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PubMed2000

Human cytochrome P450 maximal activities in pediatric versus adult liver.

Drug clearance is often higher in children than in adults, particularly when normalized to body weight. We previously showed that liver volume normalized to body weight was inversely related to age, but that the systemic clearance of a nonspecific cytochrome P450 (CYP) substrate (antipyrine) was higher in young children compared with adults even when normalized per liver volume. Our purpose herein was to evaluate whether P450 catalytic activities, expressed as maximal catalytic rates per milligram of microsomal protein, differed in up to 37 normal livers from subjects <10 (range 0.5-9 years of age), >10 but <60 years of age (range 10-59 years), and >60 year (range 63-93 years of age). There were no age-related differences in the oxidation of ethoxyresorufin (P =.83) (CYP1A2), ethoxycoumarin (P =.52) (CYP2E1 and other P450s), teniposide (P =. 58), midazolam (P =.47) (CYP3A4/3A5), or paclitaxel (P =.24) (at the 17alpha position, CYP2C8). Tolbutamide hydroxylation tended to be lower in children versus adults (P =.047) (CYP2C9), but did not reach statistical significance after correcting for multiple comparisons. No relationship was found to exist between age and microsomal recovery (P =.98); thus, recovery did not account for the lack of age-related differences in catalytic activity. We conclude that increased intrinsic cytochrome P450 activity is unlikely to account for increased clearance of most P450 drug substrates in children.

Adolescent↗

PubMed1999

Lung cancer.

The results of the many clinical trials published in 1997 had only modest impact on the treatment results using either cytostatic agents alone or combined with radiotherapy in lung cancer. In SCLC, combination chemotherapy including platin-compounds (cisplatin, carboplatin) and the podophyllotoxins (etoposide and teniposide) continue to be the cornerstone of therapy. Complete plus partial responses to combination chemotherapy occurs in 80-90% of all patients. Median survival is at present 11-17 months, and overall 5-year survival approximately 5% depending on the initial tumor stage. The duration of treatment has been shortened to 5-6 months. In relapsing patients topotecan and paclitaxel appear to have clinical useful activity. For epidermoid, adeno- and large cell carcinoma further support has arisen for the use of preoperative and preirradiatory chemotherapy in stage III NSCLC, but further studies are needed before specific recommendations can be given for general use. For patients with advanced NSCLC, new innovative treatments are still urgently needed. Platin-containing regimens with the inclusion of new agents, such as gemcitabine, taxenes, and navelbine, yielded response rates of 42-55% in phase II trials, but results from large phase III trials are necessary in order to measure the impact of these new agents in the management of NSCLC. Major improvements of therapy for mesothelioma have not occurred within the last year.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Novobiocin-induced VP-16 accumulation and MRP expression in human leukemia and ovarian carcinoma cells.

We have previously reported that novobiocin potentiates the cytotoxic activity of etoposide (VP-16) and teniposide (VM-26) in a number of experimental tumor cell lines by inhibition of the efflux of the epipodophyllotoxins by an ATP-requiring transporter. In leukemia cells from 12/19 patients and in ovarian carcinoma cells from 2/4 patients, novobiocin, in a concentration range of 150-1000 microM, increased the intracellular accumulation of VP-16 by 30-250% by inhibiting its efflux. Novobiocin did not significantly increase the intracellular concentration of VP-16 in human mononuclear bone marrow cells from two individuals with normal bone marrow, suggesting that it might be possible to selectively modulate the intracellular accumulation of the epipodophyllotoxin in tumor cells relative to normal hematopoietic tissue. Previous findings from our laboratory have provided evidence that the membrane transporter for VP-16 which is inhibited by novobiocin is distinct from the P-glycoprotein. The expression of MRP, measured by immunoblotting, was variable in novobiocin-responsive and non-responsive leukemia cells, indicating that no direct relationship existed between the modulatory activity of novobiocin on the transport of VP-16 and the expression of the MRP gene. The findings indicate that the novobiocin-sensitive VP-16 transporter is (i) present in high frequency in leukemia and ovarian carcinoma cells, and (ii) probably not the P-glycoprotein or MRP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Hyperthermia enhanced chemosensitivity of human malignant glioma cells.

In an effort to overcome chemoresistance of human malignant glioma cells, the modulation of drug-induced cell death by hyperthermia was assessed in 4 human malignant glioma cells lines, LN-18, LN-229, T98G and U87MG. Compared to normothermic conditions, pulsed 24 h drug exposure enhanced the sensitivity of glioma cells most strikingly with teniposide, treosulfan, topotecan and cisplatin, moderately with vincristine, CCNU and doxorubicin, but not with gemcitabine. Susceptibility to hyperthermia-mediated drug sensitization, varied significantly with T98G and LN-229 being strongly sensitized and U87MG being most resistant to the effects of hyperthermia. Hyperthermia did not significantly modulate drug-induced changes in cell cycle distribution. The degree of sensitization was independent of p53 status and of multidrug resistance (mdr) activity. Hyperthermia may thus be a useful approach to overcome, chemoresistance of human malignant glioma cells.

Antineoplastic Agents↗

PubMed2000

Cellular drug resistance profiles in childhood acute myeloid leukemia: differences between FAB types and comparison with acute lymphoblastic leukemia.

Determining in vitro drug resistance may reveal clinically relevant information in childhood leukemia. Using the methyl-thiazol-tetrazolium assay, the resistance of untreated leukemic cells to 21 drugs was compared in 128 children with acute myeloid leukemia (AML) and 536 children with acute lymphoblastic leukemia (ALL). The differences between 3 French-American-British (FAB) types (M1/M2, M4, and M5) were also compared. AML was significantly more resistant than ALL to the following drugs, as noted by the median resistance: glucocorticoids (greater than 85-fold), vincristine (4.4-fold), L-asparaginase (6.9-fold), anthracyclines (1.8- to 3.4-fold), mitoxantrone (2.6-fold), etoposide (4.9-fold), platinum analogues (2.4- to 3.4-fold), ifosfamide (3.5-fold), and thiotepa (3.9-fold). For cytarabine and thiopurines, the median LC50 values (the drug concentration that kills 5% of the cells) were equal. Also, busulfan, amsacrine, teniposide, and vindesine showed no significant differences, but the numbers were smaller, and the median LC50 values were 1.3- to 5.2-fold higher in AML. None of the drugs demonstrated greater cytotoxicity in AML. FAB M5 was significantly more sensitive than FAB M4 to most drugs frequently used in AML, as indicated by the following ratios of median sensitivities: the anthracyclines (2.6- to 3.2-fold), mitoxantrone (12.5-fold), etoposide (8.7-fold), and cytarabine (2.9-fold). For etoposide and cytarabine (5.4- and 3.4-fold, respectively) FAB M5 was also significantly more sensitive than FAB M1/M2. FAB M5 was equally sensitive to L-asparaginase and vincristine as ALL. Only 15% of the AML samples were "intermediately" sensitive to glucocorticoids, mainly in FAB M1/M2. The poorer prognosis of childhood AML is related to resistance to a large number of drugs. Within AML, FAB M5 had a distinct resistance pattern. These resistance profiles may be helpful in the rational design of further treatment protocols. (Blood. 2000;96:2879-2886)

Acute Disease↗

PubMed2001

[Hypercalcemia due to adult T-cell lymphoma in a man from Surinam].

A 48-year-old male patient from Surinam presented with anorexia, nausea and weight loss. An extreme hypercalcaemia of 5.08 mmol/l was found. Further diagnostic investigations showed that this patient had a HTLV-1 positive adult T-cell leukaemia/lymphoma (ATL/L). This is often associated with multilobularly nucleated lymphocytes, bone destruction and hypercalcaemia. Skin localisations are frequently observed. The combination of cytomorphology, immunophenotyping, HTLV-1 seropositivity and clinical findings points to the diagnosis. The patient was treated with 6 courses of chemotherapy consisting of cyclophosphamide, doxorubicin, teniposide, prednisone, vincristine and bleomycin. Upon inquiry it appeared that he had died elsewhere. Chemotherapy induces a short-lived remission in a minority of ATL/L patients. Antiviral therapy (alpha interferon, zidovudine) might offer new possibilities.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

[Determination of etoposide (VP16) in human serum by high performance liquid chromatography].

A rapid high performance liquid chromatographic method for the determination of etoposide (VP16) in human serum has been developed. The samples were added teniposide (VM26) as an internal standard, extracted with ethyl acetate and chromatographed on a reversed phase YWG-C18 column with UV detection at 254 nm. The mobile phase was CH3OH:H2O = 55:45 (V/V). The calibration curve was Y = 0.0160 + 0.034X, r = 0.9991. It was reticlinear in the range between 0.5-50 mg/L. The detection limit was 0.1 mg/L. The average recovery was 95.0% +/- 0.2%. Intra-day and inter-day RSD were 4.16% and 4.76% respectively. From the results it can be concluded that this method is reliable. This method has been used to determine VP16 concentration in patient serum. The data obtained showed that the sensitivity and selectivity of this method were adequate for drug monitoring in clinical research.

Antineoplastic Agents, Phytogenic↗

PubMedDate not supplied

Controversies in the management of brain metastases: the role of chemotherapy.

The role of chemotherapy (CT) for brain metastases (BrM) is still controversial. Limited life expectancy and presence of the blood-brain barrier (BBB) have been considered as contraindications for relatively aggressive therapies, such as CT. Nevertheless, more recent studies emphasise the possibility that in addition to historical nitrosoureas, also platinum derivatives, etoposide, teniposide, gemcitabine, irinotecan, topotecan and temozolomide can pass the BBB as they are active against selected BrM. Interaction of cytotoxic agents with other drugs may represent a problem in the treatment of BrM. By far, the most important factor conditioning the response to cytotoxic agents is the chemosensitivity of different tumours. CT proved to be effective in patients with BrM from lung cancer, mainly small cell lung cancer, breast cancer, choriocarcinoma and germ cell tumours. In these malignancies the responses to CT are similar to those observed in other metastatic sites. This observation, confirmed by many studies, contrasts with the theory, emphasised in the past, of the brain as a sanctuary. In fact BBB may be important in protecting normal brain tissue and micrometastases from CT, but not when BrM are symptomatic and clinically evident. The clue to the treatment of chemosensitive tumours is to assess the most active drugs and combinations. Cisplatin and etoposide was confirmed to be the treatment of choice in many situations (BrM from lung and also from breast cancer). Newer drugs are now on study: topotecan and temozolomide seem to be particularly promising (alone or in association with other drugs) in the treatment of various BrM (also from melanoma) and could represent an alternative to more widely-used drugs or as second-line treatments.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Recent advances in traditional plant drugs and orchids.

The main objective of this paper is to review recent advances in plant drug research and developments in orchid study, in an attempt to provide useful references for plant drug studies. Plants have been used as medicine for millennia. Out of estimated 250 000 to 350 000 plant species identified so far, about 35 000 are used worldwide for medicinal purposes. It has been confirmed by WHO that herbal medicines serve the health needs of about 80 percent of the world's population; especially for millions of people in the vast rural areas of developing countries. Meanwhile, consumers in developed countries are becoming disillusioned with modern healthcare and are seeking alternatives. The recent resurgence of plant remedies results from several factors: 1) the effectiveness of plant medicines; 2) the side effect of most modern drugs; and 3) the development of science and technology. It has been estimated that in the mid-1990s over 200 companies and research organizations worldwide are screening plant and animal compounds for medicinal properties. Actually, several important drugs used in modern medicine have come from medicinal plant studies, eg, taxol/paclitaxel, vinblastine, vincristine, topotecan, irinotecan, etoposide, teniposide, etc. As for drugs derived from orchids, some novel discoveries, both in phytochemical and pharmacological properties, were reported by some universities. However, studies on plants are very limited. Only about a third of the million or so species of higher plants have been identified and named by scientists. Of those named, only a tiny fraction has been studied. Nowadays the linking of the indigenous knowledge of medicinal plants to modern research activities provides a new approach, which makes the rate of discovery of drugs much more effective than with random collection.

History, Ancient↗

PubMed2003

Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein.

The breast cancer resistance protein [BCRP (BCRP/ABCG2)] has not previously been directly identified as a source of resistance to epipodophyllotoxins.However, when P-glycoprotein (P-gp)- and Mrp1-deficient mouse fibroblast and kidney cell lines were selected for resistance to etoposide, amplification and overexpression of Bcrp1 emerged as the dominant resistance mechanism in five of five cases. Resistance was accompanied by reduced intracellular etoposide accumulation. Bcrp1 sequence in all of the resistant lines was wild-type in the region spanning the R482 mutation hot spot known to alter the substrate specificity of mouse Bcrp1 (mouse cognate of BCRP) and human BCRP. Transduced wild-type Bcrp1 cDNA mediated resistance to etoposide and teniposide in fibroblast lines and trans-epithelial etoposide transport in polarized Madin-Darby canine kidney II cells. Bcrp1-mediated etoposide resistance was reversed by two structurally different BCRP/Bcrp1 inhibitors, GF120918 and Ko143. BCRP/Bcrp1 (inhibition) might thus impact on the antitumor activity and pharmacokinetics of epipodophyllotoxins. However, treatment of P-gp-deficient mice with GF120918 did not improve etoposide oral uptake, suggesting that Bcrp1 activity is not a major limiting factor in this process. In contrast, use of GF120918 to inhibit P-gp in wild-type mice increased the plasma levels of etoposide after oral administration 4-5-fold. It may thus be worthwhile to test inhibition of P-gp in humans to improve the oral availability of etoposide.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1992

Lung cancer.

In small cell lung cancer, combination chemotherapy including agents such as etoposide, teniposide, cisplatin, doxorubicin, vincristine and cyclophosphamide continues to be the backbone of therapy. Epipodophyllotoxin derivatives, together with cisplatin, are used increasingly as part of the initial therapy. Complete plus partial responses to combination chemotherapy still occur in 80-90% of all patients with a median duration of 9-11 months. Median survival in these studies is at present 11-16 months depending on the initial tumour stage. Deaths from small cell lung cancer continue to occur until 7 years after diagnosis, but rarely thereafter. At this point, overall survival is around 5% and include a small fraction of patients (1%) initially presenting with extensive disease. The optimum duration of treatment is still uncertain. For patients with extensive disease, the use of alternating chemotherapy has been shown in a couple of randomized studies to yield the best results, as judged by long-term survival. The results of several phase II studies stress the importance of dose scheduling of etoposide in small cell lung cancer, with continuous treatment of 5 days' duration or more being superior. The therapeutic results for epidermoid, adenoid, large cell carcinoma and mesothelioma are essentially unchanged. The treatment of patients with these types of lung cancer should continue to be considered experimental, since no standard chemotherapy has as yet been developed, neither when given as single modality nor in combination with surgery or radiotherapy. One single study comparing induction chemotherapy before irradiation vs irradiation alone has resulted in an improvement of median survival of 4 months and doubled the number of long-term survivors. Since three-fourths of the patients with locoregional disease will die within 3 years, further improvements in both systemic and local treatment are needed.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Chemotherapy induced gastrointestinal toxicity in rats: involvement of mitochondrial DNA, gastrointestinal permeability and cyclooxygenase -2.

PURPOSE: The gastrointestinal damage induced by xenobiotics is occurring more frequently and with greater toxicological significance than previously thought. Although there are some preliminary clinical studies and reports, there does not appear to be an extensive examination of gastrointestinal toxicity of various chemotherapeutic agents in the rat. This study was undertaken to examine the suitability of a rat model to detect the gastrointestinal damage after administration of various anti-neoplastic agents including etoposide, teniposide, melphalan, 5-fluorouracil, methotrexate and cisplatin. METHODS: Acute toxic doses of indomethacin and chemotherapeutic agents were administered to rats. The urinary excretion of orally administered sucrose and 51(Cr)-EDTA were measured as markers of gastroduodenal and intestinal permeability, respectively. Cyclooxygenase-2 messenger RNA and mitochondrial DNA damage were measured as toxicological endpoints. RESULTS: Each anti-neoplastic agent examined induced appreciable and significant dose-dependent increase in gastrointestinal permeability that correlated with gross toxicological and pathological changes to the gastrointestinal tract including ulceration and bleeding. COX-2 mRNA was upregulated > 2 fold in intestinal mucosa with enteropathy and dose-dependent mitochondrial oxidative damage was apparent in gastric and intestinal mucosa. After administration of each drug, the rats presented with histological evidence of drug-induced gastroenteropathy, ulceration and increased cecal hemoglobin. CONCLUSIONS: The rat appears to be a suitable model to study gastrointestinal toxicity of chemotherapeutic agents and non-steroidal anti-inflammatory drugs. Damage to mitochondrial DNA occurs in both the gastric and intestinal epithelium after the administration of these agents and may be an important factor in the pathogenesis and resolution of gastrointestinal toxicity.

Animals↗

PubMed1992

[Primary hepatic lymphoma in subjects with acquired immunodeficiency syndrome].

In this study the authors describe a non-Hodgkin's lymphoma histologically typed "large non-cleaved cell immunophenotype B cell", placed primitively into the liver. It affected a woman twenty seven years old, who contracted HIV infection due to heterosexual intercourse with at risk partner. At the time of diagnosis the woman was already considered AIDS patient on account of a previous Pneumocystis carinii pneumoniae and severe immunodeficiency (DC4 = 13 cells/mm3). The patient received cycles of chemotherapy (adriamycin 40 mg/iv, teniposide 50 mg/iv, cyclophosphamide 500 mg/iv, vincristine 2 mg/iv, bleomycin 15 mg/iv, betamethasone 4 mg/iv). At the 15th day of therapeutic cycle vincristine 2 mg/iv, bleomycin 15 mg/iv and betamethasone 4 mg/iv were given. After one cycle of therapy, hepatic echography showed signs that the lymphoma was reduced significantly. The authors stress the uncommon non-Hodgkin lymphoma localization, which is frequently underestimated in HIV-patients.

Acquired Immunodeficiency Syndrome↗

PubMed1992

Relationship of VP-16 to the classical multidrug resistance phenotype.

The classical multidrug resistance (MDR) phenotype is characterized by cross-resistance between a number of chemically unrelated drugs due to an increased efflux across the plasma membrane via a P-glycoprotein-mediated mechanism. The epipodophyllotoxin derivatives etoposide (VP-16) and teniposide (VM-26) are usually included among the drugs recognized by this MDR phenotype, and the MDR EHR2/DNR cell line is greater than 50-fold cross-resistant to VP-16. The steady-state accumulation of VP-16 in EHR2/DNR cells is only half that of wild-type EHR2 cells, and deprivation of energy by sodium azide surprisingly increased accumulation to a similar extent in both sublines. Efflux was rapid (halflife of 32-35 s) and similar in both sublines, while initial influx was markedly lower in the resistant cells. The temperature coefficients over 10 degrees C for VP-16 in- and efflux indicated passive transport in both sublines. In agreement with this finding, up to 10-fold molar excess (50 microM) VM-26 had no effect on VP-16 accumulation in MDR cells. VP-16 at a 100-fold molar excess inhibited azidopine photoaffinity labeling of P-glycoprotein by only 30% and vincristine binding to plasma membrane vesicles from EHR/DNR cells by 45%. However, VP-16 itself did not differentially bind to plasma membrane vesicles from EHR2 and EHR2/DNR cells. Finally, neither VP-16 accumulation nor cytotoxicity in EHR2/DNR cells were increased to the same degree as for daunorubicin and vincristine by verapamil, and the modulation was similar in wild-type and resistant cells. Thus, although VP-16 may be a substrate for P-glycoprotein, its other transport characteristics such as rapid diffusion and sensitivity to membrane perturbation in wild-type cells lessen any effect of P-glycoprotein-mediated efflux, resulting in a lack of differential modulation by verapamil. These results may be considered when planning clinical trials involving MDR modulators and epipodophyllotoxin derivatives.

Affinity Labels↗

PubMed2005

[Transfection of HL-60 cells with CYP3A5 gene induces drug-resistant phenotype].

OBJECTIVE: To investigate if CYP3A5 gene is involved in the molecular mechanisms for multiple drug resistance in leukemia cells. METHODS: A full length cDNA of CYP3A5 gene was cloned, and a recombinant eukaryotic expression plasmid was constructed, then stably transfected cell lines were established. Furthermore, the sensitivity of those cell lines to several anticancer drugs were assessed by MTT and FCM assay. RESULTS: The recombinant plasmid was designated as pcDNA3-CYP3A5. Transfecting HL-60 cells (which didn't show transcript of CYP3A5 gene) with recombinant plasmid pcDNA3-CYP3A5 generated HL-60/CYP3A5 cell line, and transfecting of HL-60 cells with the parental pcDNA3 vector served as control HL-60/pc cell line. Daunorubicin induced remarkable apoptosis peaks in HL-60 and HL-60/pc cells, while such effect did not occur in HL-60/CYP3A5 cells (apoptosis cell percentage were 7.3%, 6.3% and 1.2%, respectively). Compared with HL-60 and HL-60/pc cells, HL-60/CYP3A5 cells were statistically significantly resistant to daunorubicin, aclacinomycin A, vincristine and harringtonine (resistance multiples were 2.89, 2.01, 4.05 and 2.79 times, respectively, P < 0.05), however the sensitivity to teniposide didn't change (resistance multiple was 1.04 times). CONCLUSION: Transcription of CYP3A5 gene in leukemia cells directly induces resistance to anthracyclines and alkaloids, however the cells are still sensitive to epipodophyllotoxins. Therefore, our findings confirmed a new mechanism of multidrug resistance.

Aclarubicin↗

PubMed1991

Increased phosphorylation of DNA topoisomerase II in etoposide-resistant mutants of human cancer KB cells.

We have isolated two etoposide (VP16)-resistant cell lines, KB/VP-1 and KB/VP-2, from human cancer KB cells after stepwise exposure to increasing doses of VP16. KB/VP-1 and KB/VP-2 showed 30- and 50-fold higher resistance to VP16 and also 20- and 30-fold higher resistance to teniposide than the parent cell line. Furthermore, both resistant cell lines showed more than 2-fold cross-resistance to Adriamycin and daunomycin than KB cells. The levels of accumulation and outward transport of radioactive VP16 were similar in KB/VP-1, KB/VP-2, and KB. The activity of nuclear extracts of DNA topoisomerase II for both KB/VP-1 and KB/VP-2 assayed by decatenation of kinetoplast DNA was consistently similar to that of KB. However, in both immunoblot assay with specific anti-topoisomerase II antibody and Northern blot analysis with specific human DNA topoisomerase II complementary DNA, cellular levels of topoisomerase II in both resistant cell lines were less than one-tenth the level in KB. The cellular levels of DNA topoisomerase I, however, were similar between the mutants and their parent. A quantitative precipitation assay of covalent DNA-topoisomerase II complexes showed greatly reduced VP16-induced cleavages of 3'-32P-DNA by nuclear extracts of KB/VP-1 or KB/VP-2 cells in comparison with KB cells. The relative specific phosphorylation of DNA topoisomerase II was about 14- to 18-fold higher in the mutants than in the parental cells. Phosphoamino acid analysis of DNA topoisomerase II showed that serine was the phosphorylated amino acid in all three cell lines, KB, KB/VP-1, and KB/VP-2. These data suggest that reduced expression of DNA-topoisomerase II might account for the acquired VP16 resistance and reduced VP16-induced cleavages of DNA-topoisomerase II complexes in both VP16-resistant variants.

Carcinoma, Squamous Cell↗

PubMedDate not supplied

[The interactions of antiepileptic drugs in oncology practice].

AIMS: Antiepileptic drugs, which often have to be used in patients with cancer, can have important effects on the results offered by antineoplastic agents. Here, we review the influence of antiepileptic drugs on antineoplastic agents and the influence of antineoplastic agents on antiepileptic drugs; measures to prevent such interactions are also suggested. DEVELOPMENT: Antiepileptic drugs that induce cytochrome P450, such as carbamazepine, phenytoin and phenobarbital, can reduce the levels and effects of antineoplastics that metabolise by means of this enzyme, for example, taxanes, Vinca alkaloids, methotrexate, teniposide and camptothecin. Furthermore, enzyme-inducing antiepileptic drugs diminish the levels and effects of many other drugs that can be administered to oncology patients, such as other antiepileptic drugs used in polytherapy, narcotic analgesics, antidepressants, antipsychotics or antibiotics. In contrast, valproate can increase the toxicity of etoposide or nitrosoureas. Moreover, antineoplastic agents like cisplatin or corticoids can lower the effectiveness of phenytoin and methotrexate has a similar effect on valproate. In contrast, 5-fluorouracil can increase the toxicity of phenytoin. Pharmacodynamic interactions are also possible. CONCLUSIONS: Information about the clinical consequences of the interactions between antiepileptics and antineoplastic agents is often based on cases or series of cases, but a growing body of evidence from pharmacokinetic studies shows that enzyme-inducing antiepileptics exert an important influence on the effectiveness of the antineoplastic agents. It is therefore recommendable to avoid them and replace them with non-enzyme-inducing antiepileptics, such as gabapentin, lamotrigine, levetiracetam, pregabalin, topiramate or zonisamide. When enzyme-inducing antiepileptics have to be used, it is likely that higher doses of antineoplastic agents or other inducible drugs will have to be utilised.

Anticonvulsants↗

PubMed1991

The frequency and management of infectious episodes and sepsis in small cell lung cancer patients receiving intensive chemotherapy with granulocyte-colony stimulating factor.

The relation between degree of myelosuppression and episodes of infection was analyzed in 36 patients (92 treatment courses) with small cell lung cancer (SCLC) treated with intensive chemotherapy. The two regimens used were cisplatin (CDDP) + adriamycin (ADR) + cyclophosphamide (CPA) + etoposide (VP-16) + granulocyte-colony stimulating factor (G-CSF) and CDDP + teniposide (VM-26) + G-CSF, and they induced grade 3 or 4 leukopenia in 88% of treatment courses and febrile episodes in 60%. In the febrile courses, the mean nadirs of leukocyte and neutrophils (820 +/- 581/mm3, 101 +/- 267/mm3) were significantly longer (P less than 0.01) and the mean durations of grade 3 and 4 leukopenia and neutropenia significantly longer (P less than 0.001) than those of the non-febrile courses. It was noted, however, that febrile episodes appeared frequently in courses having the nadir of leukocytes below 1,000/mm3 (80%) or the nadir of neutrophils below 100/mm3 (74%). The administration of antibiotics was required for about 7 days to patients with febrile episodes. Sepsis was experienced in five courses, in which the neutrophils were all zero. All the patients, however, could be managed by an administration of antibiotics immediately after a febrile episode appeared, without delaying the subsequent chemotherapy except for one patient, who had had a performance status (PS) of 3 prior to chemotherapy.

Adult↗