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PubMed1981

Regional arterial infusion of an anticancer drug combined with direct hemoperfusion.

The capacity of activated charcoal to adsorb anticancer drugs, Mitomycin C, Adriamycin and Bleomycin was examined in vitro in a closed circuit through a perfuser containing uncoated activated charcoal. Samples were obtained from the inlet and outlet of the perfuser every 30 min. As in vivo experiments, regional arterial infusion of anticancer drugs combined with direct hemoperfusion was performed on dogs. In 20 male mongrel dogs a polyethylene catheter was indwelt in the internal iliac artery and anticancer drugs were infused through the catheter for 1 hr. By using the femoral vessels for the blood access, direct hemoperfusion was performed for 3 hr. The adsorptive capacity of activated charcoal was high in both in vitro and in vivo experiments. These results indicate that regional arterial infusion of anticancer drugs combined with direct hemoperfusion would be useful for preventing their toxicity.

Adsorption↗

PubMed2006

Anticancer effects of Chinese herbal medicine, science or myth?

Currently there is considerable interest among oncologists to find anticancer drugs in Chinese herbal medicine (CHM). In the past, clinical data showed that some herbs possessed anticancer properties, but western scientists have doubted the scientific validity of CHM due to the lack of scientific evidence from their perspective. Recently there have been encouraging results, from a western perspective, in the cancer research field regarding the anticancer effects of CHM. Experiments showed that CHM played its anticancer role by inducing apoptosis and differentiation, enhancing the immune system, inhibiting angiogenesis, reversing multidrug resistance (MDR), etc. Clinical trials demonstrated that CHM could improve survival, increase tumor response, improve quality of life, or reduce chemotherapy toxicity, although much remained to be determined regarding the objective effects of CHM in human in the context of clinical trials. Interestingly, both laboratory experiments and clinical trials have demonstrated that when combined with chemotherapy, CHM could raise the efficacy level and lower toxic reactions. These facts raised the feasibility of the combination of herbal medicines and chemotherapy, although much remained to be investigated in this area.

Antineoplastic Agents, Phytogenic↗

PubMed1986

Anticancer drug sensitivity by human tumor clonogenic assay.

The anticancer drug sensitivity of human cancers was tested by the human tumor clonogenic assay (HTCA). Of 152 human cancer specimens tested, 63 (41%) formed more than 30 tumor cell colonies in control plates and could be used to evaluate the drug sensitivity of tumor cells. In 42 (93%) of 45 clinical trials in 24 patients, a parallel correlation was observed between the in vitro anticancer drug sensitivity measured by the HTCA and the clinical response of tumors to anticancer drugs. These results suggest that the HTCA is a good technique for the in vitro test of the anticancer drug sensitivity of human cancers.

Agar↗

PubMed2003

Pharmacology of anticancer drugs in the elderly population.

Modifications to bodily functions and physiology are known to occur with age. These changes can have a considerable impact on the pharmacokinetic processes of absorption, distribution, metabolism and excretion and the pharmacodynamic properties of administered drugs. For many drugs with a high therapeutic index, this will be clinically unimportant, but for anticancer drugs, which usually have a low therapeutic index, these pharmacological changes can lead to dramatic consequences, such as excessive drug concentrations and unacceptable toxicity, or subtherapeutic drug concentrations and ineffective treatment. Despite the increased susceptibility of the elderly to these changes, doses are rarely adapted on the basis of pharmacokinetics and pharmacodynamics, with the exception of changes secondary to altered renal function. Until recently, only a few large prospective randomised trials have provided evidence-based data for dose adaptations in elderly patients. However, with increasing knowledge of the pharmacokinetics of anticancer drugs, advances in the knowledge of pharmacokinetic behaviour with aging, and documented efficacy and toxicity data in the elderly population, it is possible to highlight aspects of prescribing anticancer drugs in the elderly. In general, and for most drugs, age itself is not a contraindication to full-dose chemotherapy. The main limiting factors are comorbidity and poor functional status, which may be present in a significant number of the elderly population. Elderly patients with cancer are part of the daily practice of oncologists, but currently clinicians can often only estimate whether dose modification is advantageous for the elderly. This review attempts to elucidate the factors that can influence the pharmacokinetics of anticancer drugs frequently used in the elderly, and the clinical or biochemical parameters that form the basis for dose adjustments with age.

Aged↗

PubMed2006

Anticancer alpha-helical peptides and structure/function relationships underpinning their interactions with tumour cell membranes.

Cancer is a major cause of premature death and there is an urgent need for new anticancer agents with novel mechanisms of action. Here we review recent studies on a group of peptides that show much promise in this regard, exemplified by arthropod cecropins and amphibian magainins and aureins. These molecules are alpha-helical defence peptides, which show potent anticancer activity (alpha-ACPs) in addition to their established roles as antimicrobial factors and modulators of innate immune systems. Generally, alpha-ACPs exhibit selectivity for cancer and microbial cells primarily due to their elevated levels of negative membrane surface charge as compared to non-cancerous eukaryotic cells. The anticancer activity of alpha-ACPs normally occurs at micromolar levels but is not accompanied by significant levels of haemolysis or toxicity to other mammalian cells. Structure/function studies have established that architectural features of alpha-ACPs such as amphiphilicty levels and hydrophobic arc size are of major importance to the ability of these peptides to invade cancer cell membranes. In the vast majority of cases the mechanisms underlying such killing involves disruption of mitochondrial membrane integrity and/or that of the plasma membrane of the target tumour cells. Moreover, these mechanisms do not appear to proceed via receptor-mediated routes but are thought to be effected in most cases by the carpet/toroidal pore model and variants. Usually, these membrane interactions lead to loss of membrane integrity and cell death utilising apoptic and necrotic pathways. It is concluded that that alpha-ACPs are major contenders in the search for new anticancer drugs, underlined by the fact that a number of these peptides have been patented in this capacity.

Amino Acid Sequence↗

PubMed2005

Small molecule antagonists of the MDM2 oncoprotein as anticancer agents.

In this early phase of the new era of molecularly targeted patient friendly cancer chemotherapy, there is a need for novel viable anticancer molecular targets. The MDM2 oncoprotein has been validated as a potential target for cancer drug development. MDM2 amplification and/or overexpression occur in a wide variety of human cancers, several of which can be treated experimentally with MDM2 antagonists. MDM2 interacts primarily with the p53 tumor suppressor protein in an autoregulatory negative feedback loop to attenuate p53's cell cycle arrest and apoptosis functions. Inhibition of the p53-MDM2 interaction has been shown to cause selective cancer cell death, as well as sensitize cancer cells to chemotherapy or radiation effects. Consequently, this interaction has been the main focus of anticancer drug discovery targeted to MDM2. The promotion of the proteasomal degradation of the p53 protein by MDM2 is central to its repression of the tumor suppressor functions of p53, and many proteins impinge upon this activity, either enhancing or inhibiting it. MDM2 also has oncogenic activity independent of its interaction with p53, but this has so far not been explored for drug discovery. Among the approaches for targeting MDM2 for cancer therapy, small molecule antagonists have recently featured as effective anticancer agents in experimental models, although the repertoire is currently limited and none has yet entered human clinical trials. Small molecules that have been reported to disrupt the p53-MDM2 binding, thereby enhancing p53 activity to elicit anticancer effects include the following: synthetic chalcones, norbornane derivatives, cis-imidazoline derivatives (Nutlins), a pyrazolidinedione sulfonamide and 1,4-benzodiazepine-2,5-diones, as well as tryptophan derivatives. In addition to compounds disrupting p53pMDM2 binding, three compounds have been discovered that are effective in inhibiting the E3 ligase activity of MDM2 towards p53, and should serve as leads for drug discovery targeting this aspect of the p53-MDM2 interaction as well. These compounds were discovered from library screening and/or structure-based rational drug design strategies.

Animals↗

PubMed2001

DNA topoisomerases as anticancer drug targets: from the laboratory to the clinic.

DNA topoisomerases play important roles in basic cellular biology. Recently they have been identified as the molecular targets of a variety of pharmaceutical agents. Some of the drugs that target the topoisomerases are anticancer drugs. These anticancer drugs work by a novel mechanism of action. They inhibit the topoisomerase molecule from religating DNA strands after cleavage. This leaves a cell with DNA breaks, which if not repaired, become lethal. In other words, these drugs convert the topoisomerase molecule into a DNA damaging agent. This is a stoichiometric relationship. Each anticancer drug molecule has the potential of interacting with one topoisomerase molecule to cause one DNA lesion. The clinical implication of this mechanism of drug action is that sensitivity to topoisomerase targeting drugs should be dependent on high topoisomerase levels. This is clearly true in laboratory systems. With new developments in in situ immunohistochemistry, topoisomerase expression can now be easily estimated in human cancers. From this information, it may be possible to predict the sensitivity or resistance of human cancers to topoisomerase targeting anticancer drugs.

Antineoplastic Agents↗

PubMed2004

Soy saponins and the anticancer effects of soybeans and soy-based foods.

While the cancer protective effect of soy-based diets has been the subject of numerous studies, the constituents of soy that may give rise to this effect remain elusive. Recent publications describing anticancer activity of crude and purified soybean saponins have sparked a renewed interest in these compounds. In this review, I summarize the epidemiological studies concerning the cancer protective effects of soy and the efforts to elucidate the constituents responsible for this effect. The recent reports of the anticancer activity of soy saponins is placed in context with reports of promising anticancer activity of structurally related non-dietary saponins from other legumes. While recent studies have demonstrated a direct effect of soy saponins on cancer cells, alternative mechanisms of cancer prevention by these agents are also discussed. It is concluded that the soy saponins may represent promising leads both in terms of elucidating the soy constituents involved in the cancer protective effect of soy as well as in the discovery of anticancer agents with novel mechanisms of action.

Animals↗

PubMed2006

Gold coordination complexes as anticancer agents.

Metal ions are known to bind with nucleic acids and thereby alter their conformation and biological function. The metal ion-base interaction depends on the nature of both metal and bases; a certain site of coordination is preferred. One of the most notable successes for inorganic drugs has been the effectiveness of platinum complexes against cancer. These advances have spurred a surge of investigations to identify new inorganic agents for use in chemotherapy with improved specificity and decreased toxic side effects. Gold(I) and gold(III) complexes, the last isostructural and isoelectronic with platinum(II) complexes, are potentially attractive as anticancer agents. The design of an effective anticancer agent is a complicated game that must encompass not only the drug's inherent inhibitory properties but also its delivery, dosage, and residence time in vivo. Gold(I) and gold(III) complexes overcome some of these challenges by forming strong covalent attachments to targets. Au(III) isoelectronic with Pt(I1)-d8 system usually forms square planar complexes in solution. Since the square planar geometry of Pt(II) is important for its action as an anticancer drug, Au(III) compounds also can be used for the same purpose with the added advantage of decreased toxicity. This, together with the recent finding that certain transitional metal complexes like Au and Pt complexes have been found to be potentially useful in cancer chemotherapy, created a renewed interest in the study of the interactions of metal ions with respect to the site of binding and the structure and stability of the complexes. This work was motivated by the thought that information on the variety of Au(III) complexes and their effects can be obtained by studying the properties of Au complexes with various ligands. Various studies in the past have shown that Au complexes are very attractive in view of their application as anticancer agents.

Antineoplastic Agents↗

PubMed2006

Acquired resistance to the anticancer drug paclitaxel is associated with induction of cytochrome P450 2C8.

INTRODUCTION: We have previously shown that human colorectal cancer tissue is able to inactivate the anticancer drug paclitaxel through cytochrome P450 (CYP)2C8 and CYP3A4 metabolisms. The aim of this study was to evaluate whether changes in the expression levels of genes coding for such enzymes are related to anticancer drug resistance after long-term exposure to the drug. METHODS: Human colorectal cancer cells (Caco-2) that are sensitive to paclitaxel were exposed to increasing concentrations of the drug from 0-250 nM during one year, in order to select paclitaxel-resistant cells. Subsequently, we compared the sensitivity to paclitaxel and the extent of expression of the CYP2C8, CYP3A4 and CYP3A5 genes in original and resistant cells. RESULTS: Resistant cancer cells displayed a 246-fold increased lethal dose (LD)50 to paclitaxel (p < 0.004) as compared with original cancer cells. A 4.4-fold (p = 0.005) enhancement of CYP2C8 expression and a 5.6-fold (p = 0.001) increase of multidrug resistance (MDR)1 expression was observed in resistant cells exposed to paclitaxel. When paclitaxel was removed from the culture medium, CYP2C8, but not MDR1 expression, reverted to basal levels and the resistance to paclitaxel decreased 3.2-fold (p = 0.005). No major changes in the expression levels of CYP3A4 and CYP3A5 were observed. CONCLUSIONS: Caco-2 cells are capable of increasing the expression levels of CYP2C8 as a response to long-term exposure to paclitaxel. This study provides evidence for a mechanism of acquired resistance to anticancer therapy based on the induction of anticancer-metabolizing enzymes.

Antineoplastic Agents, Phytogenic↗

PubMed1992

[Growth inhibitory effect of a new anticancer antibiotics, kazusamycin A, on human transitional cancer cell lines in vitro].

Kazusamycin A (KZMA) is a new anticancer antibiotic, which has been proven to have strong anticancer effect and several characteristic features different from currently available anticancer antibiotics. However, there has as yet been no report which had concerned itself with the effect of KZMA on urological cancer. This study was undertaken to determine the inhibitory effects of KZMA on transitional cancer cells in vitro, the augmentation of the inhibitory effect by combining thermal treatment and the effect of KZMA upon DNA distribution. Human transitional cancer cells, KU-1, and T-24 were used as targets. Fifty % inhibitory concentration of KZMA was determined after these cells were exposed to graded concentrations of KZMA for 2 to 48 hours, and to the concentration of KZMA for 2 hours at the temperature of 42 degrees C. Viable cells were counted by dye exclusion assay (DEA) and by tetrazolium-based colorimetric assay (MTT-assay) exposure. KZMA inhibited the growth of the three transitional cancer cells strongly and this inhibitory effect appeared to be depend upon the exposure time and the concentration of KZMA. IC50s after 2-hour exposure at the temperature of 42 degrees C was shown to be decreased to 23 to 87% of that at the temperature of 37 degrees, indicating an augmentation of the inhibitory effect of KZMA by combining thermal treatment. MGH-U1 was the most sensitive to the combination of KZMA and hyperthermia. The cell cycle analysis showed that KZMA had G2-arresting and M-retarding effects, which were different compared with currently available anticancer antibiotics.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibiotics, Antineoplastic↗

PubMed1999

Ku autoantigen affects the susceptibility to anticancer drugs.

The Ku70/80 autoantigens (Ku) are the DNA-binding components of a DNA-dependent protein kinase (PK) involved in DNA double strand breaks repairing a V(D)J recombination. Because apoptosis is associated with DNA fragmentation and, consequently, creation of double strand breaks, and a variety of DNA-damaging drugs kill tumor cells by apoptosis, we tested the impact of Ku deficiency on the sensitivity of anticancer drugs. Ku-null mutant cell lines Ku70-/- and Ku80-/- were highly sensitive to anticancer drugs, compared with their wild-type cells. Ku-deficient cells were more sensitive to bleomycin-induced DNA fragmentation and exhibited a higher level of c-jun NH2-kinase/stress-activated PK activity than wild-type cells, whereas R7080-6 cells overexpressing both human Ku70 and Ku80 were resistant to bleomycin-induced apoptosis and exhibited a lower level of c-jun NH2-kinase/stress-activated PK activity. The Ku-protein level and Ku DNA binding activity were decreased after treatment with bleomycin, adriamycin, or vincristine, and the decreases were blocked by the treatment of z-DEVD-fmk, a specific inhibitor of caspase-3, suggesting that loss of Ku DNA binding is, in part, due to a caspase-mediated decrease in Ku protein levels. By contrast, HSF1 DNA-binding activity was increased by the treatment of these anticancer drugs and, subsequently, mitochondrial heat shock protein HSP75 was specifically induced. Our data suggest that Ku can affect the susceptibility to anticancer drug-induced apoptosis.

Animals↗

PubMed2000

Characterization of anticancer agents by their growth inhibitory activity and relationships to mechanism of action and structure.

An analysis of the growth inhibitory potency of 122 anticancer agents available from the National Cancer Institute anticancer drug screen is presented. Methods of singular value decomposition (SVD) were applied to determine the matrix of distances between all compounds. These SVD-derived dissimilarity distances were used to cluster compounds that exhibit similar tumor growth inhibitory activity patterns against 60 human cancer cell lines. Cluster analysis divides the 122 standard agents into 25 statistically distinct groups. The first eight groups include structurally diverse compounds with reactive functionalities that act as DNA-damaging agents while the remaining 17 groups include compounds that inhibit nucleic acid biosynthesis and mitosis. Examination of the average activity patterns across the 60 tumor cell lines reveals unique 'fingerprints' associated with each group. A diverse set of structural features are observed for compounds within these groups, with frequent occurrences of strong within-group structural similarities. Clustering of cell types by their response to the 122 anticancer agents divides the 60 cell types into 21 groups. The strongest within-panel groupings were found for the renal, leukemia and ovarian cell panels. These results contribute to the basis for comparisons between log(GI(50)) screening patterns of the 122 anticancer agents and additional tested compounds.

Animals↗

PubMed1999

[Cytotoxicities of low dose anticancer agents combining lymphokine activated killer cell against ovarian adenocarcinoma cell line SKOV3].

OBJECTIVE: To investigate whether low-dose anticancer agents could increase the sensitivity of ovarian adenocarcinoma cell line SKOV3 to lymphokine activated killer cell (LAK). METHODS: After SKOV3 cells were pretreated by low dose anticancer agents Taxol, cis-diamminedichloroplatin(CDDP), 5-fluorouracilum(5-FU) for 18 hours, the sensitivity of SKOV3 to LAK was detected by four 51Cr release assay. And the percentage of SKOV3 adhesion to LAK and intercellular adhesion molecule-1 (ICAM-1) expression on SKOV3 were detected by improved Grimm's assay and FACS respectively. RESULTS: After pretreatment of SKOV3 cell with 1.5 micrograms/ml Taxol, 4 micrograms/ml CDDP, 25 micrograms/ml 5-FU or without anticancer agents as control for 18 hours, the cytotoxicities of Interleukin-2 activated LAK against them were 29.7%, 45.9%, 37.2% and 28.5% respectively. The conjugation rates of SKOV3 and LAK were 20.1%, 26.1%, 24.9% and 18.7% respectively. The positive rates of ICAM-1 expression were 52.5%, 65.5%, 68.1% and 49.7% respectively. CDDP and 5-FU increased ICAM-1 expression significantly and the sensitivity of SKOV3 cell to LAK cell lysis was well related to the ICAM-1 expression. CONCLUSION: The results indicate that some low dose anticancer agents can increase the sensitivity of cancer cells to LAK cells and it would be useful in clinical practice.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

Induction of heat shock protein 70 in drug-resistant cells by anticancer drugs and hyperthermia.

The altered constitutive and inducible levels of heat shock proteins 70 (Hsp70) in drug-resistant cells may influence the efficiency of combined hyperthermia and anticancer drug treatment. In the present study, the constitutive levels of Hsp70 and induction of these proteins by hyperthermia and two anticancer drugs (used for resistance development) were determined in cervical and laryngeal carcinoma cells. The levels of Hsp70 were quantified by Western blot. Constitutive levels of Hsp70 were similar in parental and drug-resistant cells suggesting that Hsp70 is not involved in drug-resistance. Hyperthermic treatment induced Hsp70 in all examined cell lines but with different kinetics between drug-resistant and parental cells. Following the treatment with anticancer drugs, Hsp70 was induced only in cisplatin-resistant laryngeal cells. Kinetics of Hsp70 induction (stress-type and cell-type specific) was different in drug-resistant cells as compared to parental cells. The observed alterations in Hsp70 induction in drug resistant and parental cells should be taken into account when combined treatments (i. e. hyperthermia and anticancer drugs) are planned.

Antineoplastic Agents↗

PubMed2003

[Combined determination of urine uracil levels and plasma 5-FU clearance for a simple order-made treatment with anticancer agents of FU derivative].

Individual differences exist in the pharmacodynamics of fluorouracil-derived anticancer agents, with circadian variability even in the same patient probably due to individual differences in the distribution of dihydrophrimidine dehydrogenase (DPD), a decomposing enzyme. Though DPD activity is usually determined in the liver or blood, a more simplified estimation of DPD activity has been recently attempted using urine uracil levels. However, because urine uracil level has the drawback of being easily affected by food ingestion or kidney function, in this study it was determined simultaneously with the determination of plasma 5-FU clearance after sustained instillation of 250 mg 5-FU, in order to estimate DPD activity more accurately. A correlation was observed between urine uracil levels and 5-FU clearance. In cases showing a baseline urine uracil level below 25.1 mumol/g. Creatinine, the blood concentration decreased due to large 5-FU clearance, with a tendency for diminished efficacy of FU-derived anticancer agents. In cases showing a baseline urine uracil level above 99.9 mumol/g. Creatinine, on the other hand, adverse reactions due to FU anticancer agents tended to become more serious. Since urine uracil level can be determined easily, it could be the first choice in screening to detect abnormal metabolism of fluorouracil-derived anticancer agents under present circumstances. By combining determination of urine uracil level with 5-FU clearance, it seems possible to predict adverse effects and the effective rate of these agents more accurately. Under existing circumstances, where genetic analysis remains unavailable as a general practice, the combined determination of urine uracil levels and plasma 5-FU clearance may be beneficial in developing order-made treatments in cancer chemotherapy.

Adult↗

PubMed1992

[Clinical application of anticancer cytokines].

The clinical application of anticancer cytokines (interferons, interleukin-1, interleukin-2 and tumor necrosis factor) are reviewed. Although anticancer cytokines have confirmed its usefulness against some tumors which are refractory to the treatment using anticancer drugs, the results of clinical trials have generally been disappointing because the target spectrum and efficiency is somewhat limited. Recently, combined efficacy between interferon and anticancer drugs was reported in some malignancies such as multiple myeloma and colorectal carcinoma. For the development of effective combination treatment, we need more basic and clinical information on dose, schedule and sequence of drug administration.

Humans↗

PubMed2003

The anticancer effects of vitamin K.

Vitamin K, an essential nutrient often associated with the clotting cascade, has been the focus of considerable research demonstrating an anticancer potential. Much of this research has focused on vitamin K3, although vitamins K2 and K1 have also been shown to have anticancer effects. Early studies of vitamin K3 employed an oxidative model to explain the anticancer effects seen in both in vitro and in vivo studies; however, this model does not adequately address the action of vitamins K1 and K2. Recent research has demonstrated the anticancer action of vitamin K may act at the level of tyrosine kinases and phosphatases, modulating various transcription factors such as Myc and Fos. Tyrosine kinases associated with cyclins have also been shown to be affected by vitamin K, which can lead to cell cycle arrest and cell death.

Animals↗