Use Of Cytotoxic Agents Research Articles

Impact of the antimetastatic drug Batimastat on tumor growth and PO2 measured by EPR oximetry in a murine mammary adenocarcinoma.

Patients treated for early breast cancer have only a 10–15% probability of local relapse (Fowble, 1991), but the likelihood of eventual recurrence with distant metastases can be much higher depending on the original stage of the cancer. It is from this systemic disease that patients die (Willner et al., 1997). Treatment of malignant tumors has relied heavily on the use of cytotoxic agents, targeted at the increased metabolic and proliferative activity of the cancer cell. An alternative strategy has been to develop low toxicity therapies that can be administered continuously over a period of several years to stabilize malignant disease, and it is in this category that treatment with matrix metallopro-teinase inhibitors (MMPIs) lie.

Therapeutic differentiation in a human rhabdomyosarcoma cell line selected for resistance to actinomycin D.

Classical cytotoxic treatment of rhabdomyosarcoma (RMS) is accompanied often by significant morbidity and poor response. The use of cytotoxic agents may induce a multidrug resistance phenotype, which plays an important role in the sensitivity of tumoral cells to drugs. Using actinomycin D, a drug of choice in the treatment of RMS, we induced resistance in the TE.32.7 human RMS cell line. The TE.32.7-DAC-resistant cell line exhibited cross-resistance to vincristine and doxorubicin and showed mdr1/P-glycoprotein over-expression, suggesting that this mechanism was involved in the reduction in intracellular drug concentration and may be responsible for the failure of treatment of RMS with classical cycles of cytotoxics. Furthermore, this resistant cell line showed increased expression of the muscle differentiation markers desmin and alpha-actinin and ultrastructural changes which clearly indicated myogenic differentiation. Our findings suggest that, although this tumor is probably arrested along the normal myogenic pathway to maturation, induction of cell differentiation with anti-neoplastic drugs may be an alternative therapeutic approach. However, the failure of TE.32.7-DAC cells to completely re-enter the program of myogenic differentiation supports the hypothesis that multidrug resistance is a major obstacle in differentiation therapy for RMS.

Therapeutic differentiation in a human rhabdomyosarcoma cell line selected for resistance to actinomycin D

Classical cytotoxic treatment of rhabdomyosarcoma (RMS) is accompanied often by significant morbidity and poor response. The use of cytotoxic agents may induce a multidrug resistance phenotype, which plays an important role in the sensitivity of tumoral cells to drugs. Using actinomycin D, a drug of choice in the treatment of RMS, we induced resistance in the TE.32.7 human RMS cell line. The TE.32.7-DAC-resistant cell line exhibited cross-resistance to vincristine and doxorubicin and showed mdr1/P-glycoprotein over-expression, suggesting that this mechanism was involved in the reduction in intracellular drug concentration and may be responsible for the failure of treatment of RMS with classical cycles of cytotoxics. Furthermore, this resistant cell line showed increased expression of the muscle differentiation markers desmin and alpha-actinin and ultrastructural changes which clearly indicated myogenic differentiation. Our findings suggest that, although this tumor is probably arrested along the normal myogenic pathway to maturation, induction of cell differentiation with anti-neoplastic drugs may be an alternative therapeutic approach. However, the failure of TE.32.7-DAC cells to completely re-enter the program of myogenic differentiation supports the hypothesis that multidrug resistance is a major obstacle in differentiation therapy for RMS.

The use of cytotoxic agents in the treatment of immune-mediated diseases of dogs and cats.

Cytotoxic drugs are often combined with glucocorticoids in the therapy of immune-mediated diseases. Cyclophosphamide, azathioprine, chlorambucil, and methotrexate are cytotoxic drugs used most commonly for the purpose of immunosuppression. Cyclophosphamide and chlorambucil are alkylating agents, which cause cross-linking of DNA resulting in altered protein production, decreased cell division, and cell death. Azathioprine and methotrexate are anti-metabolites, which cause inhibition of DNA synthesis and a cascade of other effects. These drugs, in general, are more effective if administered during the initial phases of disease when immunocompetent lymphocytes are in a phase of rapid proliferation. This is often impractical in the clinical situation and may explain therapeutic failures. This article focuses on the use of these drugs in the treatment of immune-mediated diseases in dogs and cats and covers mechanisms of action, dosages, and side effects of individual cytotoxic agents.

Cytotoxic therapy and pregnancy

The use of cytotoxic agents during pregnancy may be unavoidable in order to ensure maternal survival—despite the dangers to the developing fetus. We review 217 such cases published between 1983 and 1995, classifying them into 5 groups according to whether the cytotoxic drugs were used to treat leukaemias, malignant lymphomas, severe rheumatic diseases, gynaecological/breast neoplasms, or other grave conditions. Various factors, such as the drug type, dose, and timing to exposure to gestational age, are analysed with respect to the outcome of these pregnancies (teratogenicity, stillbirths, spontaneous abortions, prematurity, etc.). These results are then integrated in order to determine whether one can predict the individual risk of abnormality for the newborn when cytotoxic agents must be administered to pregnant women faced with a malignancy or other serious condition.

Breast Cancer: Cell and Gene Therapy

INTRODUCTION Breast cancer will affect 1 in 9 women in the United States. Approximately 181,000 new cases are diagnosed in the United States each year. Despite early detection methods and advanced treatments, 46,000 women will die each year from breast cancer (1). Approximately 27% of all women's malignancies are breast cancer, and among women between the ages of 40 and 55, it is the leading cause of death. The primary treatments for breast cancer have not changed radically over the last 20 years and include surgery, chemotherapy, radiation, and endocrine therapy. Most newer developments involve combinational therapies, such as repetitive cycle chemotherapy together with growth factors and high-dose chemotherapy coupled with autologous peripheral blood stem cell transplantation. Each of these therapies relies on the use of cytotoxic agents that to some extent, preferentially target rapidly dividing or metabolizing cells. However, many debilitating side effects are associated with such relatively nonspecific therapies. The administration of sufficient doses of these agents to minimize tumor burden often is associated with significant morbidity and mortality risks.

Are cytotoxic agents beneficial in idiopathic membranous nephropathy? A meta-analysis of the controlled trials.

The use of cytotoxic agents for the treatment of idiopathic membranous nephropathy is controversial. Although several controlled trials have been published, both the comparison groups and the study findings have varied, resulting in clinical uncertainty. To explore this uncertainty, a meta-analysis of controlled trials of treatment with cyclophosphamide or chlorambucil was performed in patients with idiopathic membranous nephropathy and nephrotic-range proteinuria. Patients in the control groups received only symptomatic treatment or corticosteroids. Descriptive and quantitative data from each trial were abstracted independently. Outcomes included effects of treatment on renal function and proteinuria, with a complete remission (CR) or partial remission (PR) defined as the complete or partial resolution of proteinuria without deterioration of renal function. For patients having either any response (CR or PR) or only a CR, both the relative risk (RR) and the number needed to be treated were calculated. The five trials that satisfied criteria for inclusion in the analysis were clinically and statistically homogeneous. There were no placebo-controlled trials that met the criteria for inclusion. Among the 228 patients in these studies, the RR of achieving any response with cytotoxic agents was 2.3 (95% confidence interval, 1.7 to 3.2) and the RR for a CR was 4.6 (95% confidence interval, 2.2 to 9.3), with respective numbers needed to be treated of 2.9 and 4.7, meaning that between three and five patients would need to be treated with cytotoxic agents to achieve one response. Exclusion of the only nonrandomized trial had no significant effect on the results. Both chlorambucil and cyclophosphamide showed similar beneficial effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Response of six patients with idiopathic hypereosinophilic syndrome to interferon alfa*

Response of six patients with idiopathic hypereosinophilic syndrome to interferon alfa*

Infectious complications in bone marrow transplantation. Organization of clinical trials: problems, controversies, definitions, methodology.

In internal medicine, there are two disciplies in which patients are treated with curative intent - infectious disease and medical oncology. Systemic drug therapy is the cornerstone of curative treatment in both disciplines. In both areas there has been an explosion in the number of agents employed, a broadening of the types of agents available, as well as an increase in the spectrum of activity and toxicity associated with their use. With the widespread use of cytotoxic agents, treatment algorithms were required to deal with the intense, often sustained iatrogenic induction of granulocytopenia integral to the appropriate therapy of a variety of cancers. All of these historic developments have led to a welding of the activities of the infectious disease and medical oncology subspecialist.

Non-cardiogenic pulmonary oedema associated with pyrimethamine

Non-cardiogenic pulmonary oedema is a rare complication associated with the use of cytotoxic agents, opiates, nitrofurantoin, amphotericin B, aspirin and other drugs (1), but not with pyrimethamine. Extensive, peripheral lung shadowing has been reported in two patients taking Fansidar (pyrimethamine and sulphadoxine) as malarial prophylaxis, but was thought to be related to the sulphonamide component (2,3). A patient with polycythaemia rubra vera, who developed non-cardiogenic pulmonary oedema after prolonged treatment with high doses of pyrimethamine, is reported here. His lung disease resolved after withdrawal of the drug without specific therapy. This may be the first case of pyrimethamine-induced noncardiogenic pulmonary oedema.

Adjuvant chemotherapy in a pregnant patient with endodermal sinus tumor of the ovary

The development of germ cell carcinoma of the ovary during pregnancy is a rare occurrence. Recent advances in chemotherapy have improved significantly the prognosis for patients with early stage disease. Use of cytotoxic agents in pregnancy traditionally has been avoided because of possible teratogenic effects. We describe a pregnant patient who was found to have endodermal sinus tumor of the ovary, stage I, at 13 weeks gestation. She received five courses of adjuvant VAC chemotherapy, beginning with her 17th week of gestation, prior to delivery of a normal infant at term. After an additional seven courses of chemotherapy, a second-look laparotomy revealed no evidence of disease. The infant is developmentally normal at 1 year. A comprehensive review of the literature describing use of chemotherapeutic agents in pregnancy is presented.

Handling cytotoxic drugs

The rapid increase in the use of cytotoxic agents has brought their handling into the realm of the specialist nurse. Sue Robinson (pictured opposite) reports

The Surgeon and Chemotherapy: Twenty Five Years Personal Experience

The realm of cancer chemotherapy is complex and often conflicting. The massive use of cytotoxic agents during the past 25 years has now reached a point where major decisions have to be made. The respective roles of regional techniques, systemic therapy for metastatic disease and adjuvant cytotoxic chemotherapy, all need the most careful re-appraisal. It is important that surgical opinion continues to be expressed and that surgeons continue to participate in the study and practice of cancer chemotherapy.

The surgeon and chemotherapy: twenty five years personal experience.

The realm of cancer chemotherapy is complex and often conflicting. The massive use of cytotoxic agents during the past 25 years has now reached a point where major decisions have to be made. The respective roles of regional techniques, systemic therapy for metastatic disease and adjuvant cytotoxic chemotherapy, all need the most careful re-appraisal. It is important that surgical opinion continues to be expressed and that surgeons continue to participate in the study and practice of cancer chemotherapy.

Mechanisms of Action and Clinical Applications of Cytotoxic Drugs in Rheumatic Disorders

Failure to suppress disease activity in certain rheumatic disorders such as systemic lupus, polyarteritis nodosa, or Wegener's granulomatosis may significantly heighten the probability of a fatal outcome. In other rheumatic disorders (for example, rheumatoid or psoriatic arthritis) the disease left unchecked may indeed be severely crippling but rarely is it fatal. Thus the decision on whether to add a cytotoxic drug often evolves into a benefit-to-risk analysis, a decision in which the patient must also be intimately involved. There are two few well-controlled studies of the use of cytotoxic agents to make dogmatic statements regarding their use in the treatment of rheumatic disorders. Nevertheless, a review of the literature, some of which has been cited above, does permit one to make some reasoned judgments in choosing a drug for a particular disease (Table 2).

Bronchocentric Granulomatosis with Glomerulonephritis

Bronchocentric granulomatosis is a chronic pulmonary disease treated with short-term therapy with corticosteroids, and the disease has an excellent prognosis. We describe a patient, and review an additional case from the literature, in whom bronchocentric granulomatosis was accompanied by glomerulonephritis. A misdiagnosis of Wegener's granulomatosis was made, and therapy with cyclophosphamide was either considered or given in each of these cases. We emphasize the need for careful histopathologic evaluation of open lung biopsies in patients suspected of having Wegener's granulomatosis in order to rule out the possibility of bronchocentric granulomatosis with concurrent renal disease, and thus avoid the unnecessary use of cytotoxic agents.

Differentiation modifiers.

This article summarizes evidence that indicates that a variety of relatively simple chemical compounds can induce murine erythroleukemia cells (MELCs) as well as a number of other transformed cell lines to differentiate with the loss of proliferative capacity and the expression of differentiated characteristics. These studies provide a potentially important new approach in the treatment of certain neoplastic diseases that may be an alternative to the use of cytotoxic agents, namely, agents that induce transformed cells to terminal cell division, expression of differentiated characteristics, and loss of oncogenic properties. A strong note of caution is needed concerning the potential therapeutic role of these agents that are able to induce transformed cells to terminal differentiation. In general, it appears that inducer-sensitive transformed cell lines are blocked at a particular stage in the development of these cells. The evidence suggests that these compounds trigger certain events that then are involved in the progression of differentiation of these cells with loss of proliferative capacity. It is not known how to predict which transformed cell lines are blocked in a stage of differentiation susceptible to the inducer-mediated effects of agents as described above. Nevertheless, it is reasonable to suggest that the pursuit of studies in this area may permit researchers to determine the potential efficacy of these inducers for in vivo controlled trials with certain select types of neoplasms.

Radiation Therapy in the Management of Carcinoma of the Lung

Carcinoma of the lung is the most common cancer in men in the United States and a major cause of death. This is due to the inadequate techniques for screening of high-risk patients and for detection of the tumor in early stages, before distant dissemination occurs. Although some progress has been made in the past, particularly in improving the knowledge of natural history and pathological characteristics of the disease, and there are better indications for surgical treatment and irradiation and the effective use of cytotoxic agents in selected groups of patients, particularly those with small cell undifferentiated carcinoma, the mortality rate is still very high. A great deal of investigation remains to be done in carcinoma of the lung concerning the basic cell kinetics of the tumor and the optimal conditions for the use of surgery, irradiation, chemotherapy or combinations of these agents in the treatment of these patients before survival rates can be substantially improved. Since the most important factor in patient mortality is distant tumor dissemination, it must be stressed that parameters other than survival should be used to evaluate the effectiveness of irradiation, surgery or combinations in the control of local and regional bronchogenic carcinoma. These efforts should be intensified through properly designed clinical trials.

Plasma Cell Leukemia (PCL): A Report on 15 Patients

Fifteen patients presenting with plasma cell leukemia (PCL) are reported in detail. The clinicopathologic features of PCL differ from typical myeloma and resemble those of acute leukemia: patients with PCL have less bone disease but a much higher incidence of organomegaly and tissue infiltration as well as diffuse marrow involvement and more pronounced pancytopenia. One of the reported patients developed meningeal plasma cell leukemia and is reported in detail. Cytomorphologic assessment of PCL cells showed nuclear immaturity and obvious nuclear/cytoplasmic asynchrony. Despite the use of cytotoxic agents known to be effective in myeloma, the prognosis in PCL is poor, and the median survival of the reported patients was only 2 mo.

Plasma cell leukemia (PCL): A report on 15 patients

Fifteen patients presenting with plasma cell leukemia (PCL) are reported in detail. The clinicopathologic features of PCL differ from typical myeloma and resemble those of acute leukemia: patients with PCL have less bone disease but a much higher incidence of organomegaly and tissue infiltration as well as diffuse marrow involvement and more pronounced pancytopenia. One of the reported patients developed meningeal plasma cell leukemia and is reported in detail. Cytomorphologic assessment of PCL cells showed nuclear immaturity and obvious nuclear/cytoplasmic asynchrony. Despite the use of cytotoxic agents known to be effective in myeloma, the prognosis in PCL is poor, and the median survival of the reported patients was only 2 mo.