnesyl transferase include several G-proteins, which are critical intermediates of cell signalling and cytoskeletal organisation such as Ras, Rho, PxF and lamins A and B. Activated Ras proteins trigger a cascade of phosphorylation events through sequential activation of the PI3 kinase/AKT pathway, which is critical for cell survival, and the Raf/Mek/Erk kinase pathway that has been implicated in cell proliferation. Ras mutations which encode for constitutively activated proteins are found in 30% of human cancers. Because farnesylation of Ras is required for its transforming and proliferative activity, the farnesyl protein transferase inhibitors were designed as anticancer agents to abrogate Ras function. However, current evidence suggests that the anticancer activity of the farnesyl transferase inhibitors may not be simply due to Ras inhibition. This review will discuss available clinical data on three of these agents that are currently undergoing clinical trials.     

Merocyanines: potential new anticancer agents

We report the synthesis of a series of merocyanines and the structure-effect relationship as cytotoxic agents for human adenocarcinoma cells in vitro. The cytotoxicity of these compounds in vitro makes them potential anticancer agents. One of these compounds was found active on human and mouse tumor models.