Bisphosphonates as anticancer drugs

During June 1996, water supplies of the city of San Pedro Sula, Honduras, were sampled to obtain an assessment of Cryptosporidium oocyst and Giardia cyst concentrations. Each sample was concentrated and stained with an indirect immunofluorescent antibody, and parasites were counted through microscopic analysis. In three surface water supplies, Cryptosporidium oocyst concentrations ranged from 58 to 260 oocysts per 100 L, and Giardia cysts were present in concentrations ranging from 380 to 2100 cysts per 100 L. Unlike the surface water samples, groundwater had a higher concentration of Cryptosporidium oocysts (26/100 L) than Giardia cysts (6/100 L), suggesting that the groundwater aquifer protects the water supply more effectively from larger Giardia cysts. Cryptosporidium oocyst concentrations are within the typical range for surface water supplies in North America whereas Giardia cyst concentrations are elevated. Efforts should be made to protect raw water from sources of contamination.     

Retrograde intravenous perfusion with cytostatic drugs in angiosarcoma

Case-report of an 82 year old female with an angiosarcoma developing in a venous ulcer and lymphedema. The patient was successfully treated by retrograde intravenous perfusion with vinblastin and vincristin with subsequent blunt removal of the tumor.     

Tubulin as a target for anticancer drugs: agents which interact with the mitotic spindle

Tubulin is the biochemical target for several clinically used anticancer drugs, including paclitaxel and the vinca alkaloids vincristine and vinblastine. This review describes both the natural and synthetic agents which are known to interact with tubulin. Syntheses of the more complex agents are referenced and the potential clinical use of the compounds is discussed. This review describes the biochemistry of tubulin, microtubules, and the mitotic spindle. The agents are discussed in relation to the type of binding site on the protein with which they interact. These are the colchicine, vinca alkaloid, rhizoxin/maytansine, and tubulin sulfhydryl binding sites. Also included are the agents which either bind at other sites or unknown sites on tubulin. The literature is reviewed up to October 1997.     

Excretion of Dische positive compounds in rats after irradiation and after administration of some cytostatic drugs

In order to verify some pathophysiological aspects in radio- and chemotherapy of tumors the excretion of Dische positive compounds in rats was followed. During fractionated whole-body irradiation of animals it was found that up to the exposure with 50 R/day the organism is able to repair the disturbances provoked by irradiation for a certain time and that within the course of irradiation a permanently higher excretion of Dische positive compounds occurs. On the contrary, following the exposure of 100 R/day after a short increase continual decrease occurs lasting until the death of the animal. The excretion of Dische positive compounds in rats was followed also after the application of Cyclophosphamide, cis-dichlorodiammineplatinum (II) and Vinblastine. All these three cytostatic drugs produce an increased excretion of Dische positive compounds on the first day after the application. In the case of Cyclophosphamide, it was demonstrated that the excreted amount of Dische positive compounds was dose dependent.     

Interaction of taxol and other anticancer drugs with alpha-cyclodextrin

The interaction between 23 anticancer drugs and alpha-cyclodextrin (alpha-CD) was studied by reversed-phase charge-transfer thin-layer chromatography and the relative strength of interaction was calculated. As alpha-CD has smaller cavity than beta- and tau-CD it interacted only with 10 anticancer drugs proving the relatively poor complex forming capacity of alpha-CD. The hydrophobicity of host-guest inclusion complex was always different from that of the uncomplexed drug suggesting that the complex formation may influence the uptake, absorption, half-life etc. of the original drug. The inclusion forming capacity of drugs differed considerably according to their chemical structure. The intensity of interaction significantly depended on the hydrophobicity of the guest molecule proving the preponderant role of hydrophobic interactions in inclusion complex formation.     

Clinical effects of anticancer drugs to pancreatic diseases as protein synthesis inhibitors

The anticancer drugs, like 5-Fluorouracil, which are believed to interfere with enzyme protein synthesis in the exocrine cells of pancreas were administered intravenously to fifteen patients with various pancreatic diseases. The improvement of clinical symptoms and the diminution of serum and urinary amylase levels were observed in four cases with acute pancreatitis and two cases with chronic relapsing pancreatitis. The postoperative complications, namely the formation of pancreatic fistula and the rupture of pancreaticojejunostomy, or the aggravation of concomitant pancreatitis were not observed in three cases with benign surgical pancreatic diseases and six cases with pancreatic carcinoma. Furthermore, the diminution of amylase and protein output of pancreatic juice from canulae inserted into pancreatic ducts were observed.     

Novel molecular targets for anticancer drugs

Numbers of molecular targets for anticancer agents have been increased during the recent scientific progress in cancer biology. Of these targets, one should understand which target is clinically applicable. The forthcoming approach to evaluate such "molecular targets" is expected to provide novel diagnostic markers for adequate cancer therapy, and also novel targets for development of potent and useful therapeutic agents.     

NMR spectroscopy as a tool to investigate the structural basis of anticancer drugs

NMR spectroscopy has been shown to be useful in determining the structures of nucleic acid fragments in solution. Over the last several years NMR spectroscopy, in conjunction with restrained molecular dynamics, has been employed to understand the 3D structures of a number of anticancer drugs and to rationalize their DNA binding behavior. In this review we address the methodologies used most frequently to determine nucleic acid structures in solution. In subsequent sections, we examine how these methods have been applied to rationalize the activities of a number of anticancer agents that target duplex DNA such as cisplatin, bleomycin and calicheamicin. Non-duplex DNA and RNA also represent interesting nucleic acid targets for anticancer drug design and applications of solution NMR spectroscopy to understanding the structures of these types of molecules (e.g. Okazaki fragments, DNA tetraplexes) are also reviewed. In the final sections, advances in NMR methodologies (e.g. linear prediction, superconducting probes) that are likely to impact the research conducted in this area are reviewed. The success of NMR spectroscopy in understanding the structural basis for clinically useful anticancer drugs bodes well for future applications of this methodology not only in rationalization of existing biological activity, but in the design of novel agents that will be useful in treating neoplastic disease.     

Preclinical evaluation of anticancer drugs: a model remaining a model!

Two criteria are firstly used in the selection of new anticancer agents:--originality of the mechanism of action and significant experimental antitumor activity in an in vivo animal model. Murine tumors grafted in syngenic mice and human tumor xenografts implanted in nude mice are old models which continue to be widely used. Such models are useful but have the tendency to select many false positives (compounds active in mice but inactive in patients). This discrepancy can be explained by differences due to biological materials and also to the methodologies used in laboratories and clinic. Such models will certainly continue to play a major role in the future but they will have to be used in conditions more relevant for clinical extrapolation. Transgenic mice developing in situ tumors constitute new innovative models for in vivo evaluation of anticancer agents. Finally, a putative new class of antitumor agents emerges with the signal transduction modulators: such compounds have antitumor and toxicological properties very different from those of conventional chemotherapeutic agents. If the first representatives prove to be useful in clinic, rules for toxicology, preclinical and clinical evaluation will have to be changed.     

High-dose therapy with cytostatic agents as primary treatment of advanced breast cancer

Thousands of women with breast cancer have received high dose chemotherapy prior to the results from controlled clinical trials being known. As one of these patients the author reviews and discusses the results of the first randomised study from South Africa. High dose therapy with autologous stem cell support was compared with conventional chemotherapy in 90 young women with metastatic aggressive breast cancer. Though survival was short in both groups the disease free survival was doubled in the high dose group. A significant increase was found in response rate, duration of response and survival. Data from America show the cost effectiveness of this treatment to be comparable to that of other life-saving therapies. A comparison is made with the absolute and relative survival benefit of simvastatin treatment. A Norwegian White Paper on high dose therapy does not include advanced breast cancer in the planned trial protocols. It is argued that future health planning should give high priority to the treatment of advanced breast cancer in young women.     

Analysis of traditional Chinese anticancer drugs by capillary electrophoresis

The recognition and removal of human apoptotic peripheral lymphocytes in selected populations of periportal and perivenous endothelial cells was studied in in situ and in vitro experiments. Apoptotic peripheral blood lymphocytes once injected into the liver circulation were retained by the sinusoids showing a large heterogeneity of distribution: apoptotic cells are found in the periportal tract double the amount found in the perivenous region. Apoptotic PBL adhesion was lowered to a sixth of the control after preinjection with a sugar mixture (Mannose, N-acetylgalactosamine, N-acetylglucosamine, D-galactose), as suggested by the expression of modified surface glycoconjugates on the plasma membrane of apoptotic cells. A bimodal profile of the distribution of the hepatic sinusoidal cell population, regarding the number of galactose and mannose receptors and the porosity index, was found. Two endothelial cell subsets were present: low porosity cells (average index 14 +/- 6%; periportal tract) with a high number of carbohydrate binding sites, and high porosity cells (average index 26 +/- 7%; perivenous tract), with a low number of carbohydrate binding sites.     

Place of in vitro models in preclinical evaluation of anticancer drugs

In vitro models have been intensively developed for several years for selecting new anticancer agents. The National Cancer Institute has even chosen as a primary screen of new molecules a panel of 60 human tumor cell lines. However, it may seem hazardous to rely too much on in vitro models for the discovery and selection of new anticancer drugs: (1 because no metabolism of the compounds occurs in cell culture; (2 because an in vitro cell line cannot be representative of an in situ tumor cell population; (3 because antiproliferative activity is only part of antitumor activity; (4 because the toxicologic properties of the molecules are not taken into account by in vitro systems; (5 because cell cultures do not allow any selectivity study between tumor cells and normal cells. With examples drawn from three different therapeutic classes, anthracyclines, taxoids and camptothecin derivatives, we show that in vitro tests are insufficiently predictive of antitumor potential. The excess of confidence allowed to these models may lead to premature decisions which are not after that justified by clinical trials.     

An anticancer drug-sensitive murine erythroleukemia clone: implications for the mechanism of action of antineoplastic drugs

The mechanism(s) by which anticancer drugs kill tumor cells remains obscure. The studies reported here were undertaken with the view that the mechanism may be understood in part through an analysis of anticancer drug-sensitive clones. We have isolated a murine (Friend) erythroleukemia clone in which drug sensitivity was correlated with increased differentiation, suggesting that anticancer drug-induced cell death may be based on differentiation or a differentiation-dependent mechanism. In addition, this clone showed a high propensity for constitutive differentiation and frequent appearance of large multinucleate cells. Morphologically similar large aberrant cells were observed after the treatment of parental (745A) cells with Adriamycin (or bleomycin). We attribute these morphological defects occurring in clone 3-1 or in the parental cell line after anticancer drug treatment to a defective or inhibited cell cycle function. We suggest that the putative cell cycle defect in clone 3-1 is coupled to the increased drug-induced differentiation and resulting cell death. From a broader perspective, the studies reported here suggest that the search for and design of new anticancer drugs be directed at agents that modulate differentiation functions.     

Poisoning with anti-hypertensive drugs: beta-adrenoceptor blocker drugs

The effects of poisoning with beta-blockers may be serious, but are usually self-limiting provided adequate support is given. If there is no evidence of toxicity and the degree of overdose is small, clinical observation may be all that is required. This review examines the cases of overdosage with beta-blockers reported in the literature, the presenting symptoms and possible strategems of management for such patients.