Use Of Chemotherapy For Cancer Research Articles

Potent Prostaglandin A1 Analogs That Suppress Tumor Cell Growth through Induction of p21 and Reduction of Cyclin E

Although the cyclopentenone prostaglandin A1 (PGA1) is known to arrest the cell cycle at the G1 phase in vitro and to suppress tumor growth in vivo, its relatively weak activity limits its usefulness in cancer chemotherapy. In an attempt to develop antitumor drugs of greater potency and conspicuous biological specificity, we synthesized novel analogs based on the structure of PGA1. Of the newly synthesized analogs, 15-epi-delta7-PGA1 methyl ester (NAG-0092), 12-iso-delta7-PGA1 methyl ester (NAG-0093), and ent-delta7-PGA1 methyl ester (NAG-0022) possess a cross-conjugated dienone structure around the five-member ring with unnatural configurations at C(12) and/or C(15) and were found to be far more potent than native PGA1 in inhibiting cell growth and causing G1 arrest in A172 human glioma cells. These three analogs induced the expression of p21 at both RNA and protein levels in a time- and dose-dependent fashion. Kinase assays with A172 cells treated with these analogs revealed that both cyclin A- and E-dependent kinase activities were markedly reduced, although cyclin D1-dependent kinase activity was unaffected. Immunoprecipitation-Western blot analysis showed that the decrease in cyclin A-dependent kinase activity was due to an increased association of p21 with cyclin A-cyclin-dependent kinase 2 complexes, whereas the decrease in cyclin E-dependent activity was due to a combined mechanism involving reduction in cyclin E protein itself and increased association of p21. Thus, these newly synthesized PGA1 analogs may prove to be powerful tools in cancer chemotherapy as well as in investigations of the structural basis of the antiproliferative activity of A series prostaglandins.

Chemical Stability and Human Plasma Pharmacokinetics of Reduced Folates

The in vitro stability and plasma pharmacokinetics of 5,10-methylenetetrahydrofolic acid (CH2FH4), tetrahydrofolic acid (FH4), 5-methyltetrahydrofolic acid (CH, FH4), and 5-formyltetrahydrofolic acid (5-CHOFH4) were studied in view of their potential usefulness in cancer chemotherapy. Analysis of reduced folates was done on a high-performance liquid chromatography (HPLC) system. The high sensitivity of FH4 and CH2FH4 to oxidation can be circumvented by use of high concentrations of the folates, addition of ascorbate, and by thorough exclusion of atmospheric O2. Intravenous injection of 200 mg FH4 or CH2FH4 resulted in average peak concentrations of 69.2 ± 3.2 nmol/ml and 46.3 ± 2.6 nmol/ml, respectively. The plasma concentration curves support the concept that these highly oxygen-sensitive reduced folates can be reliably administered as pharmaceuticals to cancer patients through the use of a suitable air-occlusive system for their preparation and administration.

Cancer chemotherapy in older adults. A tolerability perspective.

The incidence of cancer increases with age. Since the geriatric population is growing, we will be confronted with an increasing number of patients with cancer who are > 65 years of age. The purpose of this review is to address the use of cancer chemotherapy in older persons with respect to its tolerability. We performed a review of the literature using 'Medline' and the bibliographies of pertinent publications. Information about cancer treatment in older adults was extracted with particular attention to chemotherapy-related toxicity in patients aged > 65 years. Comorbid disease, polypharmacy/drug interactions, psychosocial issues and age-related physiological changes are major issues in caring for older patients with cancer. Since older individuals may have a greater number of comorbid illnesses, treatment should be initiated on the basis of physiological rather than chronological age. Comparative studies show that chemotherapy-related toxicity is similar in older and younger patients, with the exception of haematological toxicity, which may be more severe in older patients, and cardiotoxicity, which is more frequent in the elderly. Other evidence suggests that gastrointestinal and neurotoxicities may also be more severe in older individuals. The dosages of chemotherapeutic agents that are primarily renally excreted may require adjustment in older patients. Haematological reserve is decrease in older individuals, and drugs that cause myelosuppression must be used with care. The use of haemopoietic growth factors in geriatric patients is currently being investigated.

Improving the cancer chemotherapy use process.

Reports of the tragic consequences of erroneous cancer chemotherapy overdoses at a prominent cancer center and a university hospital prompted a review of our institution's practices and those of 123 other hospitals to ascertain for each the current in-house process to prevent chemotherapy errors. A multidisciplinary committee of oncologists, nurses, and pharmacists reviewed the chemotherapy use process and identified opportunities for improvement. A 1-page facsimile survey was answered by 150 of 215 members of the American Society of Clinical Oncology (ASCO) who received it. We further restricted the writing of cytotoxic chemotherapy orders to physicians who were board-certified or -eligible in hematology or medical, pediatric, and gynecologic oncology and their approved fellows. Dispensation of drugs is limited to oncology-certified pharmacists, and administration to chemotherapy-certified nurses. Standard orders are used either on special oncology forms or designated order sets in the computer. Procedures to regulate the ordering of antineoplastic drugs for nonmalignant indications by nononcology specialists are outlined. A process to prevent chemotherapy errors is in place in 95% of hospitals. Dedicated medical oncology units are ubiquitous, and most cancer centers and university hospitals have dedicated gynecologic and pediatric oncology units. Chemotherapy orders are generally written by oncology fellows and countersigned by an attending oncologist in cancer centers and university hospitals, whereas private oncology attending physicians write them in most community hospitals. Drugs are administered by oncology-certified nurses in most institutions. These recommendations should improve the safety and effective use of chemotherapy and reduce the error rate to as close to zero as human fallibility will allow.

Erratum to Vinorelbine: a review of its pharmacological properties and clinical use in cancer chemotherapy

Erratum to Vinorelbine: a review of its pharmacological properties and clinical use in cancer chemotherapy

Erratum to Vinorelbine: a review of its pharmacological properties and clinical use in cancer chemotherapy

Erratum to Vinorelbine: a review of its pharmacological properties and clinical use in cancer chemotherapy

Effect of a bifunctional monoclonal antibody directed against a tumor marker and doxorubicin on the growth of epidermoid vulvar carcinoma grafted in athymic mice

Even though the first monoclonal antibodies (MAbs) directed against tumor cells were produced 15 yr ago, the therapeutic application of immunoconjugates is still at the beginning. This is principally because of the enormous work that is required for the development of completely new therapeutic tools. An alternative could be to only use MAbs to improve conventional treatment such as chemotherapy. To this aim, a MAb directed against doxorubicin (DXR) was produced. DXR is an anthracycline antibiotic of which the clinical usefulness in cancer chemotherapy is limited by serious side effects, such as cardiomyopathy, bone marrow depression, and gastrointestinal tract mucositis. This toxicity was found to be reduced by treatment with the antidrug MAb, as shown by reduction in body weight loss and mortality of experimental mice. To improve the DXR therapeutic index, a bifunctional hybrid MAb (DOXER2), capable of simultaneously recognizing DXR and the epidermal growth factor (EGF) receptor, was produced. This reagent was found in vitro to increase the drug toxicity on the epidermoid carcinoma cell line A431, which overexpresses the EGF-R and, at the same time, to reduce DXR cytotoxicity on EGF-R negative cells. The effect of DOXER2 on the DXR biodistribution in vivo was also investigated. In mice previously injected ip with the DOXER2, the uptake of the drug, in comparison to the control group, was found to be reduced in the intestine and in myocardial tissue, and significantly increased in the tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

Antitumor Protein: Abrin

AbstractA family of toxic proteins, the isoabrins, which possess N-glycosylase activity toward eukaryotic 28S rRNA, may have potential use in cancer chemotherapy. By polymerase chain reaction techniques, cDNA clones of three isoabrins, carrying A and B-chain sequences, were isolated and their nucleotide sequences were determined. The isoabrins consist of an A-chain comprised of 250 or 251 amino acids, followed by a 10 amino acid linker and a B-chain of 267 amino acids. There is substantial conservation in the B-chain of the three isoabrins, with less than six amino acid substitutions, whereas as many as 46 amino acid substitutions occur in the A-chains.

Primary Structure of Three Distinct Isoabrins Determined by cDNA Sequencing: Conservation and Significance

A family of toxic proteins, the isoabrins, which possess N -glycosylase activity toward eukaryotic 28 S r-RNA, may have potential use in cancer chemotherapy. By polymerase chain reaction techniques, cDNA clones of three isoabrins, carrying A and B-chain sequences, were isolated and their nucleotide sequences were determined. The isoabrins consist of an A-chain comprised of 250 of 251 amino acids, followed by a 10 amino acid linker and a B-chain of 267 amino acids. There is substantial conservation in the B-chain of the three isoabrins, with less than six amino acid substitutions, whereas as many as 46 amino acid substitutions occur in the A-chains. Based on the relationships between the biological activities and the putative amino acid sequences of the isoabrins, three isoabrins, abrin-a, -b and -d, could be identified and the potential epitope of immunological response of these isoabrins could be assigned.

Long-term stability of 5-fluorouracil and folinic acid admixtures

5-Fluorouracil (5-FU) and d,l-folinic acid (FA) are used in association to treat a wide variety of malignancies. The stability and the compatibility of 5-FU and FA in combination in intravenous admixtures were studied under various storage conditions and with drug concentrations matching their clinical use (0.9% sodium chloride, 5% dextrose, protected from light or not). 5-FU and FA concentrations (mg/ml) were 6.5 or 50 and 4.0 or 30.8, respectively. Successive aliquots of the drugs mixtures were withdrawn during 60 h from 500 ml glass bottles and 500 ml polyvinyl chloride (PVC) bags (at room temperature) and during 120 h from cassettes (at 32°C). Drug concentrations were measured by high performance liquid chromatography. For all conditions tested, the changes in 5-FU and FA relative to the initial concentrations remained within the assay reproducibility (10%). In complement, infrared Fourier transformation spectrophotometry has not shown a significant fixation of FA or 5-FU on the PVC bags, in all tested conditions. Under the conditions examined above 5-FU and FA can be mixed in the same container for their use in cancer chemotherapy. This can have practical consequences by simplifying the widely used treatment protocols associating 5-FU and FA.

Drug-polymer conjugates: potential for improved chemotherapy.

Use of polymeric drug delivery systems is rapidly becoming an established approach for improvement of cancer chemotherapy. Zoladex, a poly lactide-co-glycolide subcutaneous implant that delivers a luteinizing hormone releasing hormone analog over 28 days, is now the treatment of choice for prostate cancer, and a polyanhydride matrix containing BCNU is currently in phase III evaluation for treatment of glioma multiforme. Soluble polymers were first proposed as targetable drug carriers in the mid-1970s, and although the first conjugates are still at an early stage of development some, e.g. SMANCS (styrene maleic acid-neocarzinostatin) and monomethoxypolyethyleneglycolasparaginase, are now undergoing clinical evaluation and show considerable promise. Polymeric drug delivery systems are usually designed to produce an improved pharmacokinetic profile of an antitumor agent (controlled release) and in addition soluble carriers can achieve either first-order (organ specific) or second-order (tumor specific) drug targeting by virtue of the fact that they are usually administered intravenously and should theoretically access primary and secondary disease. Soluble polymeric carriers have the potential to improve the activity of conventional antitumor agents, peptide and protein drugs, and have recently been used in constructs for delivery of oligonucleotides. With increased awareness that the successful design of a polymeric drug delivery systems can only be achieved with prior consideration of the pathology and stage of the disease, tumor accessibility, biochemistry and cell biology of the target site, choice of appropriate therapeutic agent(s) and understanding of their fundamental mode of action, we have seen the emergence of a number of exciting and potentially more selective antitumor therapies based on polymer technologies. Here, the basic principles for design of soluble polymeric drug delivery systems are explained and illustrated using examples drawn from our studies on the development of N-(2-hydroxypropyl)methacrylamide copolymer conjugates for use in cancer chemotherapy. Those soluble polymeric carriers that are undergoing clinical evaluation are briefly reviewed.

Trends in Transfusion Therapy

Summary Trends in transfusion practices reflect developments in other areas of medicine. Advances in surgical techniques made possible open heart surgery and liver transplantation, which markedly increased the demand for blood. The widespread use of cancer chemotherapy also increased the need for blood products. Recognition that HIV could be transmitted through transfusion was the most potent stimulus for limiting homologous transfusion and promoting autologous transfusion. Technologic advances made possible component therapy, salvage and reinfusion of shed blood, and hemapheresis. While it is reasonable to assume that the current trends in transfusion practices will continue, new discoveries in medical science could potentially dramatically alter these practices.

Safety by Design

Safety by design for any kind of drug requires it to act selectively on the cells which mediate the desired effect, and affect other cellular functions as little as possible. To illustrate this, the treatment of bronchial asthma was much improved during the past 20 years by the development of inhalation treatment based on drugs such as salbutamol (albuterol), a selective beta 2-adrenoceptor stimulant, and beclomethasone dipropionate, a topical anti-inflammatory steroid, from their parent physiological mediators epinephrine (adrenaline) and hydrocortisone (cortisol). Their development and that of H1- and H2-antagonists from histamine are described. From these and other sources the general conditions for safe, selective drug action and the range of drug effects that may be attained by modifying physiological mediators are deduced. This involves the identification and definition of type 1 and type 2 agonism. This analysis led to the discovery of salmaterol (salmeterol), a new uniquely long acting beta 2-adrenergic bronchodilator, by modification of salbutamol. The development, by modification of serotonin (5-hydroxytryptamine), of ondansetron, a new antiemetic for use in cancer chemotherapy, and sumatriptan, a new type of drug for treating migraine, are also described. All these new drugs are more efficacious and safer than their predecessors.

Stabilization of cytosine deaminase from bakers' yeast by immobilization.

Cytosine deaminase (EC 3.5.4.1) from bakers’ yeast, which is labile to heat, the half-life being about 30 min at 37°C, was stabilized through immobilization by various techniques. Our purpose was to prepare implantable enzyme capsules for long-term use in cancer chemotherapy [J. Biotechnol., 2, 13 (1985)]. When the enzyme was immobilized on Eupergit C, a commercial epoxy-acrylic resin, the highest yield of apparent enzymic activity was about 80% of the starting activity, and the enzymic activity decayed exponentially at 37°C over a few weeks, the half-life being about 10 days. With lower yields, other commercial adsorbents resulted in good stability; with yields of 20~67 and 21 %, and half-lives of 15 and 24 days for Formyl-Cellulofine and CNBr-activated Sepharose 4B, respectively.

Improving the therapeutic index of systemic therapy with special emphasis on cisplatin and carboplatin

Systemic cancer therapy can be used to achieve cure or palliation depending upon the tumor of origin and its stage. Curative treatment can be accomplished in clinically evident disease or as adjuvant treatment after surgery and/or irradiation when there is no clinically evident disease remaining. Palliation, which is still the major role for systemic therapy, can be defined as prolongation of survival and the alleviation of symptoms resulting in an improved quality of life. All cancer therapy is toxic and must be evaluated within the context of a therapeutic index (Table 1). The efficacy of the treatment must be balanced against the toxicity, arriving at a cost-benefit analysis. The therapeutic index can be evaluated in a research orientated manner or in a practice orientated manner. The literature reporting of clinical trials tends to be dominated by the research orientated perspective. It is distinctly uncommon to find any part of the discussion section of papers devoted to community practice recommendations based upon a patient care oriented therapeutic index analysis of the results being reported. The efficacy parameters for the use of cancer chemotherapy against clinically evident disseminated malignant disease are varied. The most commonly used criteria are objective response and its duration, measured either from the initiation of therapy, or from when response is first achieved. Objective response is an excellent research orientated parameter in that it is reflective, albeit imperfectly, of cell kill and can be measured in a relatively reproducible manner, utilizing generally accepted, although somewhat variable, criteria. While objective shrinkage of tumor is gratifying to the physician, and, therefore, to the patient as well, it does not benefit the patient per se. What benefits the patient is alleviation of symptoms and living longer. Objective regression without a quality of life improvement, or survival prolongation is of little practical benefit. Therefore, in a patient care orientated sense, overall survival, and time to progressive disease, are the more critical efficacy criteria. Toxicity can be reported in a variety of ways. The major focus in the toxicity reporting of cancer chemotherapy trials is on acute toxicity. This acute toxicity can be reported as laboratory results (leukopenia, thrombocytopenia , creatinine, liver function enzymes, etc.), clinical signs (alopecia, stomatitis, skin rash) and symptoms (anorexia, nausea, vomiting, diarrhea, fatigue). Each of these have varying impacts on quality of life, with symptoms carrying the greatest weight and laboratory parameter changes per se, the least. In the research reporting of chemotherapy side effects, the manifold signs, symptoms and laboratory changes are usually listed in tabular form, or objectively described in mathematical terms, with little if any attempt at a holistic integration of the toxicity

Characterization of alkylcarbamoyl derivatives of 5-fluorouracil and their application to liposome

Four alkylcarbamoyl derivatives of 5-fluorouracil (I): butyl- (II), hexyl- (III), octyl- (IV), and octadecylcarbamoyl 5-fluorouracil (V), were prepared and their physicochemical and biological properties were investigated. In addition, the utility of their liposomal formulations was evaluated. The compounds showed an increase in lipophilicity according to the natures of the functional groups introduced. The derivatives except for V showed antimicrobial activities equal to I because of their rapid conversion to I in pH 7.4 buffer. They were also converted to I at various rates in rat plasma and liver homogenate. Although V was stable in the buffer, it showed conversion in biological media. Test compounds, I, II, IV and V, showed antitumor activities against murine L1210 leukemia in i.p.-i.p. system. Degree of incorporation into liposomes of the derivatives was proportional to their lipophilicities. Compound I was not efficiently entrapped into liposomes. V showed the highest incorporation and the slowest release among them, and thus, was chosen as the best prodrug for applying to liposomes. Liposomal V showed prolonged retention in the injection site and enhanced delivery into the lymphatics after intramuscular injection in rats, suggesting its usefulness in cancer chemotherapy. Furthermore, V maintained the higher antitumor activity when administered in the form of liposome.

Adult esophageal candidiasis: a radiographic spectrum.

With the increasing use of cancer chemotherapy and organ transplantation requiring immunosuppressive therapy, and with the incidence of immunodeficiency states such as AIDS increasing, it is to be expected that candida esophagitis will occur with increasing frequency. Though fiberoptic endoscopy is a more specific and more sensitive approach to the diagnosis of candida esophagitis than barium esophagography, it is also more invasive, and many patients will continue to be examined radiologically, at least initially. The radiologist continues, therefore, to play a significant role in suggesting the diagnosis and it is incumbent on him to familiarize himself with the spectrum of common and unusual radiographic manifestations of this disease.

Benzimidazole Fungicides: Mechanism of Action and Biological Impact

The wide application of benzimidazoles in agriculture and veterinary medi­ cine as fungicides and anthelminthic drugs, and their experimental use in cancer chemotherapy, has led to intensive research to elucidate their mode of action in detail. These studies show that bioactive benzimidazoles are specific inhibitors of microtubule assembly that act by binding to their heterodimeric subunit, the tubulin molecule. Most of the original literature on antifungal benzimidazoles has already been discussed in a number of reviews (4, 10, 1 3, 14, 19, 52). This chapter, therefore, does not give an extensive review of the complete literature but rather discusses those experiments that made essential contributions to the development of the research area. Much of our knowledge stems from research in fungal cell biology and molecular genetics that uses benzimidazoles as tools to study tubulin structure and the organization and function of microtubules. Rapid progress is being made in the latter areas, which ultimately will lead to a complete characterization of the benzimidazole binding site at the tubulin molecule and its role in microtubule assembly.

New beta-lactam antibiotics in granulocytopenic patients: New options and new questions

Infectious complications are a frequent cause of morbidity and, at many centers, the major cause of death in patients with cancer. The increased risk and severity of Infectious sequelae result from profound alterations in normal host defenses that occur secondary to the underlying malignancy and the treatment thereof. During the last decade, early empiric antibiotic therapy has become standard practice in the Initial management of febrile granulocytopenic patients and has contributed significantly to the improved outcome among patients undergoing cancer therapy. Although early death due to unsuspected or inadequately treated bacterial infection has been largely overcome, new problems—also with life-threatening implications—have emerged. As the use of cancer chemotherapy continues to increase, new populations of patients are being placed at increased risk of infection. Defining the host and environmental factors that contribute to this risk assumes central importance for delineating those patients who require the most intense surveillance. Changing medical practices (e.g., increased use of indwelling catheters) have contributed to the emergence of new pathogens. Recent drug developments (e.g., the third-generation cephalosporins and extended-spectrum penicillins) offer new treatment options, as well as generate controversy and confusion. For example, authorities disagree on the optimal duration and modifications in treatment that are required by cancer patients who remain granulocytopenic and who thus are at continued risk of multiple infectious episodes or superinfections. A question of current interest is whether combination therapy with synergistic agents is important in light of the development of the third-generation cephalosporins and extended-spectrum penicillins. Several of these new antibiotics have an exceedingly broad spectrum of activity that includes Pseudomonas aeruginosa, as well as Enterobacterlaceae, Serratia, Citrobacter, indole-positive Proteus, and anaerobes (including Bacteroides fragilis). However, the third-generation cephalosporins are not as active against staphylococci and streptococci as are the first-generation cephalosporins, and none is effective against enterococci. Nonetheless, these agents achieve serum levels that can be 10 to 100 times greater than the minimal inhibitory and bactericidal concentrations of gram-negative bacteria, raising the possibility that these drugs might be effective as single agents. The advantages of the third-generation cephalosporins are their minimal toxicity and long serum half-lives. Although these new drugs are expensive, their cost must be evaluated within the context of their efficacy and clinical application.

Convulsive syndrome induced by the intracerebroventricular injection of alpha-difluoromethylornithine in rats.

In adult rats, the intracerebroventricular injection of alpha-difluoromethylornithine (DFMO), a polyamine antimetabolite which specifically inhibits ornithine-decarboxylase, induces a typical convulsive syndrome (ED50 = 100 micrograms/rat) and death (LD50 = 300 micrograms/rat). Histological lesions are seen only with the highest doses and are essentially restricted to the Ammon's horn neurones. Since DFMO is currently undergoing clinical trials for use in cancer chemotherapy, including brain tumours, its CNS toxicity should be carefully considered.