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PubMed1995

Prevention and management of extravasation of cytotoxic drugs.

Extravasation of certain cytotoxic agents during peripheral intravenous administration may cause severe local injuries. Most extravasation can be prevented with the systematic implementation of careful administration techniques. However, the management of this complication, the aim of which is to prevent progression to tissue necrosis and ulceration, remains an important challenge in the care of cancer patients. Many antidotes have been evaluated experimentally and a few may be able to reduce the local toxicity of the more common vesicant cytotoxic drugs. Because no randomised trial on the management of cytotoxic drug extravasation in humans has ever been completed, recommendations must be based on the more consistent experimental evidence and on cumulative clinical experience from available case reports and uncontrolled studies, which are reviewed in this article. Empirical guidelines recommend the use of topical dimethylsulfoxide (DMSO) and cooling after extravasation of anthracyclines or mitomycin, locally injected hyaluronidase after extravasation of vinca alkaloids, and locally injected sodium thiosulfate (sodium hyposulfite) after extravasation of chlormethine (mechlorethamine; mustine). Plastic surgery may be necessary when conservative treatment fails to prevent ulceration. The possibility of late local reactions must also be considered in the management of patients receiving chemotherapy.

Adrenal Cortex Hormones↗

PubMed2006

ROS and protein oxidation in early stages of cytotoxic drug induced apoptosis.

Cytotoxic drugs induce cell death through induction of apoptosis. This can be due to activation of a number of cell death pathways. While the downstream events in drug induced cell death are well understood, the early events are less clear. We therefore used a proteomic approach to investigate the early events in apoptosis induced by a variety of drugs in HL60 cells. Using 2D-gel electrophoresis, we were able to identify a number of protein changes that were conserved between different drug treatments. Identification of post-translational modifications (PTM) responsible for these proteome changes revealed an increase in protein oxidation in drug treated cells, as well as changes in protein phosphorylation. We demonstrate an accumulation of oxidised proteins within the ER, which lead to ER stress and calcium release and may result in the induction of apoptosis. This study demonstrates the importance of ROS mediated protein modifications in the induction of the early stages of apoptosis in response to chemotherapeutic drug treatment.

Antineoplastic Agents↗

PubMed1980

Renal tubular damage without glomerular damage after cytotoxic drugs and aminoglycosides.

Cytotoxic agents and aminoglycosides when given for a maximum of eleven days damaged the renal tubules as indicated by an increased urinary beta 2-microglobulin (beta 2-m), N-acetyl-beta-D-glucosaminidase (NAG) and total protein. Methotrexate (MTX) caused the greatest changes among the cytotoxic agents studied. Prophylactic doses of aminoglycosides in surgical patients also caused tubuloproteinuria. The tubular damage was greatest when aminoglycosides were given to treat septicaemia complicating haematological malignancies in patients who had previously had cytotoxic drugs. However, even in these patients there was no evidence of glomerular failure or increased glomerular permeability seven days after beginning chemotherapy.

Acetylglucosaminidase↗

PubMed1984

The problem of permanent bone marrow damage after cytotoxic drug treatment.

The majority of cytotoxic drugs exert a dose-dependent injury to the hemopoietic bone marrow. In experimental systems, two different types of damage to the hemopoietic stem cell compartments have been demonstrated to occur following cytotoxic drug exposure. First, a reversible reduction of the size of these stem cell compartments; recovery of compartment size results from a transiently increased proliferative activity of those stem cells surviving the cytotoxic drug exposure. Second, irreversibly decreased proliferative potential of pluripotent stem cells has been observed after some cytotoxic agents. Experimental evidence indicates that such permanent stem cell damage may lead to the failure of the hemopoietic bone marrow to produce sufficient numbers of blood cells. There are indications that a similar permanent damage to the hemopoietic system may occur in man following repeated exposure to at least some cytotoxic agents.

Animals↗

PubMed1980

Kurloff cell levels in the peripheral blood of normal guinea-pigs treated with cytotoxic drugs.

The effect of cytotoxic drugs on Kurloff cell levels in the peripheral blood of normal female guinea-pigs has been studied. Single doses of cyclophosphamide, azathioprine, methotrexate, busulphan and melphalan all failed to reduce Kurloff cell levels. Repeated high dose treatment with cyclophosphamide caused a significant fall in circulating Kurloff cells, but also resulted in the dealth of animals. The similarity between these findings and those obtained by other authors using whole body radiation is discussed. The results show that Kurloff cells are much more resistant than some lymphocyte populations to the effect of cytotoxic drugs.

Animals↗

PubMed1999

Therapeutic drug monitoring of antimetabolic cytotoxic drugs.

Therapeutic drug monitoring is not routinely used for cytotoxic agents. There are several reasons, but one major drawback is the lack of established therapeutic concentration ranges. Combination chemotherapy makes the establishment of therapeutic ranges for individual drugs difficult, the concentration-effect relationship for a single drug may not be the same as that when the drug is used in a drug combination. Pharmacokinetic optimization protocols for many classes of cytotoxic compounds exist in specialized centres, and some of these protocols are now part of large multicentre trials. Nonetheless, methotrexate is the only agent which is routinely monitored in most treatment centres. An additional factor, especially in antimetabolite therapy, is the existence of pharmacogenetic enzymes which play a major role in drug metabolism. Monitoring of therapy could include assay of phenotypic enzyme activities or genotype in addition to, or instead of, the more traditional measurement of parent drug or drug metabolites. The cytotoxic activities of mercaptopurine and fluorouracil are regulated by thiopurine methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD), respectively. Lack of TPMT functional activity produces life-threatening mercaptopurine myelotoxicity. Very low DPD activity reduces fluorouracil breakdown producing severe cytotoxicity. These pharmacogenetic enzymes can influence the bioavailability, pharmacokinetics, toxicity and efficacy of their substrate drugs.

Antimetabolites, Antineoplastic↗

PubMed1999

Use of V79 cells with stably transfected cytochrome P450 cDNAs in studying the metabolism and effects of cytotoxic drugs.

PURPOSE: Studying the metabolism of cytotoxic drugs has become increasingly necessary to predict clinically significant drug-drug interactions and to understand the basis of interindividual variations in the pharmacokinetics of anticancer agents. The aim of this study was to determine the feasibility of using V79 Chinese hamster fibroblasts, which are stably transfected with cytochrome P450 (CYP) cDNAs, to study the metabolism of cytotoxic drugs in vitro. METHODS: The 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine cell survival after incubation with drugs. Gas chromatography/mass spectroscopy was used for the quantitation of metabolites of cyclophosphamide and ifosfamide in culture medium. The coculture technique was used to study the generation of cytotoxic metabolites in culture medium. RESULTS: After treatment with either cyclophosphamide or ifosfamide (100 microM to 1 mM) cytotoxicity was demonstrated in only cytochrome CYP2B1- and cytochrome CYP3A4-expressing cells. Treatment of parental nontransfected cells that were cocultured with CYP-expressing cells with cyclophosphamide resulted in increased sensitivity to this drug. All active and inactive metabolites of cyclophosphamide and ifosfamide were detected in the culture medium. Cyclophosphamide-induced cytotoxicity in CYP2B1- and CYP3A4-expressing cells was abrogated by metyrapone and midazolam/ troleandomycin, respectively. Paclitaxel showed greater cytotoxicity against parental V79 cells than against the CYP2BI-, 2E1-, or 3A4-expressing cells, which was also influenced by cotreatment with CYP inhibitors. CONCLUSIONS: Stable expression of CYP cDNAs by V79 cells provided an in vitro system to study cytotoxic drug metabolism. Cell viability and metabolite assays were used to determine the differential metabolism and effects in different CYP-transfected cell lines treated with cytotoxic drugs. The potential use of this V79 cell expression system is in studying enzymes involved in the metabolism of cytotoxic drugs, especially early in drug development. In addition, this system may be used to determine drug interactions that may influence the outcome of therapy in patients with cancer.

Animals↗

PubMed1985

Tamoxifen-citrate counteracts the antitumor effects of cytotoxic drugs in vitro.

Hormones and cytotoxic drugs are often combined in the treatment of patients with breast carcinoma to broaden the antitumor spectrum of the therapy. We found that, in vitro, the most commonly used endocrine agent, tamoxifen citrate, attenuates the cytotoxic potential of 5-fluorouracil (5-FU) and of doxorubicin. The effect was observed on estrogen receptor positive and on estrogen receptor negative breast tumor cells. Combinations of growth inhibitory hormones and cytotoxic drugs may therefore be counter-productive. For the treatment of hormone-independent tumors they may even be harmful since in these tumors tamoxifen exerts no independent cell kill that compensates for its modifying effect on the cytotoxicity of drugs.

Animals↗

PubMed1994

Detection of tumor-specific cytotoxic drug activity in vitro using the fluorometric microculture cytotoxicity assay and primary cultures of tumor cells from patients.

The semi-automated fluorometric microculture cytotoxicity assay (FMCA), based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA) by viable cells, was employed for cytotoxic drug sensitivity testing of tumor cells from patients with hematological or solid tumors. In total, 390 samples from 20 diagnoses were tested with up to 12 standard cytotoxic drugs. The technical success rate for different tumor types ranged from 67 to 95%. Fluorescence was linearly related to cell number but variably steep depending on tumor type. Samples from most solid tumors thus showed higher signal-to-noise ratios than hematological samples. A wide spectrum of in vitro drug activity was obtained, with acute leukemias and non-Hodgkin's lymphomas being sensitive to almost all tested drugs, whereas renal and adrenocortical carcinomas were essentially totally resistant. Between these extremes were samples of breast and ovarian carcinomas and sarcomas. When in vitro response was compared with known clinical response patterns, a good correspondence was observed. The results indicate that the FMCA is a rapid and efficient method for in vitro measurement of tumor-specific drug activity both in hematological and in solid tumors. The assay may be suitable for new drug development and direction of phase-2 trials to suitable patients.

Antineoplastic Agents↗

PubMed1993

[Acute drug-induced lung diseases with hypoxemia, cytotoxic drugs excluded].

Drug-induced acute lung diseases constitute a chapter of pneumology and intensive care that is now in full mutation. In practice, these diseases are still inadequately indexed and little known, the only exception being those caused by cytotoxic drugs observed in onco-haematology. They create for clinicians difficult diagnostic and therapeutic problems. From the cases reported in the literature, recent review papers and 10 personal cases, the authors ask five successive questions concerning hypoxic pneumopathies: 1) which patients?; 2) which clinical features?; 3) which initial diagnostic discussion?; 4) which are the elements likely to support the drug-induced hypothesis?; 5) which outcome?

Acute Disease↗

PubMed2002

Occupational exposure to cytotoxic drugs in two UK oncology wards.

AIMS: To investigate the potential exposure to cytotoxic drugs of staff on two oncology wards in a large district, UK hospital under normal working conditions. METHODS: Cytotoxic drug exposure was monitored in urine samples, surface wipes, and on disposable gloves by using a number of commonly used marker drugs, namely cyclophosphamide, ifosfamide, methotrexate, and the platino coordinated drugs. Questionnaire data on their work practices, potential exposure, use of protective personal equipment, and relevant training were collected from nursing, domestic, and clerical staff on two oncology wards. RESULTS: The majority of staff were female with a mean age of 31 years. Roughly half of the staff studied were specifically trained nurses with an average of 3.5 years experience of administering cytotoxic drugs. No cytotoxic drug preparation or reconstitution was carried out on the wards. Disposable gloves, plastic armlets and aprons, but not eye protection, were invariably worn where there was potential exposure to cytotoxics. No cytotoxic drug was detected in any of the staff's urine samples. Isolated disposable latex gloves from nurses administering drugs showed some contamination, as did some surfaces within the wards' sluice rooms, but not in the ward areas where the drugs were stored and checked prior to administration. CONCLUSIONS: The risk management strategies in place, including use of personal protective equipment, staff training, and other organisational measures, have ensured that internal exposure is lower than the detection limits for the current biological monitoring methods. Levels of contamination appear significantly lower than earlier, non-UK published studies where different risk management strategies were in place and, in particular, ward staff may have been involved in some degree of cytotoxic drug reconstitution.

Adult↗

PubMed1999

Cytotoxic drugs and the CD95 pathway.

Cytotoxic drugs commonly used in chemotherapy of leukemia and solid tumors have been shown to primarily act by inducing apoptosis in sensitive target cells. Apoptosis may involve activation of death-inducing ligand/receptor systems such as CD95 (APO-1/Fas). Treatment with anticancer drugs such as doxorubicin, methotrexate, cytarabine, etoposide and cisplatin at therapeutic concentrations leads to induction of CD95-ligand (CD95-L). CD95-L can mediate cell death in an autocrine/paracrine manner by crosslinking CD95 receptor (CD95). Interfering with CD95-ligand/receptor interaction by antagonistic antibodies to the receptor reduces sensitivity to drug-mediated apoptosis in some cell systems. In addition, treatment with cytotoxic drugs may result in upregulation of CD95, thereby increasing the sensitivity to the CD95 death signal. Apoptosis depends on activation of caspases. Deficient activation of the CD95 system was found in drug-resistant cells. In addition, CD95-resistant and doxorubicin-resistant cells displayed cross-resistance for induction of cell death. Thus, intact apoptosis pathways such as the CD95 system may play a role in determining sensitivity or resistance of tumor cells to chemotherapy.

Antineoplastic Agents↗

PubMed1997

Sensitization of cancer cells treated with cytotoxic drugs to fas-mediated cytotoxicity.

BACKGROUND: The transmembrane receptor Fas, together with its protein-binding partner (Fas ligand), is a key regulator of programmed cell death (i.e., apoptosis). Fas and Fas ligand also influence the ability of cytotoxic T lymphocytes and natural killer cells to eliminate tumor cells. However, by inducing apoptosis in activated T cells, the Fas/Fas ligand system may protect some tumor cells from clearance by the immune system. Anticancer drugs enhance Fas ligand expression on the surface of Fas receptor-expressing leukemia cells, thus suggesting that apoptosis caused by these drugs may be mediated via the Fas/Fas ligand system. PURPOSE: This study was conducted to further investigate the relationship between the modulation of Fas receptor gene and protein expression by treatment of cells with cytotoxic drugs and the immune clearance of tumor cells. METHODS: Fas expression on human HT29 colon carcinoma cells treated with a variety of anticancer drugs (cisplatin, doxorubicin, mitomycin C, fluorouracil, and camptothecin) was analyzed by use of quantitative flow cytometry. Human HCT8R and HCT116 colon carcinoma cells and human U937 leukemia cells were treated with cisplatin only and analyzed in the same way. Fas ligand messenger RNA and protein levels were studied by use of a reverse transcription-polymerase chain reaction assay and by flow cytometry. Fas gene expression and messenger RNA levels in cisplatin-treated HT29 cells were characterized by use of in vitro nuclear run-on and northern blot hybridization assays. The cytotoxic activities of agonistic anti-Fas antibodies, Fas ligand, and allogeneic peripheral blood leukocytes, in the absence or presence of Fas-blocking monoclonal antibodies, against tumor cells were assessed by methylene blue staining and chromium-51 release assays. RESULTS: Clinically relevant concentrations of cisplatin, doxorubicin, mitomycin C, fluorouracil, or camptothecin enhanced Fas receptor expression on the plasma membrane of HT29 cells. Cisplatin-mediated increases in Fas expression were confirmed in HCT8R, HCT116, and U937 cells. The enhancement of Fas protein expression was associated with an increased sensitivity of cisplatin-treated tumor cells to agonistic anti-Fas antibodies, to soluble Fas ligand, and to allogeneic peripheral blood leukocyte-mediated cytotoxicity. Each of these effects was blocked by co-treatment of the cells with antagonistic anti-Fas antibody. CONCLUSION AND IMPLICATIONS: In addition to their direct cytotoxic effects, chemotherapeutic drugs sensitize tumor cells to Fas-mediated cytotoxicity and Fas-dependent immune clearance. On the basis of these findings, new strategies might be developed to improve the efficacy of these drugs.

Animals↗

PubMed1997

In vitro determination of cytotoxic drug response in ovarian carcinoma using the fluorometric microculture cytotoxicity assay (FMCA).

The fluorometric microculture cytotoxicity assay (FMCA), a short-term in vitro assay based on the concept of total tumor cell kill, was used for testing the cytotoxic drug sensitivity of tumor cells from patients with ovarian carcinoma. A total of 125 fresh specimens was obtained, 98 (78%) of which were analyzed successfully. Data from 45 patients were available for clinical correlations. The FMCA appeared to yield clinically relevant cytotoxic drug sensitivity data for ovarian carcinoma as indicated by a comparison with tumor samples obtained from patients with non-Hodgkin's lymphoma or kidney carcinoma. Considering the most active single agent in vitro actually given in vivo, and using the median drug activity among all ovarian carcinoma samples as a cut-off, the sensitivity of the assay and its specificity were 75 and 52%, respectively. Cross-resistance in vitro was frequently observed between standard drugs but not between standard drugs and Taxol. Ten percent of the specimens showed an extreme resistance for at least 4 of 6 of the drugs investigated.

Antineoplastic Agents↗

PubMed1991

Ovarian and testicular damage by cytotoxic drugs.

The use of cytotoxic drugs has improved the survival figures in malignancies. These drugs exert harmful effects on the tumour cell and normal cells as well. The detrimental effects on gonads were studied in 36 patients who had cytotoxic chemotherapy for various malignancies. In Group I (20 adults in clinical remission after chemotherapy), sterility was noted in 93.7% of men and hundred percent of women experienced irregularly mensus during treatment, 50% of them subsequently developing persistent amenorrhoea. In Group II, (16 adults undergoing chemotherapy) 100% of men had oligospermia, with 75% of them developing azoospermia after 2-3 cycles of treatment. Women also showed similar effect, but were less vulnerable than men.

Adolescent↗

PubMed1984

Legal issues associated with the handling of cytotoxic drugs.

Legal issues associated with the handling of cytotoxic drugs are discussed. The essential legal elements of negligence and proof requirements are briefly reviewed as they relate to the liability of various parties for injury caused or aggravated by the handling of cytotoxic drugs. Legal remedies in these cases--such as workmen's compensation claims, claims against independent contractors, and claims against product manufacturers--are outlined, and common defenses to product-liability cases are presented. The legal basis for determining liability for injury associated with the handling of cytotoxic drugs and the remedies available for such injury should be familiar to hospital administrators, drug manufacturers, and all personnel dealing with these drugs.

Antineoplastic Agents↗

PubMed1994

Cytotoxic drug sensitivity testing of tumor cells from patients with ovarian carcinoma using the fluorometric microculture cytotoxicity assay (FMCA).

The automated fluorometric microculture cytotoxicity assay (FMCA) is based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA) to fluorescein by viable cells after a 72-hr culture period in microtiter plates. The FMCA was adopted for chemosensitivity testing of tumor cells from patients with ovarian carcinoma. Thirty-seven samples of solid tumors and malignant effusions were obtained from 35 patients at diagnosis or relapse. Tumor cells from solid samples and effusions were prepared by enzymatic digestion and centrifugation, respectively, followed by Percoll or Ficoll purification. The fluorescence was proportional to the number of cells/well and considerably higher in tumor cells than in contaminating normal cells. The effect of up to 19 cytotoxic drugs was successfully assessed in 70% of the samples and there was a good correlation between drug sensitivity data reported by the FMCA and the DiSC assay performed in parallel. The overall drug sensitivity pattern in vitro corresponded well to the clinical experience. The effect of cisplatin varied considerably between patients and resistance was found also in cases not previously exposed to cytotoxic drugs. The FMCA is a rapid and simple method that seems to report clinically relevant cytotoxic drug sensitivity data in ovarian carcinomas. In the future, this method may contribute to optimizing chemotherapy by assisting in individualized drug selection and new drug development.

Antineoplastic Agents↗

PubMed2005

Environmental contamination with cytotoxic drugs in healthcare using positive air pressure isolators.

Occupational exposure to cytotoxic drugs of hospital personnel involved in their preparation and administration is a major issue: ever since the introduction of protective measures in recent decades, the handling of these drugs has always been referred to as an occupational health hazard. Isolator technology was one of the protective equipments aimed at providing safe handling, but it has not yet been studied regarding contamination. The present study evaluates surface contamination with four cytotoxic drugs [cyclophosphamide (CP), ifosfamide (IF), 5 fluorouracil (5FU) and methotrexate (MTX)] by wipe sampling in two hospital pharmacies. Wipe samples were taken from work surfaces both located inside and outside the isolators. In addition, working gloves, the surface of infusion bags filled with 5FU or CP, and gloves used in simulation of drug administration were analyzed. Contamination was routinely found inside the isolators but rarely outside the isolators, indicating that the isolator technology is offering good protection of the cytotoxic drug handlers as well as the environment during preparation. On the other hand, contamination was found on the surfaces of infusion bags and gloves in contact with infusion bags filled with cytotoxic drugs. Consequently, personal protective equipment is still recommended during the manipulation and administration of the drugs because of potentially contaminated drug vials and final products.

Antineoplastic Agents↗