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PubMed1984

Effect of antineoplastic agents on gamma-interferon production in human peripheral blood mononuclear cells.

Since gamma-interferon (IFN-gamma) is a potent immunomodulator and patients receiving certain antineoplastic agents are at risk of unusual infections, we have determined the effect of certain antineoplastic agents on IFN-gamma production. Induction of peripheral blood mononuclear cells from normal donors in the presence and absence of various antineoplastic agents was achieved using phytohemagglutinin (8 micrograms/ml). Supernatants were then separated by centrifugation, dialyzed, and assayed for interferon. Cell viability was always greater than 85% with or without the presence of drugs. Hydrocortisone was found to eliminate IFN-gamma production if added within 24 hr after the phytohemagglutinin. The suppression of IFN-gamma production occurred with hydrocortisone concentrations as low as 0.65 microgram/ml, was associated with a diminished proliferative response to the lectin, and occurred with other interferon inducers including staphylococcal enterotoxin A. Adriamycin (0.4 microgram/ml) and vincristine (0.08 microgram/ml) also diminished IFN-gamma production, but only if the peripheral blood mononuclear cells were pretreated with the drugs. Methotrexate, 5-fluorouracil, and 6-mercaptopurine failed to influence the yield of IFN-gamma. These results are significantly different from experiments previously reported using alpha- and beta-interferons and suggest an important mechanism by which these drugs can produce immunosuppression.

Antineoplastic Agents↗
PubMed1992

Targeted delivery of biologic and other antineoplastic agents.

This review summarizes several strategies under investigation for targeted delivery of antineoplastic agents to tumor cells, which avoids normal tissue damage. Monoclonal antibodies remain the molecules of choice for targeted therapy, and several improvements to immunotargeting are discussed. These improvements include the use of novel radioisotopes, cytokines, new linkers for chemotherapeutic drugs, more potent drugs, and improved immunotoxins. Bifunctional antibodies, in which one antigen-binding site recognizes a tumor-associated antigen and the other an antineoplastic agent, have been investigated for radioimmunotherapy and for the activation of cytotoxic cells for targeted immunotherapy. The activation of relatively nontoxic prodrugs by antibody-enzyme conjugates is increasingly being investigated in an effort to reduce the systemic toxicity associated with conventional chemotherapy. Finally, the use of liposomes as carriers of drugs or as activators of macrophages is described.

Antibodies, Monoclonal↗
PubMed1979

[Cis-diamminedichloroplatinum(II). A new antineoplastic agent derived from the group of heavy metal complexes (author's transl)].

Platinum coordination complexes represent a new class of antineoplastic agents among which only cis-diamminedichloroplatinum(II) (cis-DDP) has undergone extensive clinical trials. Cis-DDP and some of its congeners share the potential to form DNA-crosslinks with the group of bifunctional alkylating agents, yet cross-resistance is incomplete. The prominent dose-limiting nephrotoxicity can be effectively circumvented by forced diuresis. Cis-DDP not only displays outstanding activity against non-seminomatous testicular cancer but also has a broad spectrum of clinical activity. It ranks very high in activity against bladder cancer and head and neck tumors. Since myelosuppression by cis-DDP is mild, it combines well with other antineoplastic agents. Synergism has been experimentally shown for cyclophosphamide and several other antineoplastic agents. For testicular cancer combination chemotherapy including cis-DDP has become accepted treatment. The simple geometry of platinum coordination complexes allows substitutions of leaving and remaining ligands with anorganic or organic moieties thus altering pharmakokinetic, antineoplastic, and toxic properties in comparison to the parent compound. Mechanism of action, pharmacology, and clinical use of cis-DDP as well as of potentially useful congeners are discussed in this review, since cis-DDP is expected to be available for general use in medical oncology in the near future.

Animals↗
PubMed2002

Effects of antineoplastic agents on cytoplasmic and membrane-bound heat shock protein 70 (Hsp70) levels.

Here we report on the study of the effects of different antineoplastic agents, including cytarabine, 4-hydroperoxyifosfamide, the activated form of ifosfamide, vincristine, and paclitaxel, with regard to their capacity to modulate the amount of cytoplasmic and membrane-bound heat shock protein 70 (Hsp70). Hsp70 levels were measured in the myelogenous leukemic cell line K562, in the human colon carcinoma cell line CX2, and in peripheral blood lymphocytes (PBL) under physiological conditions (37 degrees C), and following non-lethal heat shock at 41.8 degrees C. A concentration of 1 microM and an incubation period of 2 h were determined as non-lethal, since none of the different antineoplastic agents induced necrosis or apoptosis in untreated or heat-shocked cells under these conditions. Our results show that tubulin-interacting agents, including vincristine and paclitaxel, but not DNA-interacting agents, including cytarabine and ifosfamide, selectively increase the amount of cytoplasmic Hsp70 in tumor and normal cells, as measured by semi-quantitative Western blot analysis. Mechanistically, a vincristine- and paclitaxel-induced tubulin assembly, as demonstrated by immunofluorescence microscopy, might be responsible for the elevated cytoplasmic Hsp70 levels. Interestingly, an increased membrane expression of Hsp70 following treatment with vincristine or paclitaxel was selectively observed on tumor cells, but not on normal cells.

Annexins↗
PubMed1989

The effect of liposome encapsulated antineoplastic agents on transitional cell carcinoma in tissue culture.

Liposomes are microscopic vesicles composed of one or more phospholipid bilayers separated by an equal number of aqueous interspaces. These "capsules" are formed when dried lipid is combined with excess water, agitated, and warmed above the transition temperature of the lipid (the temperature at which the lipid changes from a gel state to a fluid state). If a chemical in solution is present when the vesicles form, the chemical will be trapped in either the aqueous interspaces (hydrophilic compounds), or the lipid bilayer (hydrophobic compounds). The urinary bladder is an attractive site for the topical application of liposome encapsulated compounds due to its accessibility and since the introduction of various agents, including antineoplastic compounds, into the bladder is a well established treatment option. Utilization of liposome technology may provide the means for a more effective intravesical treatment of transitional cell carcinoma.

Administration, Intravesical↗
PubMed1997

Cytotoxic synergy between flavopiridol (NSC 649890, L86-8275) and various antineoplastic agents: the importance of sequence of administration.

Flavopiridol, the first potent cyclin-dependent kinase inhibitor to undergo clinical trials as an antineoplastic agent in the United States, has attracted considerable attention because of its unique cellular targets and its ability to kill noncycling tumor cells in vitro. To better understand how flavopiridol might be used clinically, the present study used colony-forming assays to examine the cytotoxicity resulting from combining flavopiridol with eight other antineoplastic agents in four different administration schedules in A549 human non-small cell lung carcinoma cells in vitro. Cytotoxic synergy, as assessed by the median effect method, resulted when flavopiridol was combined with seven of the eight tested antineoplastic agents but was highly dependent upon administration schedule. Cisplatin was the only agent that resulted in sequence-independent synergy when combined with flavopiridol. For paclitaxel, cytarabine, topotecan, doxorubicin, and etoposide, synergy was more pronounced when the agents were administered before flavopiridol rather than concomitant with or following flavopiridol. Examination suggested that this sequence dependence reflected arrest of cells in G1 and G2 phases of the cell cycle during and for 24 h following flavopiridol treatment. Interestingly, 48-72 h after flavopiridol removal, the fraction of surviving cells in S phase increased 2-3-fold relative to untreated controls. Consistent with these results, administration of flavopiridol for 24 h followed 3 days later by exposure to an S phase-active agent (cytarabine or 5-fluorouracil) resulted in a highly synergistic interaction. These results highlight the importance of administration schedule when combining flavopiridol with other agents and provide a starting point for examining the effect of flavopiridol in drug combinations in vivo.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

[A case report of hemolytic uremic syndrome (HUS) induced by antineoplastic agents].

An autopsy case of hemolytic uremic syndrome after treatment with antineoplastic agents for advanced gastric carcinoma is reported. A 70 year-old woman underwent partial gastrectomy for gastric carcinoma on April 16, 1987 (P0H0S2N4, Stage IV). She was treated with Mitomycin C (MMC), UFT, OK-432 and PSK as post operative chemotherapy. Total doses were 60 mg of MMC, 33.9 g of UFT, 55 KE of OK-432 and (507 g) of PSK. She suffered from occult blood in urine in September 1987, thrombocytopenia and anemia in October, edema and hypertension in November and died due to acute renal failure and pulmonary failure on December 5, 1987. It seemed that the cause of death was hemolytic uremic syndrome induced by antineoplastic agents.

Aged↗
PubMed1988

Human tumor cloning assays: applications in clinical oncology and new antineoplastic agent development.

The human tumor cloning assay (HTCA) has been available for preclinical and clinical applications for the last 11 years. This article examines the usefulness of that assay both in the practice of clinical oncology and in the development of new antineoplastic agents. In the area of prediction of response of an individual patient's tumor to a particular antineoplastic agent, in a total of 2274 correlations in a variety of clinical trials, the assay has shown a remarkably good ability to predict whether a patient's tumor would respond to a particular agent (percent true positives 69%; percent true negatives 91%). However, despite this ability to predict these responses, the assay has not yet been accepted for general clinical use, because there have not been rigorous trials to prove the assay will improve patient survival. These rigorous clinical trials are now underway. In the area of drug development, the HTCA has been used to screen for new antineoplastic agents as well as to pinpoint tumor types against which the new agent will be active in phase II clinical trials. As will be seen in this review, the HTCA has been most successful in this area.

Animals↗
PubMed2000

Development of target-based antineoplastic agents.

The elucidation of multiple potential targets in cancer cells and the development of multiple target-based antineoplastic agents provide unique challenges in clinical trial design. Many of these agents are predicted to have cytostatic as opposed to cytotoxic effects and thus the traditional surrogate endpoint of radiologic tumor shrinkage may be inadequate. The ethical and safety issues of obtaining multiple tumor biopsies further complicate the assessment of appropriate target inhibition in patients. We discuss specific issues that need to be addressed during preclinical, phase I, II, and III testing of these agents. We propose clinical trial designs, including a randomized discontinuation design during phase II evaluation, that may be particularly useful for cytostatic antineoplastic agents.

Antineoplastic Agents↗
PubMed2005

Improving delivery of antineoplastic agents with anti-vascular endothelial growth factor therapy.

It is believed that impairments in delivery of antineoplastic agents to solid tumors result from abnormalities of the tumor microenvironment. Vascular endothelial growth factor (VEGF), the prototypical angiogenic molecule, is one of the main factors responsible for the development and maintenance of the aberrant tumor vascular network, which is characterized by chaotic, leaky blood vessels with high interstitial fluid pressure and inefficient blood flow. The authors proposed that anti-VEGF therapy would reduce the elevated interstitial fluid pressure in tumors, thereby improving blood flow and potentially improving delivery of cytotoxic agents to tumor cells. For the current report, the authors reviewed characteristics of the abnormal tumor vasculature created under the influence of VEGF, the resulting tumor microenvironment, how the tumor microenvironment may impede delivery of antineoplastic agents, and how the combination of anti-VEGF and cytotoxic therapy may maximize the efficacy of antineoplastic treatment regimens.

Animals↗
PubMed2006

A probabilistic assessment of the impact of interventions on oncology nurses' exposure to antineoplastic agents.

OBJECTIVE: The main goal was to investigate the potential of a probabilistic approach for exposure assessment and use this information to evaluate the impact of a complex of policy actions/interventions on dermal exposure to antineoplastic agents among oncology nurses. The central theme of this study was to make optimal use of existing data, supplemented only with limited additional information from a questionnaire survey. METHODS: A task based exposure model was used to estimate dermal exposure of the hands among oncology nurses in non-academic hospitals in the Netherlands. Monte Carlo simulation was used to integrate information from available (exposure) studies and generate exposure distributions for the total population of oncology nurses in both pre- and post-intervention situation. Graphs and descriptive statistics of the simulated exposure distributions were used to evaluate trends in population exposure. RESULTS: The inventory showed that important intervention occurred in the preparation and administering of antineoplastic agents and in the handling of urine. Hardly any changes were identified in de nursing tasks. The use of gloves seemed to have decreased for a number of tasks. The results of the analysis show that the interventions did not affect the median exposure. However frequencies of occurrence of individuals with very high and very low total dermal exposures decreased substantially in the post-intervention situation. Analysis of the effect of pregnancy showed that pregnancy is very unlikely to influence exposure or any of the key input variables. CONCLUSIONS: The present study shows that the probabilistic approach adds valuable information to deterministic exposure assessment, especially when extrapolating data on a subpopulation to populations of individuals at large. The results show that the identified changes in the past decade in Dutch non-academic hospitals resulted in changes in the exposure distribution of antineoplastic agents among oncology nurses.

Antineoplastic Agents↗
PubMed1999

Occupational exposure to antineoplastic agents: self-reported miscarriages and stillbirths among nurses and pharmacists.

Insult to the germ cells of an ovum or sperm prior to pregnancy as well as exposures to a fetus during pregnancy can affect the outcome of a pregnancy. Antineoplastic agents are mutagenic and teratogenic, so the potential effects of exposure on reproduction are of concern to the workers who handle them. This study investigates pregnancy loss associated with occupational exposures to antineoplastic drugs by comparing rates of spontaneous abortion and stillbirths for pregnancies without antineoplastic exposure and exposed pregnancies in which the pregnant woman or the father handled antineoplastic agents either before or during the pregnancy. A total of 7094 pregnancies of 2976 pharmacy and nursing staff were examined. After age during pregnancy, prior gravidity, maternal smoking during the pregnancy, and occurrence of a spontaneous abortion or stillbirth in a prior pregnancy were controlled for, exposure of the mother to or the handling of antineoplastic agents during the pregnancy was associated with a significantly increased risk of spontaneous abortion (odds ratio = 1.5; 95% confidence interval, 1.2 to 1.8) and combined risk of spontaneous abortion and stillbirth (odds ratio = 1.4; 95% confidence interval, 1.2 to 1.7) but not stillbirth alone. Among the wives of exposed men, too few stillbirths occurred to allow analysis. However, for spontaneous abortion and any loss, the patterns of increased risk were similar to those seen for women, although the odds ratios were not statistically significant.

Abortion, Spontaneous↗
PubMed1979

Cutaneous irritation in the topical application of 30 antineoplastic agents to New Zealand white rabbits.

Of 30 antineoplastic agents studied for their primary irritation potential in rabbits, 9 showed some potential for irritation. Five of these 9 agents produced a significant dermal irritation. None of the irritation observed was considered to be irreversible skin damage. The study further showed a strong correlation between irritation observed by the Draize method and acute inflammation evaluated histopathologically. There was a tendency toward increased epidermal thickness of irritated skin sites. None of the agents produced gross or microscopically visible lesions in the internal organs observed.

Administration, Topical↗
PubMed2002

Induction of morphological alterations by antineoplastic agents in yeast.

Saccharomyces cerevisiae was used as an alternative experimental model in order to investigate the effects of antineoplastic agents on eukaryotic cells. After being exposed to the most common clinically used antineoplastic agents, yeast cells were examined under the light microscope. Folate and pyrimidine antagonists, platinum derivatives, mitomycin C, actinomycin D and bleomycin induced alterations in yeast cellular morphology, which were not observed following treatment with drugs belonging to any category other than the antineoplastics, leading to the suggestion that these alterations could potentially be used as an experimental tool in pre-screening for new chemotherapeutic leads.

Antineoplastic Agents↗
PubMed1986

Effects of antineoplastic agents on the cell cycle progression.

Almost all antineoplastic drugs are able to delay--or block--cells in a particular phase of the cell cycle. Few clinically active drugs seem to interact with the G1-states where cell growth can be arrested, although new compounds could be of interest with this respect. In contrast, most antineoplastic agents interact with DNA and/or DNA metabolism and have been shown to provoke a delay in G2. This could be the consequence of the DNA damage or of interference with controls which take place within the G2 phase.

Animals↗
PubMed1977

Antineoplastic agents and their oral manifestations.

The use of antineoplastic agents is rapidly increasing. A general classification of these drugs and their mechanisms of action is presented. Many of the drugs have an adverse effect on oral tissue, and the practicing dentist today must be well acquainted with these effects. A discussion of the features of these reactions and their management is presented.

Antineoplastic Agents↗
PubMed1999

Antifungal activities of antineoplastic agents: Saccharomyces cerevisiae as a model system to study drug action.

Recent evolutionary studies reveal that microorganisms including yeasts and fungi are more closely related to mammals than was previously appreciated. Possibly as a consequence, many natural-product toxins that have antimicrobial activity are also toxic to mammalian cells. While this makes it difficult to discover antifungal agents without toxic side effects, it also has enabled detailed studies of drug action in simple genetic model systems. We review here studies on the antifungal actions of antineoplasmic agents. Topics covered include the mechanisms of action of inhibitors of topoisomerases I and II; the immunosuppressants rapamycin, cyclosporin A, and FK506; the phosphatidylinositol 3-kinase inhibitor wortmannin; the angiogenesis inhibitors fumagillin and ovalicin; the HSP90 inhibitor geldanamycin; and agents that inhibit sphingolipid metabolism. In general, these natural products inhibit target proteins conserved from microorganisms to humans. These studies highlight the potential of microorganisms as screening tools to elucidate the mechanisms of action of novel pharmacological agents with unique effects against specific mammalian cell types, including neoplastic cells. In addition, this analysis suggests that antineoplastic agents and derivatives might find novel indications in the treatment of fungal infections, for which few agents are presently available, toxicity remains a serious concern, and drug resistance is emerging.

Acyltransferases↗