Treatment Of Neoplastic Diseases Research Articles

Aspects of practical oncology. Oncologic dietetics--treatment of anorexia and cachexia

Tumor- and/or therapy-related malnutrition can be a crucial factor in the success of treatment of neoplastic diseases. The aetiology of anorexia in many patients is still unknown. Impaired survival rates and the outcome of therapy are related to the nutritional status, although this has not been investigated in well controlled clinical studies. However, it is generally accepted that it is possible to improve therapy by balancing the diet. It is not known whether additional parenteral nutrition improves survival rates. Therefore, the individually adjusted diet which considers the patient's tastes and disease-related abnormalities (i.e. stomatitis or therapy-related mucosal dryness) should be preferred. Balanced formulas allow an additional caloric intake. In advanced disease status, a difficulty in swallowing or tumors which obstruct the oesophagus or the cardia may make tube feeding necessary. Total parenteral nutrition is possible via venous catheters for weeks or even months if antiseptic principles are followed very carefully. If a dietary concept is included early in cancer therapy, the quality of life is improved and surgical, radio- and/or chemotherapy, when performed, is made easier and more successful.

Molecular mechanisms of action of auranofin and other gold complexes as related to their biologic activities

The molecular mechanisms of action of gold complexes in the treatment of rheumatoid arthritis are partially known, as are the mechanisms of action and potential utility of gold complexes in the treatment of neoplastic disease. In this paper, data relative to the mechanism of cytotoxicity and structure activity relationships are presented. Concepts of future research are also discussed.

Pulmonary toxicity of antineoplastic agents: anaesthetic and postoperative implications.

Agents commonly used in the treatment of neoplastic diseases may impair pulmonary function, and a wide spectrum of agents are currently implicated as toxic to the pulmonary system. Agents most commonly implicated are bleomycin, carmustine, busulfan, methotrexate, and thoracic radiotherapy. Less commonly implicated agents include mitomycin, procarbazine, melphalan, chlorambucil, and cyclophosphamide. Therapeutic interactions at time of operation and postoperatively may exacerbate existing pulmonary damage. It is imperative for the physicians treating patients receiving antineoplastic therapy to recognize potentially dangerous therapeutic interactions, and adjust the therapeutic regimen accordingly. Concentrations of inspired oxygen must be maintained as low as is safely possible. Intraoperative monitoring of arterial and mixed venous oxygen tensions will enable the clinician to adjust inspired oxygen concentrations to the lowest possible level while maintaining adequate oxygen tensions to the tissues. A systematic review of antineoplastic agents currently implicated, drug-oxygen interactions, and a review of the pathophysiology are presented.

Clinical pharmacology and toxicology of cyclophosphamide: emphasis on use in rheumatic diseases

N UMEROUS cytotoxic drugs are available for the treatment of severe forms of rheumatic diseases-’ Biologic effects of alkylating agents were first reported in 1887,4 and over the years, these agents have been used extensively in the treatment of neoplastic disease.5.6 Intravenous nitrogen mustard, in 195 1, was reported as clinically effective in the management of two patients with rheumatoid arthritis (RA).’ It is only during the past 20 years that the use of alkylating agents has increased dramatically in the management of rheumatic diseases. Chlorambucil and cyclophosphamide (CP) are the two alkylating agents currently used most often in the management of rhematic disease. Cyclophosphamide, a bifunctionally substituted nitrogen mustard compound, was synthesized in 1958.’ The first major report, albeit uncontrolled, suggesting the benefit of CP for treatment of RA appeared in 1968.9 Since then, numerous controlled and uncontrolled studies have been reported which variably support the use of CP for treatment of a number of rheumatic diseases. These diseases include RA,“” systemic lupus erythematosus, (SLE)12,13 and numerous systemic vasculidites2 The purpose of this review is to summarize the clinical pharmacology and toxicology of CP, with special emphasis on its use in rheumatic diseases.

Chronobiological aspects of phosphohexoseisomerase in monitoring multiple myeloma.

In the field of oncology, the most important aim to date has been the finding of new means to improve the diagnosis and treatment of neoplastic diseases. Chronobiologically we have studied the behavior of phosphohexoseisomerase (PHI) in 11 multiple myeloma patients before treatment and in another group of 11 patients undergoing polychemotherapy treatment. From all patients, under the same standard conditions, 6 venous samples were taken at 4-hour intervals starting at 08.00 h, for a day. PHI serum levels were determined spectrophotometrically. The data obtained were analyzed by 'group mean cosinor' and from this analysis a mesor reduction of more than 50% was noted in subjects after polychemotherapy (M2) correlated with the absence of a circadian rhythm. The data suggest that PHI levels can be related to the characteristics of tumor growth and we feel they can be used as a guide in monitoring multiple myeloma patients.

Emerging immunologic approaches to treatment of neoplastic diseases.

Recent research on the immunobiology of the tumor-host relationship has demonstrated that nonspecific cellular immune reactions, like natural killer cells and cytotoxic autoreactive cells, may be far more potent antineoplastic mechanisms than specific T lymphocyte cytotoxicity. The hybridoma technique, making it possible to raise monoclonal antibodies against predefined antigens, has rendered passive immunotherapy more attractive. It is suggested that the combination of nonspecific cellular immune reactions with monoclonal antibodies may be a highly efficient antineoplastic therapy for minimal residual disease.

Mechanism of adriamycin cardiotoxicity: Evidence for oxidative stress

Adriamycin is a widely used anticancer agent but the cumulative dose-dependent cardiotoxicity severely limits the use of Adriamycin in the treatment of neoplastic diseases. Recent evidence suggests that Adriamycin forms reactive free radical species which may oxidize cellular components and produce the cardiomyopathy. Sulfhydryl donors and antioxidants have been effective in preventing acute Adriamycin cardiotoxicity in animal models presumably by scavenging the free radicals generated by Adriamycin. The sulfhydryl donors, namely cysteamine and N-acetyl cysteine, do not interfere with Adriamycin's antitumor activity. The results from these studies give considerable hope that the chronic cardiotoxicity from Adriamycin may be attenuated in people, thereby givinh additional therapeutic benefit from this antitumor agent.

Nephrotoxic acute renal failure due to common drugs.

Antibiotics are the most common drugs implicated in clinical reports of drug-induced nephrotoxicity. The experimental basis for proposed mechanisms of acute renal failure in association with three groups of antibiotics--aminoglycoside, cephalosporin, and amphotericin B--are reviewed in detail. Proposed mechanisms of antibiotic-induced acute renal tubular necrosis involve either altering plasma membrane permeability or interference with cellular energy derived from mitochondria, For either aminoglycoside or cephalosporin antibiotics, cellular accumulation followed by interruption of mitochondrial respiration is the concept that has greatest support, although the possibility of an induced phospholipidosis involving intracellular lysosomes cannot be excluded. Altered renal tubular cell permeability due to the incorporation of amphotericin B into the pore structure of the plasma membrane is consistent with in vivo observation in either clinical or experimental examples of nephrotoxicity with this agent. The metal cis-platinum, used in treatment of neoplastic disease, has a clearly defined incidence of clinical nephrotoxicity with little insight as to cellular mechanisms. A possible mediation involving cis-platinum reducing the protein-bound sulfhydryl group of renal tissue has been proposed. With the ever increasing potency of modern pharmacologic agents come a rising risk of serious toxic side effects.

The influence of several anticancer agents on cell proliferation, differentiation and the cell cycle of murine erythroleukemia cells.

The influence of homoharringtonine, hydroxycamptothecin and lycobetaine on the cell cycle progression of murine erythroleukemia cells was studied by using flow microfluorometry (FMF) technique and centrifugal elutriation to obtain specific fractions of the cell cycle. FMF histogram analysis showed that homoharringtonine could strongly arrest cells in the G1 phase of the immediate cell cycle. This effect was more pronounced and persisted longer with G1 cells than with S or G2 cells. Hydroxycamptothecin mainly delayed the progression of S cells of the subsequent cell cycle (daughter cells). Lycobetaine caused a marked accumulation of G2 cells. These 3 compounds possess a relatively specific action on cell progression through the cell cycle. Homoharringtonine and hydroxycamptothecin can inhibit the cell proliferation of murine erythroleukemia cells (MELC) at low concentrations (ng/ml) whereas lycobetaine, cantharidin and oxalysine are less potent. Among them only hydroxycamptothecin had a weak activity to induce MELC differentiation. These results may provide some basic knowledge for designing new protocols of the combination treatment of neoplastic diseases.

Lack of mutagenicity and metabolic inactivation of aphidicolin by rat liver microsomes

In view of the possible utilization of aphidicolin, a specific inhibitor of DNA polymerase α, in the treatment of neoplastic diseases, it seemed important to assess the mutagenic effect of the drug and the possible modification induced by metabolic activation in the liver. This paper shows that aphidicolin lacks mutagenicity in the Ames' Salmonella -microsome test in agreement with our previous observation that it does not induce DNA repair synthesis in HeLa cells. During the studies of mutagenicity we have observed that aphidicolin is converted to inactive derivative(s) by rat liver microsomal oxidases. The reaction is dependent on time and temperature and requires NADP + and glucose-6-P. The metabolites are not mutagenic and they do not induce DNA repair synthesis in HeLa cells. Therefore the possible anti-cancer use of aphidicolin is not hampered by its partial metabolic inactivation in liver. Our results suggest however that aphidicolin will possibly be clinically useful at concentrations higher than those expected from our studies with human DNA polymerase α in vitro and human neoplastic cell lines in vivo . The metabolic derivative(s) of aphidicolin is inactive both against cellular DNA polymerase α and Herpes simplex viral DNA polymerase.

Antitumor Activities of Marine Algae Constituents

Recently immunotherapy has been considered to be an important method to increase immunopotentiating activity of host in the treatment of neoplastic diseases. In the therapy, polysaccharides have attracted attention because of their activity to enhance host defense mechanisms against neolpastic diseases. Some kinds of polysaccharides have been fouud to provide immunopotentiating activity which brought about regression of tumors and helped protect against infectious diseases.In this study, screening tests were conducted for several years for the selection of suitable polysaccharides for clinical trials, and several marine algae containing polysaccharides with immunopotentiating activity were found. Immunostimulant substances, which were collected from brown algae, Sargassum fulvellum C. Agardh, Sargassum thunbergii O. Kuntze and Eisenia bicyclis Setchell, markedly potentiated host antitumor activity which was proved by regression and elimination of the tumor.

Bioassay program for carcinogenic hazards of cancer chemotherapeutic agents.

Various compounds and combinations thereof, of promise in the treatment of neoplastic diseases, were tested for possible carcinogenicity in Swiss mice and Sprague-Dawley rats. Some of the compounds were fairly active carcinogens, while others showed little or no evidence of carcinogenicity. The carcinogenicity of the drug combinations was generally less than that of the individual components.

Second Neoplasm — A Complication of Cancer Chemotherapy

Chemotherapy has become increasingly important in the treatment of neoplastic disease in the past two decades. Appreciable numbers of patients with advanced Hodgkin's disease, choriocarcinoma, acute lymphocytic leukemia, testicular carcinoma and histiocytic lymphoma have achieved long-term disease-free survival largely as the result of aggressive chemotherapy. In addition, the use of antineoplastic drugs has recently been extended to the "adjuvant" situation and appears to delay, if not to prevent, recurrence in high-risk patients after primary surgical treatment of breast cancer.1 , 2 This progress has been realized despite substantial drug-related morbidity, and occasional mortality. The acute toxicity of antineoplastic chemotherapy affects a broad . . .

The use of androgens in the treatment of neoplastic disease

The use of androgens in the treatment of neoplastic disease

Absorption of large oral doses of 5-formyltetrahydrofolate in man.

In the treatment of neoplastic diseases, the therapeutic use of folate antagonists such as methotrexate is often accompanied by the concurrent or subsequent administration of 5-formyltetrahydrofolate (folinic acid, leucovorin) in order to reverse its effects (Mead et al., 1963; Hryniuk and Bertino, 1969). In vitro, this reduced folate is readily altered by acid conditions (May et al., 1951) such as may exist in the stomach, and it has, therefore, been administered parenterally. It has been recognized for some time (Nixon and Bertino, 1972) that an effective, orally administered, reduced folate would have a useful place in the increasing use of cancer chemotherapy, and effective absorption of oral doses up to 1 mg has been demonstrated (Chanarin, 1969; Nixon and Bertino, 1972). Such doses are small compared to those employed therapeutically (often greater than 20 mg) and further evidence of acceptable absorption in this dose range would be desirable. Each of three pairs of healthy Caucasian male volunteers (Table) were ran-

Gastrocutaneous fistula following radiation therapy for seminoma of the testis.

A case presentation of a gastrocutaneous fistula following orthovoltage radiotherapy for prophylactic lymph node sterilization for seminoma of the testis is recorded. Many factors determine the response of an organ to radiation and with certain circumstances irreversible damage ensues. The pathologic effects of radiation on the stomach in the reported patient illustrates two stages of injury, acute and chronic. The insidious course of chronic injury eventually destroyed gastric and abdominal wall tissue to create a gastrocutaneous fistula 45 months after radiotherapy. Radiation therapy is a critical therapeutic modality in the treatment of neoplastic diseases and should be carefully administered with close followup of patients for acute and latent radiation effects.

Procabazine induced oxidative haemolysis: relationship in vivo red cell survival.

Summary. A new hydrazinc derivative, N‐isopropyl‐α‐(2‐methyl‐hydrazino)‐p‐toluarnide hydrochloride (MIH, Procarbazine, Natulan), has been used widely in the treatment of neoplastic disease. When in vitro incubations of normal and C6PD‐deficient red cells with procarbazine were performed, oxidative changes in red cells were detected similar to those found with other hydrazine derivatives. These changes consisted of an increased osmotic fragility, decreased levels of reduced glutathione (GSH), increased percentages of methaemoglobin, and the generation of intracellular hydrogen peroxide. G6PD‐deficient red cells appeared more susceptible to these effects. When the known degradation products of procarbazinc metabolism were studied, the hydrazone was found to be the most potent oxidant while the other metabolites exhibited only minimal activity. Since the potential for in vivo haemolysis in patients receiving large doses of parenteral procarbazinc was suggested, the 51Cr survival of G6PD deficient red cells was performed in two patients receiving procarbazinc (1.5 g/m2, intravenously). No decrease in the red‐cell survival was detected.

Definition, activity and training in medical oncology (author's transl)

Medical oncology has been defined by the Italian Association of Medical Oncology as a common branch of internal medicine and of clinical oncology. The principal activity of medical oncology is the study and treatment of neoplastic disease with chemotherapy, endocrine therapy and immunotherapy. The field of medical oncology is expanding by broad-based interaction of the multiple disciplines involved in the cancer care. The medical oncologist is therefore an essential component of the team making the initial management decision, and coordinates the selection of appropriate therapy in case of relapse after primary treatment or initially disseminated disease. Since optimal management should be available to all cancer patients regardless of economic, social or geographic considerations, new structures should be created to train young physicians in the field of medical oncology after they have completed their educational program in internal medicine. It is essential that the control of neoplastic diseases should no longer be confined to highly-specialized centers where new treatment modalities should continue to develop, but become an integral part of cancer care for the entire population. To accomplish this goal, medical oncology should become part of formal training.

Adriamycin--an antitumor antibiotic in the treatment of neoplastic diseases.

Adriamycin was given to 234 patients with leukemia and other types of neoplastic diseases. In children with acute leukemia previously treated, adriamycin produced complete remissions (12%) and good partial remissions (26%). Tumor regressions were seen in 60% of the patients with solid tumors. These included lymphoma, embryonal rhabdomyosarcoma, neuroblastoma, Ewing's sarcoma, Wilms' tumor, ovarian tumor, hepatoma, embryonal carcinoma, malignant teratoma, and retinoblastoma. The therapeutic responses in adults have been less consistent and were confined to lymphomas and soft tissue sarcomas. The dose in children was 0.5 mg/kg daily to a total of 2-4 mg/kg per course. In adults, the single dose was 0.4 mg/kg to a total of about 2.5 mg/kg in 10 days. Adriamycin at half the dose of daunomycin produced comparable toxicities, except for earlier and more frequent oral ulcers and alopecia. Varying degrees of transient electrocardiographic changes have been seen in children. Adriamycin may have contributed to cardiac failure and death in one child, who had recurrent pulmonary metastases.

Combination of chemotherapy with dual antagonists and radiotherapy in the treatment of neoplastic disease.

AbstractThe theoretical justification for combination chemotherapy and for the combination of radiation and chemotherapy in the treatment of neoplastic diseases is discussed, literature on the synthesis and biological activity of the ‘dual antagonist’ group of drugs is reviewed. Studies on the radiation‐potentiating effect of certain members of this group of drugs are reviewed, and prospects for therapeutic applications are discussed.