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Biomedical subjects

G Giaccone

Publications and source records attributed to G Giaccone.

At least 91 records · Page 5Linked to original sources
PubMed2000

Synergistic effect of KRN7000 with interleukin-15, -7, and -2 on the expansion of human V alpha 24+V beta 11+ T cells in vitro.

KRN7000, (2S, 3S, 4R)-1-O-(alpha-D-galactopyranosyl)-2-(N-hexacosanoylamino)-1, 3, 4-octadecanetriol, has been shown to prevent tumor metastasis to the liver through the activation of natural killer (NK) T cells in mice. In this study, the proliferation of human NK T cells, which express an invariant T cell antigen receptor (TCR) consisting of a Valpha24 chain and a Vbeta11 chain, was investigated using KRN7000, interleukin (IL)-15, IL-7, and IL-2 in vitro. KRN7000 stimulated the expansion of Valpha24(+)Vbeta11(+) T cells derived from peripheral blood mononuclear cells in a dose-dependent fashion, with some fluctuation between donors. IL-15, IL-7, and IL-2 synergistically stimulated the expansion of Valpha24(+)Vbeta11(+) T cells when combined with KRN7000. Intracellular expression of interferon (IFN)-gamma and IL-4 in Valpha24(+)Vbeta11(+) T cells expanded in the presence of KRN7000 was identified using flow cytometry. Valpha24(+)Vbeta11(+) T cells, expanded in the presence of KRN7000, contained granzyme (Gr) B-positive granules and perforin-positive granules. The addition of IL-15 to the culture containing KRN7000 increased GrB expression in Valpha24(+)Vbeta11(+) T cells while IL-7 and IL-2 failed to do it. In conclusion, the antitumor effect of KRN7000 may depend, in part, on granule-mediated cell killing through the activation of NK T cells and IL-15 may potentiate this effect.

Adjuvants, Immunologic↗
PubMed2000

A bone biopsy is mandatory in the optimal management of bone lesions in patients with a long-term history of malignancy of the breast.

Bone lesions, present in two women with primary breast cancer treated more than 5 years ago, were investigated thoroughly by biochemical markers and imaging techniques. The definite diagnosis was established by bone biopsy, which revealed two totally unrelated disorders that altered the management and prognosis for these two patients. One patient had Paget's disease, and the other had metastatic hepatocellular carcinoma.

Aged↗
PubMed2000

Severe acute lung injury induced by gemcitabine.

Gemcitabine is a nucleoside analog that is active in the treatment of various solid tumors. In general it is well tolerated and has few side effects. Pulmonary toxicity reported with gemcitabine use is usually mild and self-limiting. We present a case of severe pulmonary dysfunction after intravenous administration of a single dose of gemcitabine in a 58-year-old female patient with metastatic carcinoma of the pancreas. She developed tachypnea, marked hypoxemia, and an interstitial infiltrate on chest radiograph consistent with pulmonary edema, 4 days after receiving this drug. Diuretics and corticosteroids were beneficial in treating the acute respiratory failure. Pulmonary damage was completely resolved by means of clinical and radiological assessment. Because of the severity of this side effect, no further treatment with gemcitabine was given. Eventually, the patient died because of obstruction of the bowel due to progression of tumor growth. Publications concerning severe pulmonary toxicity due to gemcitabine are sparse. Pathophysiology and treatment are considered and a review of the literature is presented.

Acute Disease↗
PubMed2000

Cross-resistance in the 2',2'-difluorodeoxycytidine (gemcitabine)-resistant human ovarian cancer cell line AG6000 to standard and investigational drugs.

Gemcitabine (2'-2'-difluorodeoxycytidine; dFdC) is a deoxycytidine analogue which is effective against solid tumours, including lung cancer and ovarian cancer. dFdC requires phosphorylation by deoxycytidine kinase (dCK) for activation. In the human ovarian cancer cell line A2780 and its 30,000-fold dFdC-resistant variant AG6000 (P<0.001), we investigated the cross-resistance profile to several drugs. AG6000, which has a complete dCK deficiency, was approximately 1000-10,000-fold resistant to other deoxynucleoside analogues such as 1-beta-D-arabinofuranosyl cytosine, 2-chloro-deoxyadenosine, aza-deoxycytidine and 2', 2'-difluorodeoxyguanosine (dFdG) (P<0.001). dFdG can be activated by dCK and deoxyguanosine kinase (dGK), but the latter enzyme was not altered in AG6000 cells. Thus dFdG resistance was only due to dCK deficiency. AG6000 was 1.6- and 46.7-fold resistant to 5-fluorouracil (5-FU) and ZD1694, respectively (the latter was significant; P<0.01), which may be due to the 1.7-fold higher thymidylate synthase (TS) activity, but AG6000 cells were also 2. 7-fold resistant to the lipophilic TS inhibitor AG337 (P<0.05). Remarkably, AG6000 cells were 2.5-fold more sensitive to methotrexate (MTX) (P<0.01) than A2780 cells, but 1.6-fold more resistant to trimetrexate (TMQ) (P<0.10). However, no differences in reduced folate carrier activity, folylpolyglutamate synthetase (FPGS) activity and polyglutamation of MTX were found between the cell lines. AG6000 cells were approximately 2 to 7.5-fold more resistant to doxorubicin (DOX), daunorubicin (DAU), epirubicin and vincristine (VCR) (the latter was significant; P<0.02) and approximately 4-fold more resistant to the microtubule inhibitors paclitaxel and docetaxel (P<0.001). Fluorescent activated cell sorter (FACS) analysis revealed no P-glycoprotein (Pgp) or multidrug resistance-associated protein (MRP) expression, but less fluorescence of intercalated DAU in AG6000 cells. An approximately 2-fold resistance to the topoisomerase I and II inhibitors etoposide, CPT-11 and SN38 was found in AG6000 cells. Topoisomerase I and IIalpha RNA expression was decreased in AG6000 cells. AG6000 was 2.4, 2.4, 2.3 and 3.7-fold more resistant to EO9 (P<0.02), mitomycin-C (MMC) (P<0.05), cisplatin (CDDP) (P<0.10) and maphosphamide (MAPH), respectively. DT-diaphorase (DTD), which activates EO9, was 2.2-fold lower in AG6000 cells. CDDP resistance might be related to a reduced retention of DNA adducts in AG6000. However, glutathione levels were equal in A2780 and AG6000 cells. A 24 h exposure to DOX, VCR and paclitaxel at equimolar and equitoxic concentrations, resulted in more double-strand breaks (1.5- to 2-fold) in A2780 than in AG6000 cells. MAPH at 1120 nM and 17 nM of EO9 did not cause DNA damage in either cell line. In conclusion, AG6000 is a cell line highly cross-resistant to a wide variety of drugs. This cross-resistance might be related to altered enzyme activities and/or increased DNA repair.

Antineoplastic Agents, Phytogenic↗
PubMed2000

Schedule-dependent pharmacodynamic effects of gemcitabine and cisplatin in mice bearing Lewis lung murine non-small cell lung tumours.

The combination of 2',2'-difluorodeoxycytidine (gemcitabine, dFdC) and cis-diammine-dichloroplatinum(II) (cisplatin, CDDP) is increasingly applied in clinical oncology. We studied the underlying mechanisms of the in vivo schedule dependency and supraadditive interaction between dFdC and CDDP in C57/B16 mice bearing Lewis lung (LL) tumours. Mice were treated with CDDP (6 mg/kg) and dFdC (60 mg/kg) either simultaneously or in a 4 or 24 h interval with dFdC preceding CDDP or vice versa. Four, 8 (in some cases 12) and 24 h after treatment mice were sacrificed and tumours, kidneys, blood and bone marrow (BM) were collected. Since CDDP acts by formation of Platinum (Pt)-DNA adducts and dFdC by incorporation of its triphosphate (dFdCTP) into DNA, we measured total Pt levels, dFdCTP accumulation and Pt-DNA adducts by atomic absorption spectrometry (AAS), high performance liquid chromatography (HPLC) and 2P-postlabelling, respectively. These levels were related to the previously determined antitumour efficacy and toxicity of the dFdC/CDDP combination. Peak dFdCTP accumulation in tumours (11 pmol/mg) was found 4 h after dFdC treatment, while CDDP tended to reduce this in a time-dependent way. Peak levels of total Pt in tumours were found 4 h after CDDP treatment (581 fmol/mg) and dropped 1.8-fold after simultaneous treatment with dFdC (P = 0.04). Treatment with dFdC 4 h after or simultaneously with CDDP increased Pt retention (level 24 h after CDDP treatment) 1.4- and 1.6-fold (P = 0.04 and P = 0.03, respectively). Peak Pt-DNA adduct levels in tumours were also found 4 h after CDDP treatment (7 fmol/microg DNA) and were decreased 3-fold by dFdC treatment 24 h prior to CDDP (P = 0.04). Pt-DNA adduct retention was only decreased when dFdC was given 4 h before CDDP (8-fold (P < 0.01)). The retention and the area-under the concentration time curve of Pt-DNA adducts were related to decreased tumour doubling time (linear regression coefficient (R) = 0.95; P < 0.05, 0.96 P = 0.04 and 0.90; P = 0.04. Pt-DNA adduct levels in the BM cells reached a plateau level 4-24 h after CDDP treatment (approximately 10 fmol/microg DNA), which was increased by dFdC when given either simultaneously with, 4 h before or 4 h after CDDP (6-, 3- and 5-fold at 28 h, 8 h and 28 h, respectively (P < or = 0.04)). Peak Pt-DNA adduct formation (24 h: 8 fmol/microg DNA) in kidneys was enhanced by dFdC when given simultaneously with or 4 h before CDDP (4 h timepoint) (P < 0.01). However, retention was 4- and 6-fold decreased when dFdC was given 4 or 24 h after CDDP, respectively (P < or = 0.01). dFdC given 24 h before CDDP decreased all Pt-DNA adduct levels in kidneys 3-fold or more (P < or = 0.03). Pt-DNA adduct levels were inversely related to kidney toxicity when the most toxic schedule was excluded from the analysis. Peak levels of total Pt in kidneys were reached 24 h after CDDP treatment (4.3 fmol/mg) and the 8 h levels were increased 2-fold by dFdC when given 4 h after CDDP (P = 0.07).

Animals↗
PubMed2000

A phase I-II study of gemcitabine and paclitaxel in advanced non-small-cell lung cancer patients.

Thirty patients with chemotherapy-naïve advanced non-small-cell lung cancer (NSCLC) were given escalating doses of paclitaxel (150, 175, 200 mg/m2) on day 1 in three consecutive cycles, together with a fixed dose of gemcitabine 1000 mg/m2 on days 1 and 8; cycles were repeated every three weeks. The dose escalation of paclitaxel was feasible in the majority of patients. Subsequently, 30 other NSCLC patients received a dose of 200 mg/m2 paclitaxel with gemcitabine 1000 mg/m2 in a phase II study. The major side effect was mild myelosuppression. A response rate of 24% was achieved in 49 fully evaluable patients. This regimen proved to be safe and easy to administer on an out-patient setting, and constitutes now one of the arms of the current EORTC randomized study for advanced NSCLC.

Antimetabolites, Antineoplastic↗
PubMed2000

Caelyx in malignant mesothelioma: a phase II EORTC study.

BACKGROUND: The use of doxorubicin has shown some activity in malignant mesothelioma but prolonged administration is hampered by cardiotoxicity. Caelyx, a new liposomal and pegylated form of doxorubicin has shown a better pharmacokinetic and toxic profile then doxorubicin. In a phase II study, the efficacy and toxicity of Caelyx was tested in previously untreated patients with malignant pleural mesothelioma. PATIENTS AND METHODS: Thirty-three patients who had measurable or evaluable histologically confirmed malignant pleural mesothelioma were included in the study. Caelyx (45 mg/m2) was given i.v. on outpatient base every four weeks for nine cycles or till progression or unacceptable toxicity occurred. RESULTS: Of the 33 patients, 32 were evaluable for toxicity and 31 for response. Two patients had a partial response (6%, 95% confidence interval: 0.2%-20.2%). The median survival was 13 months. Forty percent of the patients received >6 cycles. Toxicity was mild with palmar plantar erythrodysesthesia being most pronounced (62% grade 1-2, 6% grade 3) and of limited duration. Ten percent of patients had grade 3 anemia and 3% grade 3 thrombocytopenia. Two patients (6%) had grade 3 or 4 cardiac toxicity, which was not drug related. CONCLUSION: At the prescribed dose, single agent Caelyx is well tolerated but its activity in chemotherapy-naive mesothelioma patients does not warrant further investigation as a single agent.

Adolescent↗
PubMed2000

Downstream molecular determinants of response to 5-fluorouracil and antifolate thymidylate synthase inhibitors.

Thymidylate synthase (TS) is an essential enzyme for the de novo synthesis of thymidylate and subsequently DNA synthesis. TS has been used as a target for cancer chemotherapy in the development of fluoropyrimidines such as 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine and of novel folate-based TS inhibitors such as ZD1694 (Tomudex, Raltitrexed), ZD9331, LY231514 (ALIMTA, Pemetrexed), AG337 (Thymitaq, Nolatrexed) and AG331. Although TS has been considered as a target for chemotherapy, the precise mechanism by which TS inhibition leads to cell death is still not completely resolved. TS inhibition results in depletion of dTTP, an essential precursor for DNA, and an increase in dUTP. This results in the so-called thymine-less death due to misincorporation of dUTP into DNA; its excision, catalysed by uracil-DNA glycosylase, results in DNA damage. Both this imbalance in dTTP/dUTP and DNA damage can result in induction of downstream events, leading to apoptosis. On the other hand a specific interaction exists between oncogenes and TS, by binding of TS protein to the p53 and c-myc RNA, while wt p53 can also inhibit TS promotor activity. TS inhibition by either 5-FU or antifolates can also result in a depression of TS protein mediated inhibition of TS mRNA translation leading to induction of more TS protein synthesis, and p53 protein may further deregulate this process. These complex indirect and direct interactions between oncogenes and TS may have as yet unclear clinical implications, since most data are based on in vitro or in vivo studies and some results are contradictive. In some preliminary clinical studies evidence was postulated for a combined prognostic role for TS and p53. This knowledge should be used to design clinical studies with the aim to deliver effective treatment to potentially sensitive patients both in the adjuvant setting and in advanced stage disease.

Antimetabolites, Antineoplastic↗
PubMed2000

Skin tests predict survival after autologous tumor cell vaccination in metastatic melanoma: experience in 81 patients.

BACKGROUND: Currently there is no standard adjuvant treatment following surgical resection of metastatic melanoma. We investigated whether surgery followed by autologous tumor cell-BCG vaccination was beneficial for malignant melanoma patients. In this study we focus on the prognostic value of DTH response following vaccination therapy. PATIENTS AND METHODS: Eighty-one patients with AJCC stage III and IV melanoma were selected. Whenever feasible, radical metastasectomy was performed. ASI was initiated by the administration of three weekly intra-cutaneous vaccinations with 10(7) irradiated autologous tumor cells, starting four weeks after surgery. Depending on the size of DTH response to the first three injections, subsequent vaccinations were planned. The first two vaccines also contained 10(7) BCG organisms as an immune stimulatory adjuvant. RESULTS: Induration as well as erythema correlated strongly with survival (P < 0.0001 and P = 0.0004). After radical metastasectomy in stage III melanoma patients a five-year survival of 48% was observed. In stage IV disease, a five-year survival of 34% was seen, after radical surgery had been performed. When macroscopic disease was present at start of vaccination treatment, no clinical responses occurred. Apart from transient skin ulceration at the site of BCG-containing vaccinations, no serious side effects were observed. CONCLUSIONS: This study shows that large-scale preparation of autologous melanoma cell vaccines is feasible. while vaccination results in DTH responses that correlate significantly with survival. ASI seemed to be beneficial in stage III and stage IV melanoma when given in the adjuvant setting, while causing only very mild side effects.

Adjuvants, Immunologic↗
PubMed2000

Hepatic arterial 5-fluorouracil in patients with liver metastases of colorectal cancer: single-centre experience in 145 patients.

BACKGROUND: Hepatic arterial chemotherapy for liver metastases of colorectal cancer is still under discussion. Mainly because of the technical complications of this mode of treatment and the lack of a survival benefit in randomized studies. We performed an analysis of hepatic arterial 5-fluorouracil (5-FU) chemotherapy in 145 consecutive patients treated at a single institution. PATIENTS AND METHODS: One hundred forty-five patients with inoperable liver metastases from colorectal cancer were included. 5-FU, 1000 mg/m2/day continuous infusion for five days every three weeks, was delivered in the hepatic artery by percutaneous catheter or arterial access device. RESULTS: The response rate was 34% for all patients, 40% in patients with extrahepatic disease, and 15% in patients with i.v. 5-FU-based pretreatment. TTP and OS for all patients were 7.5 and 14.3 months, respectively. In patients with extrahepatic disease or i.v. 5-FU-based pretreatment, OS was significantly shorter compared to patients without extrahepatic disease or 5-FU-based pretreatment (9.7 vs. 19.3 months and 10.1 vs. 17.4 months, respectively), forty-seven percent of patients stopped treatment because of a complication. Complications most often seen in patients with arterial ports were hepatic artery thrombosis (48%) and dislocation of the catheter (22%). CONCLUSIONS: The results of our analysis are in line with previous phase III studies. Extrahepatic disease and i.v. 5-FU-based pretreatment were prognostic for reduced OS. The complication rate of hepatic arterial delivery was worrisome. although, no negative impact on survival could be established. There is a strong need for improvement of hepatic arterial delivery methods before further evaluation of hepatic arterial

Adult↗
PubMed2000

Sequence dependent effect of paclitaxel on gemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-cell lung cancer cell lines.

Gemcitabine and paclitaxel are active agents in the treatment of non-small-cell lung cancer (NSCLC). To optimize treatment drug combinations, simultaneously and 4 and 24 h intervals, were studied using DNA flow cytometry and multiple drug effect analysis in the NSCLC cell lines H460, H322 and Lewis Lung. All combinations resulted in comparable cytotoxicity, varying from additivity to antagonism (combination index: 1.0-2.6). Gemcitabine caused a S (48%) and G1 (64%) arrest at IC-50 and 10 x IC-50 concentrations, respectively. Paclitaxel induced G2/M arrest (70%) which was maximal within 24 h at 10 x IC-50. Simultaneous treatment increased S-phase arrest, while at the 24 h interval after 72 h the first drug seemed to dominate the effect. Apoptosis was more pronounced when paclitaxel preceded gemcitabine (20% for both intervals) as compared to the reverse sequence (8%, P = 0.173 for the 4 h and 12%, P = 0.051 for the 24 h time interval). In H460 cells, paclitaxel increased 2-fold the accumulation of dFdCTP, the active metabolite of gemcitabine, in contrast to H322 cells. Paclitaxel did not affect deoxycytidine kinase levels, but ribonucleotide levels increased possibly explaining the increase in dFdCTP. Paclitaxel did not affect gemcitabine incorporation into DNA, but seemed to increase incorporation into RNA. Gemcitabine almost completely inhibited DNA synthesis in both cell lines (70-89%), while paclitaxel had a minor effect and did not increase that of gemcitabine. In conclusion, various gemcitabine-paclitaxel combinations did not show sequence dependent cytotoxic effects; all combinations were not more than additive. However, since paclitaxel increased dFdCTP accumulation, gemcitabine incorporation into RNA and the apoptotic index, the administration of paclitaxel prior to gemcitabine might be favourable as compared to reversed sequences.

Animals↗
PubMed2000

Cremophor EL pharmacokinetics in a phase I study of paclitaxel (Taxol) and carboplatin in non-small cell lung cancer patients.

The purpose of our study was to investigate the pharmacokinetics of Cremophor EL following administration of escalating doses of Taxol (paclitaxel dissolved in Cremophor EL/ethanol) to non-small cell lung cancer (NSCLC) patients. Patients with NSCLC stage IIIb or IV without prior chemotherapy treatment were eligible for treatment with paclitaxel and carboplatin in a dose-finding phase I study. The starting dose of paclitaxel was 100 mg/m2 and doses were escalated with steps of 25 mg/m2, which is equal to a starting dose of Cremophor EL of 8.3 ml/m2 with dose increments of 2.1 ml/m2. Carboplatin dosages were 300, 350 or 400 mg/m2. Pharmacokinetic sampling was performed during the first and the second course, and the samples were analyzed using a validated high-performance liquid chromatographic assay. A total of 39 patients were included in this pharmacokinetic part of the study. The doses of paclitaxel were escalated up to 250 mg/m2 (20.8 ml/m2 Cremophor EL). Pharmacokinetic analyses revealed a low elimination-rate of Cremophor EL (CI=37.8-134 ml/h/m2; t 1/2=34.4-61.5 h) and a volume of distribution similar to the volume of the central blood compartment (Vss=4.96-7.85 l). In addition, a dose-independent clearance of Cremophor EL was found indicating linear kinetics. Dose adjustment using the body surface area, however, resulted in a non-linear increase in systemic exposure. The use of body surface area in calculations of Cremophor EL should therefore be re-evaluated.

Adult↗
PubMed2000

Creutzfeldt-Jakob disease: Carnoy's fixative improves the immunohistochemistry of the proteinase K-resistant prion protein.

The neuropathological diagnosis of Creutzfeldt-Jakob disease relies on the immunohistochemical demonstration of the proteinase-K resistant form of the prion protein (PrPres) in the brain tissue. The antigenicity of PrPres is strongly reduced by the formalin solution widely used to fix the tissue, thus the PrPres immunoreactivity is inconsistently detectable in formalin-fixed tissue. A better PrPres immunostaining can be obtained by using Carnoy's fixing solution, which is composed of ethanol, chloroform and acetic acid (6:3:1). PrPres can easily be extracted from Carnoy's-fixed, paraplast-embedded tissue. Accordingly, Carnoy's-fixed tissue can prior to immunolabeling be subjected to proteinase K and guanidine thiocyanate, which respectively eliminate the normal cellular form of prion protein and promote protein denaturation. In comparison with the best protocols for formalin-fixed tissue (i.e.--hydrolytic autoclaving or autoclaving in distilled water followed by formic acid and guanidine thiocyanate), PrPres immunostaining carried out on sections cut from Carnoy's-fixed, paraplast-embedded tissue blocks and subjected to proteinase K and guanidine thiocyanate, proved more successful to detect and map both diffuse and focal PrPres immunoreactivity, and to correlate the immunoreactivity pattern with MV polymorphism at PRNP codon 129 and PrPres banding and glycosylation pattern revealed by Western blot.

Adult↗
PubMed2000

Hepatic arterial chemotherapy for colorectal cancer metastatic to the liver.

In advanced colorectal cancer, liver metastases are a major problem. In patients with liver metastases as the major site of disease hepatic arterial chemotherapy is a valid alternative to systemic treatment. In this review about hepatic arterial chemotherapy we will discuss the theoretical and practical aspects, the results and complications, the selection of patients for hepatic arterial chemotherapy, and its future developments.

Antimetabolites, Antineoplastic↗
PubMed2000

Gemcitabine and cisplatin as induction regimen for patients with biopsy-proven stage IIIA N2 non-small-cell lung cancer: a phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group (EORTC 08955).

PURPOSE: Our objective was to better define the activity/feasibility of gemcitabine/cisplatin (GC) as induction chemotherapy in patients with stage IIIA N2 non-small-cell lung cancer (NSCLC) followed by surgery or radiotherapy within a large, ongoing comparative study (EORTC 08941). PATIENTS AND METHODS: Forty-seven chemotherapy-naive patients with NSCLC, median age of 58 years, stage IIIA N2 disease, World Health Organization performance status of 0 or 1, and the ability to tolerate a pneumonectomy received gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 and cisplatin 100 mg/m(2) on day 2, every 4 weeks. Patients received induction chemotherapy (three cycles) before re-evaluation and randomization to surgery or radiotherapy. RESULTS: Grade 3/4 thrombocytopenia, the main hematologic toxicity, occurred in 60% of patients but was not associated with bleeding. Full-dose gemcitabine was given in 48% of the courses. Severe nonhematologic toxicity was uncommon. Two patients with preexisting, autoimmune pulmonary fibrosis had deterioration of pulmonary function after radiotherapy. Thirty-three (70.2%; 95% confidence interval, 55.1% to 82.7%) of the 47 eligible patients had objective responses (three complete responses and 30 partial responses). Mediastinal nodes were tumor-free after induction therapy in 53% of cases. Resections were considered complete in 71% of the patients who underwent thoracotomy after induction therapy. Median survival for all recruited patients (N = 53) was 18.9 months, with an estimated 1-year survival rate of 69%. CONCLUSION: In patients with N2 stage IIIA NSCLC, GC is a highly active and well-tolerated induction regimen. GC should be explored in combination with surgery or radiotherapy in stage I and II patients.

Adult↗
PubMed2000

Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors.

PURPOSE: To investigate the side effects, determine the maximum-tolerated dose (MTD), and study the pharmacokinetics of S-1, an oral fluoropyrimidine-based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. PATIENTS AND METHODS: Patients with advanced solid tumors received S-1 bid for 28 days, followed by 1 week of rest. 5-FU pharmacokinetics were investigated after a single initial dose of S-1 during the first 24 hours and weekly thereafter. RESULTS: Twenty-eight patients received S-1 at the four consecutive dose levels of 25, 45, 35, and 40 mg/m(2). The MTD was initially found at 45 mg/m(2), with diarrhea as the dose-limiting toxicity (DLT). Diarrhea was also the DLT at the dose of 40 mg/m(2), which was the MTD for patients exposed to extensive prior chemotherapy. Other toxicities were generally mild. Two patients had a reduction of more than 50% in tumor dimension. Plasma pharmacokinetics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 micromol/L, and the half-life of 5-FU was 3 to 4 hours. A statistically significant relationship was observed between the severity of diarrhea and pharmacokinetic parameters of 5-FU. CONCLUSION: The recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m(2) bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m(2) bid. Phase II trials are warranted in tumors known to be responsive to 5-FU treatment.

Administration, Oral↗
PubMed2000

Clinical perspectives on platinum resistance.

The platinum compounds cisplatin and carboplatin are widely used in the treatment of a number of solid malignancies. Although some platinum-sensitive tumours may be cured by combination chemotherapy (e.g. testicular cancer), most will relapse and subsequently prove resistant to platinum compounds. The mechanisms of platinum resistance in patients are still poorly understood. Clearly, when a tumour relapses a long time after successful first-line treatment, there is a high chance that it will still be sensitive to platinum compounds. A number of studies have attempted to assess the role of drug transport, the glutathione system, DNA repair and apoptosis genes in the development of resistance in tumours, but no conclusive evidence is available. Approaches to increasing the potency of platinum therapy (to overcome resistance) have been devised and some have proved to be effective; in particular, intraperitoneal administration of cisplatin has shown superiority over intravenous administration in selected patients with ovarian cancer. The development of drugs and techniques to reduce the adverse effects of platinum chemotherapy has greatly improved their administration. Investigations attempting to modulate platinum activity and toxicity have also been performed. Further investigation of in vivo resistance mechanisms should be valuable in allowing prediction of clinical response to chemotherapy and may identify new treatments with the potential to improve outcomes for patients with a variety of platinum-resistant tumour types.

Animals↗