Biomedical subjects

G Stoter

Publications and source records attributed to G Stoter.

At least 73 records · Page 4Linked to original sources

PubMed1998

Expression of the multidrug resistance protein (MRP) in squamous cell carcinoma of the oesophagus and response to pre-operative chemotherapy.

One of the major problems in the treatment of squamous cell carcinoma of the oesophagus (ESCC) is the unresponsiveness to cytotoxic drugs. So far, the mechanisms underlying the intrinsic drug resistance of ESCC remain unclear. The aim of this study was to determine the role of the newly recognised drug resistance protein, the multidrug resistance protein (MRP), in ESCC drug resistance. Tumour biopsies from ESCCs were analysed by RNase protection assay (RPA) as well as by immunohistochemistry (IHC) for the presence of MRP mRNA or protein, respectively. The ESCC samples were obtained from patients participating in a prospective randomised clinical phase III trial, evaluating pre-operative chemotherapy (cisplatin and etoposide) followed by surgery versus surgery alone in patients with operable ESCC. For most patients, tumour biopsies taken at diagnosis by endoscopy as well as surgically resected primary tumours were available. Of 58 ESCC patients enrolled, 28 received chemotherapy before surgical resection of their tumours, and 30 were treated with surgery alone. 12 patients (3 complete and 9 partial responses; 43%) showed a major response after chemotherapy, 10 patients (36%) had stable disease (SD), and 6 (21%) progressive disease (PD). On 14 surgically resected, untreated, primary ESCCs, the IHC scores correlated with the MRP mRNA levels, quantitated by RPA (multiple testing, P < 0.01). MRP expression was detected by IHC in the vast majority (52/58; 90%) of the diagnostic biopsies. MRP expression did not differ significantly between CR + PR, and patients with SD or PD. In addition, multivariate analysis by logistic regression did not show any effect of tumour cell differentiation or UICC tumour stage on the outcome of pre-operative chemotherapy in relation to MRP expression. However, a difference became apparent (Sign-test, P < 0.05) for higher MRP expression in tumours from patients with PR or SD, when comparing MRP levels in paired tumour samples before and after chemotherapy, suggesting that chemotherapy selected for drug-resistant cell clones.

ATP-Binding Cassette Transporters↗

PubMed1998

The effect of dexamethasone on the uptake of cisplatin in 9L glioma and the area of brain around tumor.

The negative influence of dexamethasone (Dex) on the uptake of cisplatin in brain tumors was investigated in rats bearing 9L glioma. Dex or saline was given intraperitoneally prior to intravenous administration of cisplatin 5 mg/kg. Total Platinum (Pt) concentration was quantified with atomic absorption spectroscopy (AAS) in tumor, brain around tumor (BAT), normal brain and plasma. In the second experiment DNA-adducts of cisplatin were determined in tumor and BAT by AAS. In tumor, there was no difference in the Pt concentration and in the DNA-adduct level between the two treatment groups. In BAT, the Pt level in the Dex group was 0.20 microg/g (SD=0.10 microg/g), which was significantly lower than in the controls (0.53 microg/g (SD=0.21 microg/g); p < 0.001). In addition, the DNA-adduct level in BAT was 23% lower in the Dex treated rats (p=0.05). In normal brain the Pt concentration was 10-fold lower than in tumor tissue. Thus, Dex did not significantly limit the uptake of cisplatin in brain tumor nor did it influence the uptake in normal brain parenchyma. In contrast, in BAT that has a partially disrupted BBB, the concentrations of Pt and DNA-adduct formation were significantly decreased following pretreatment with Dex. The influence of Dex on limiting the effects of chemotherapy for brain tumors needs further study.

Animals↗

PubMed1998

Expression of p53, Bcl-2 and Bax in cisplatin-induced apoptosis in testicular germ cell tumour cell lines.

We examined the sensitivity for cisplatin-induced apoptosis in a panel of four testicular germ cell tumour (TGCT) cell lines and monitored the cellular expression of the apoptosis-related proteins p53, Bcl-2 and Bax. Three of four TGCT cell lines (NT2, NCCIT and S2) were hypersensitive for cisplatin-induced apoptosis, while the TGCT cell line 2102 EP appeared to be resistant for cisplatin-induced apoptosis, even at relatively high drug concentrations (12.5 microM). For all four cell lines, the induction of apoptosis by cisplatin correlated with drug sensitivity in the MTT assay. The differences in chemosensitivity and induction of apoptosis could not be attributed to differences in cellular platinum accumulation, DNA platination or platinum-DNA adduct removal. We next analysed the relationship between p53 status and cisplatin-induced up-regulation of p53, and the susceptibility to cisplatin-induced apoptosis. Wild-type p53 containing NT2 and 2102 EP cells showed p53 up-regulation upon drug treatment, and NCCIT (mutant p53) and S2 (no p53 protein) cells did not. Consistently, the increase in wild-type p53 protein in NT2 and 2102 EP cells led to an increase in mRNA level of the p53 downstream gene p21/WAF/CIP, whereas mutant p53-containing NCCIT cells and p53-non-expressing S2 cells could not transactivate this p53-responsive gene. As NT2, NCCIT and S2 were readily triggered into apoptosis, while 2102 EP cells failed to undergo cisplatin-induced apoptosis, our data suggest that the presence of wild-type and/or transactivation-competent p53 might not be an absolute prerequisite for efficient induction of apoptosis in TGCT cell lines. Also endogenous levels of Bcl-2 and Bax expression did not correlate with cisplatin-induced apoptosis. In addition, the endogenous Bcl-2 and Bax expression was not affected by cisplatin treatment. The present study suggests that, at least in our panel of TGCT cell lines, hypersensitivity for cisplatin-induced apoptosis might not be necessarily correlated with the presence of wild-type p53 and is probably not associated with Bcl-2 and Bax expression.

Cisplatin↗

PubMed1998

Reduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line.

In order to unravel possible mechanisms of clinical resistance to topoisomerase I inhibitors, we developed a topotecan-resistant human IGROV-1 ovarian cancer cell line, denoted IGROV(T100r), by stepwise increased exposure to topotecan (TPT). The IGROV(T100r) cell line was 29-fold resistant to TPT and strongly cross-resistant to SN-38 (51-fold). However, the IGROV(T100r) showed only threefold resistance to camptothecin (CPT). Remarkably, this cell line was 32-fold resistant to mitoxantrone, whereas no significant cross-resistance against other cytostatic drugs was observed. No differences in topoisomerase I protein levels and catalytic activity as well as topoisomerase I cleavable complex stabilization by CPT in the IGROV-1 and IGROV(T100r) cell lines were observed, indicating that resistance in the IGROV(T100r) cell line was not related to topoisomerase I-related changes. However, resistance in the resistant IGROV(T100r) cell line to TPT and SN-38 was accompanied by decreased accumulation of the drugs to approximately 15% and 36% of that obtained in IGROV-1 respectively. No reduced accumulation was observed for CPT. Notably, accumulation of TPT in the IGROV-1 cell line decreased under energy-deprived conditions, whereas the accumulation in the IGROV(T100r) cell line increased under these energy-deprived conditions. The efflux of TPT at 37 degrees C was very rapid in the IGROV-1 as well as the IGROV(T100r) cell line, resulting in 90% efflux within 20 min. Importantly, the efflux rates of TPT in the IGROV-1 and IGROV(T100r) cell lines were not significantly different and were shown to be independent on P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP). These results strongly suggest that the resistance of the IGROV(T100r) cell line to TPT and SN-38 is mainly caused by reduced accumulation. The reduced accumulation appears to be mediated by a novel mechanism, probably related to impaired energy-dependent uptake of these topoisomerase I drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

A phase I/II study of multicyclic dose-intensive chemotherapy supported with G-CSF, or G-CSF and haematopoietic progenitor cells in whole blood, in two consecutive cohorts of patients.

We investigated the reconstitutive potential of haematopoietic progenitor cells collected in autologous whole blood during multicycle dose-intensified chemotherapy. Forty patients with metastatic solid tumours were treated with up to six cycles of cisplatin and escalating doses of ifosfamide every 14 days. Cisplatin was administered in 3% sodium chloride over 3 h, followed by ifosfamide over 24 h and mesna over 36 h. The first cohort of patients received granulocyte colony-stimulating factor (G-CSF) days 4-14. Once dose-limiting toxicity was reached in cohort 1, the study continued with a second cohort of patients, in whom, in addition to G-CSF on days 4-14, 500 ml of G-CSF and chemotherapy-'primed' whole blood was collected on day 15, i.e. on day 1 of treatment cycles two to six, before cisplatin administration. This volume of blood was kept unprocessed at 4 degrees C and reinfused 20-24 h after the completion of ifosfamide. In cohort 1, dose-limiting toxicity (DLT) was reached at ifosfamide 6.0 g m(-2) with two out of six of the patients developing neutropenic fever. Although in cohort 2 no neutropenic fever was encountered, neither the frequency nor the duration of grade 4 neutropenia and thrombocytopenia were reduced. Cumulative asthenia resulted in DLT at 7.0 g m(-2). The median number of CD34+ cells in 500 ml of whole blood after the first cycle (i.e. at start of cycle 2) was 1.15 x 10(6) kg(-1). This number was significantly greater after the second cycle (2.06 x 10(6) kg(-1), P = 0.01) and then gradually decreased after cycles three to six. After storing whole blood, the number of CD34+ cells had not decreased (median + 10%). We conclude that the method of combined bone marrow support by G-CSF and haematopoietic progenitor cells in autologous whole blood collected before each cycle of a 2-weekly regimen of cisplatin-ifosfamide does not result in clinically measurable reduced bone marrow toxicity compared with what can be expected by the use of G-CSF alone.

Adult↗

PubMed1998

Four cycles of BEP vs four cycles of VIP in patients with intermediate-prognosis metastatic testicular non-seminoma: a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group. European Organization for Research and Treatment of Cancer.

We investigated the efficacy and toxicity of induction chemotherapy with cisplatin and etoposide with either bleomycin or ifosfamide in patients with intermediate-prognosis testicular non-seminoma. A total of 84 eligible patients were randomized to receive four cycles of etoposide, ifosfamide, cisplatin (VIP), or four cycles of bleomycin, etoposide, cisplatin (BEP). Intermediate prognosis was defined as any of the following: lymph node metastases 5-10 cm in diameter, lung metastases more than four in number or > 3 cm, HCG 5000-50,000 IU l(-1), AFP > 1000 IU l(-1). The complete response (CR) rates to VIP and BEP were similar, 74% and 79% respectively (P = 0.62). Including the cases in whom viable cancer was completely resected with post-chemotherapy debulking surgery, the percentages of patients who achieved a no-evidence-of-disease status were 80% on VIP and 82% on BEP (P = 0.99). In addition, there were no differences in relapse rate, disease-free and overall survival after a median follow-up of 7.7 years. The 5-year progression-free survival was 85% (95% CI 74-96%) in the VIP arm and 83% (95% CI 71-96%) in the BEP arm, hazard ratio (VIP/BEP) 0.83 (95% CI 0.30-2.28). The VIP regimen was more toxic with regard to bone marrow function; the frequency of leucocytes below 2000 microl(-1) throughout four cycles was 89% on VIP and 37% on BEP (P < 0.001). Our study does not indicate that ifosfamide is superior to bleomycin in combination with cisplatin and etoposide. The sample size in this study is small as the study was prematurely discontinued when data became available from a competing study that showed no improved effectiveness of VIP compared with BEP. Taken together with these data, bleomycin should not be replaced by conventional-dose ifosfamide.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Docetaxel (Taxotere): an active agent in metastatic urothelial cancer; results of a phase II study in non-chemotherapy-pretreated patients.

The semisynthetic taxoid docetaxel was investigated in a phase II study in non-chemotherapy pretreated patients with metastatic urothelial cell cancer. Thirty patients (median age 61, range 45-72) were treated with docetaxel 100 mg m(-2) administered as a 1-h infusion every 3 weeks. Of 29 evaluable patients, four achieved a complete response and five a partial response, for an overall response rate of 31%. The median duration of response was 6 months (range 4-51+). A total of 104 cycles were administered. The median number of cycles given was three (range 1-9). Toxic effects of docetaxel mainly consisted of neutropenia, which, however, rarely caused infectious complications (5%). Fluid retention or neuropathy necessitated treatment cessation in two patients. We conclude that docetaxel is an effective agent in urothelial cell cancer, and should be further tested in combination chemotherapy.

Aged↗

PubMed1998

Serum alpha-fetoprotein surge after the initiation of chemotherapy for non-seminomatous testicular cancer has an adverse prognostic significance.

It has been recognized that the tumour markers alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) may show a transient elevation after the initiation of chemotherapy in non-seminomatous testicular cancer. We investigated the prognostic importance of these so-called marker surges in a cohort of patients treated with cisplatin combination chemotherapy between 1983 and 1991. A total of 669 patients were studied. Of 352 patients who had an elevated AFP at the start of treatment and for whom we had data at both day 1 and day 8, 101 (29%) had a surge. Of 317 patients for whom we had data for HCG, 80 patients (25%) had a surge. It was found that an AFP surge was a strong adverse prognostic factor for progression [hazard ratio (HR) 2.28, P=0.005]. There was no statistically significant difference in survival (HR 1.65, P=0.13). There was no prognostic significance of a HCG surge, either for progression or for survival. To investigate whether a surge was an independent prognostic factor for progression and survival, multivariate Cox regression models were fitted using the independent prognostic factors for progression and survival and the surge/decline variable. An AFP surge was retained in the final model for progression. A HCG surge was of no prognostic importance for progression or survival. We conclude that an AFP surge has an adverse prognostic significance, independent of pretreatment characteristics.

Antineoplastic Agents↗

PubMed1998

In vivo model systems in P-glycoprotein-mediated multidrug resistance.

In this article we review the in vivo model systems that have been developed for studying P-glycoprotein-mediated multidrug resistance (MDR) in the preclinical setting. Rodents have two mdr genes, both of which confer the MDR phenotype: mdr 1a and mdr 1b. At gene level they show strong homology to the human MDR1 gene and the tissue distribution of their gene product is very similar to P-glycoprotein expression in humans. In vivo studies have shown the physiological roles of P-glycoprotein, including protection of the organism from damage by xenobiotics. Tumors with intrinsic P-glycoprotein expression, induced MDR or transfected with an mdr gene, can be used as syngeneic or xenogenic tumor models. Ascites, leukemia, and solid MDR tumor models have been developed. Molecular engineering has resulted in transgenic mice that express the human MDR1 gene in their bone marrow and in knockout mice missing a murine mdr gene. The data on pharmacokinetics, efficacy, and toxicity of chemosensitizers of P-glycoprotein in vivo are described. Results from studies using monoclonal antibodies directed against P-glycoprotein and other miscellaneous approaches for modulation of MDR are mentioned. The importance of in vivo studies prior to clinical trials is being stressed and potential pitfalls due to differences between species are discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Cisplatin-DNA adducts and protein-bound platinum in blood of testicular cancer patients.

DNA adducts formed by cisplatin [cis-diamminedichloroplatinum(II)] were measured in blood samples from 48 testicular cancer patients treated in four centers in Europe during four to six cycles with cisplatin infusions on five successive days (total samples, 112). Total protein-bound platinum (Pt) in blood was also measured (total samples, 84). The mean on the main DNA adduct, cis-Pt(NH3)2d(pGpG) (Pt-GG), was 0.75 fmol/microg DNA [standard deviation (SD) = 0.66] on the first day of the first cycle, increased after the infusion at day 5 of the cycle (mean 1.74 fmol/microg DNA, SD = 0.90) and decreased on the following day (mean 1.09 fmol/microg DNA, SD = 0.62). In subsequent cycles, there was a tendency to an increase in the mean Pt-GG levels. The values of protein-bound Pt in blood showed little reduction between day 5 and 6 of each cycle, and a stable increase during the course of the therapy. Strong correlations were seen between day 1, 5 and 6 of the first cycle for both Pt-GG and protein-bound Pt in blood. A strong correlation (r = 0.62, p < 0.001, 69 pairs) was found between the levels of Pt-GG and protein-bound Pt. Only two patients relapsed during the follow-up; therefore, the analysis of the association between Pt-GG levels and response to therapy was not informative. The results of this study suggest that DNA adducts formed by cisplatin at the beginning of chemotherapy are predictive of values found during later days and cycles, and that the value of protein-bound Pt in blood is predictive of the value of DNA adducts.

Adult↗

PubMed1998

Corticosteroid co-medication does not reduce the incidence and severity of neurotoxicity induced by docetaxel.

Docetaxel is a new antimicrotubule agent that induces a predominantly sensory neuropathy that is mild in most patients. This prospective study was performed to determine if corticosteroid co-medication reduces the incidence and severity of docetaxel-induced neuropathy. Two groups of patients treated with docetaxel in subsequent cohorts were prospectively analyzed for neurotoxicity. Group A consisted of 38 patients with a variety of solid tumors, who were treated in studies before corticosteroid co-medication was recommended, while 49 female patients in group B with metastatic breast cancer were treated after co-medication with corticosteroids was introduced as a routine. Neuropathy was evaluated by a clinical sum-score for symptoms and signs, and by measurement of the vibration perception threshold (VPT). The severity of neuropathy was graded according to NCI Common Toxicity Criteria. In 42% of patients of group A and in 65% of patients of group B a mainly mild neuropathy was documented. There was no statistically significant difference in neurotoxicity between group A and B. The cumulative dose of docetaxel showed a significant correlation with post-treatment scores of VPT, sensory sum-score, grade of paresthesias, and grade of neurosensory and neuromotor toxicity. Corticosteroid co-medication does not reduce the development of docetaxel-related neuropathy.

Adult↗

PubMed1998

Disposition of Cremophor EL in humans limits the potential for modulation of the multidrug resistance phenotype in vivo.

The purpose of the present study was to characterize the distribution and elimination kinetics of the paclitaxel vehicle Cremophor EL (CrEL), a polyoxyethylated castor oil that can modulate P-glycoprotein-mediated multidrug resistance in vitro. The pharmacokinetics of CrEL were studied using noncompartmental models in 23 patients with histological proof of malignant solid tumors, receiving paclitaxel as a 3-h i.v. infusion at dose levels ranging from 100-225 mg/m2 (corresponding to CrEL doses of 8.33-18.8 ml/m2). Serial plasma samples were obtained before and up to 72 h after drug administration, and were analyzed for the presence of CrEL by a novel colorimetric dye-binding microassay. The area under the plasma concentration versus time curves and the peak plasma levels of CrEL increased from 253+/-36.8 (mean+/-SD) to 680+/- 180 microl.h/ml, and from 3.40+/-0.10 to 6.58+/-0.52 microl/ml, respectively, consistent with linear pharmacokinetics. Disappearance of CrEL from the central plasma compartment was characterized by a terminal elimination half-life of 84.1+/-20.4 h, resulting in extended persistence of substantial levels even at 1 week after paclitaxel treatment. The observed volume of distribution was extremely low and averaged 3.70+/-0.49 liters/m2, implying that the tumor delivery of CrEL is insignificant. Our results indicate that CrEL is a relatively slow clearance compound and that its distribution is limited to the central plasma compartment. Hence, CrEL is not likely to play a role in reversing P-glycoprotein-mediated multidrug resistance to paclitaxel in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Irinotecan (CPT-11) metabolism and disposition in cancer patients.

The objective of this study was to determine the metabolic fate and disposition of the antitumor camptothecine derivative irinotecan (CPT-11). Ten patients with histological proof of malignant solid tumor received 200 mg/m2 CPT-11 as a 90-min i.v. infusion, followed by a 1.5-h i.v. infusion of cisplatin (60 or 80 mg/m2). Plasma, urine, and feces were collected for 56 h and analyzed by a specific reversed-phase high-performance liquid chromatographic assay for the parent drug and all four metabolites positively identified to date: SN-38; its beta-glucuronide conjugate, SN-38 beta-glucoronide (SN-38G); 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecine (APC); and 7-ethyl-10-[4-N-(1-piperidino)-1-amino]-carbonyloxycamptothecine (NPC). A three-exponential decline was observed in plasma for all compounds, with a clear predominance of the parent drug [25.6+/-5.71 microM x h (CPT-11) versus 15.8+/-3.51 microM x h (total metabolites)]. Total urinary excretion was 28.1+/-10.6% of the dose, with unchanged CPT-11 and SN-38G as the main excretion products. Whereas renal clearance of SN-38 was only a minor route of drug elimination, fecal concentrations of this compound were unexpectedly high (on average, 2.45% of the dose), suggestive of intestinal hydrolysis of SN-38G by bacterial beta-glucuronidase. CPT-11 and the other metabolites could also be identified from fecal extracts, with a very minor contribution overall of the cytochrome P-450-mediated compounds 7-ethyl-10-[4-N-(1-piperidino)-1-amino]-carbonyloxycamptothecine and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecine. Surprisingly, fecal excretion accounted for only 24.4+/-13.3% of the dose, leading to a total excretion of approximately 52%. These data indicate that half of the dose in urine and feces may constitute some further unknown nonextractable or nonfluorescent metabolites. The findings from this study should be of importance as a guide to further therapeutic evaluation of this drug.

Adult↗

PubMed1997

Lack of correlation between cisplatin-induced apoptosis, p53 status and expression of Bcl-2 family proteins in testicular germ cell tumour cell lines.

We investigated the role of p53 and of the Bcl-2 family proteins in the apoptotic response of a panel of testicular tumour cell lines (NT2, NCCIT, S2 and 2102 EP). The p53 gene status and the capacity of the p53 protein to transactivate the p21/WAF/CIP gene were determined, and we examined the correlation between p53 status and the susceptibility to cisplatin-induced apoptosis. In contrast to wild-type p53-containing NT2 and 2102 EP cells, NCCIT (mutant p53) and S2 (no p53 protein) cells were shown to be p53-transactivation defective. However, NCCIT and S2 cells with non-functional p53 were readily triggered into apoptosis by cisplatin, whereas p53-transactivation competent 2102 EP cells failed to undergo cisplatin-induced apoptosis. The defective apoptotic pathway in 2102 EP cells was reflected by a 4-fold decreased sensitivity to cisplatin in the MTT assay. We further demonstrated that the p53-independent differential cisplatin sensitivity among the testicular germ cell tumour (TGCT) cell lines was not due to differences in cellular cisplatin accumulation or DNA platination. The pattern of endogenous expression levels of Bax, Bcl-2, Bcl-x and Bak, which was not modulated by cisplatin treatment, demonstrated that these Bcl-2 family proteins are not involved in drug-induced apoptosis in the TGCT cell lines. Our results suggest a lack of correlation between cisplatin-induced apoptosis, p53 status and expression of Bcl-2 family proteins in our panel of TGCT cell lines. We conclude that the cisplatin-induced apoptotic pathway in TGCT cell lines might be p53-independent and is probably not associated with differences in the Bcl-2/Bax rheostat.

Antineoplastic Agents↗

PubMed1997

Local but no systemic immunomodulation by intraperitoneal treatment of advanced ovarian cancer with autologous T lymphocytes re-targeted by a bi-specific monoclonal antibody.

We have reported a 27% overall anti-tumor response using i.p. immunotherapy of advanced ovarian carcinoma with autologous, ex vivo expanded, T lymphocytes re-targeted with bi-specific monoclonal antibody OC/TR, combined with soluble OC/TR and low-dose recombinant interleukin-2 (IL-2). This treatment had no effect on extraperitoneal disease. Therefore we studied in 13 patients whether this immunotherapeutic protocol resulted only in local or also in systemic immunomodulation. The phenotype of the ex vivo expanded lymphocytes was mainly CD3+, 4-, 8+, 16-, 56-. Their OC/TR-re-targeted cytolytic activity against Igrov-1 ovarian-carcinoma cells was approximately as high in responders as in non-responders. Following most therapeutic cycles, the immunophenotype of lymphocytes recovered from the peritoneal fluid was similar to that of the infused T cells (i.e., mainly CD3+, 4-, 8+) and they were coated with OC/TR. However, cytolytic activity of the recovered lymphocytes against Igrov- 1 cells was low in direct assays, and only slightly increased after additional in vitro re-targeting with OC/TR. Systemically, the i.p. immunotherapy resulted in a transient lymphopenia lasting for about 7 days, low (i.e., 5 to 13 ng/ml) serum concentrations of free, functional OC/TR, and very weak coating of circulating T lymphocytes with OC/TR. These peripheral-blood T lymphocytes did not exert OC/TR-re-targeted cytolytic activity. Thus, locoregional OC/TR-re-targeted cellular immunotherapy resulted in substantial local immunomodulation and anti-tumor effects but virtually no systemic immunomodulation.

Antibodies, Bispecific↗

PubMed1997

Risk of second malignant neoplasms among long-term survivors of testicular cancer.

BACKGROUND: We have quantified the site-specific risk of second malignant neoplasms among nearly 29,000 survivors (> or = 1 year) of testicular cancer, taking into account the histologic type of initial cancer and the primary therapy used to treat it. METHODS: The study cohort consisted of 28,843 men identified within 16 population-based tumor registries in North America and Europe; over 3300 men had survived more than 20 years. New invasive cancers were identified through a search of registry files. RESULTS: Second cancers were reported in 1406 men (observed-to-expected ratio [O/E] = 1.43; 95% confidence interval = 1.36-1.51), with statistically significant excesses noted for acute lymphoblastic leukemia (O/E = 5.20), acute nonlymphocytic leukemia (O/E = 3.07), melanoma (O/E = 1.69), non-Hodgkin's lymphoma (O/E = 1.88), and cancers of the stomach (O/E = 1.95), colon (O/E = 1.27), rectum (O/E = 1.41), pancreas (O/E = 2.21), prostate (O/E = 1.26), kidney (O/E = 1.50), bladder (O/E = 2.02), thyroid (O/E = 2.92), and connective tissue (O/E = 3.16). Overall risk was similar after seminomas (O/E = 1.42) or nonseminomatous tumors (O/E = 1.50). Risk of solid tumors increased with time since the diagnosis of testicular cancer, yielding an O/E = 1.54 (O = 369) among 20-year survivors (two-sided P for trend = .00002). Secondary leukemia was associated with both radiotherapy and chemotherapy, whereas excess cancers of the stomach, bladder, and, possibly, pancreas were associated mainly with radiotherapy. CONCLUSIONS: Men with testicular cancer continue to be at significantly elevated risk of second malignant neoplasms for more than two decades following initial diagnosis. Patterns of excess second cancers suggest that many factors may be involved, although the precise roles of treatment, natural history, diagnostic surveillance, and other influences are yet to be clarified.

Antineoplastic Agents↗

PubMed1997

Determination of irinotecan (CPT-11) and its active metabolite SN-38 in human plasma by reversed-phase high-performance liquid chromatography with fluorescence detection.

Sensitive high-performance liquid chromatographic assays have been developed to determine the levels of the lactone and lactone plus carboxylate (total) forms of the antitumor agent irinotecan (CPT-11) and its active metabolite SN-38, in human plasma. The related compound camptothecin was used as the internal standard. The selective sample pretreatment for the lactone forms involved a single solvent extraction with acetonitrile-n-butyl chloride (1:4, v/v), whereas the sample clean-up for the total forms was a simple protein precipitation with aqueous perchloric acid-methanol (1:1, v/v), which results in the conversion of the carboxylate to the lactone forms. Chromatography was carried out on a Hypersil ODS column, with detection performed fluorimetrically. The methods have been validated, and stability tests under various conditions have been performed. The lower limits of quantitation are 0.5 and 2.0 ng/ml for the lactone and total forms, respectively. The assays have been used in a single pharmacokinetic experiment in a patient to investigate the applicability of the method in vivo.

Antineoplastic Agents, Phytogenic↗

PubMed1997

Determination of the lactone and lactone plus carboxylate forms of 9-aminocamptothecin in human plasma by sensitive high-performance liquid chromatography with fluorescence detection.

Two sensitive reversed-phase high-performance liquid chromatographic fluorescence methods, with simple sample handling at the site of the patient, are described for the determination of the lactone and lactone plus carboxylate forms of 9-aminocamptothecin (9AC). For 9AC lactone, the sample preparation was a liquid-liquid extraction with acetonitrile-n-butyl chloride (1:4, v/v), whereas the sample preparation for 9AC total (lactone plus carboxylate) was a simple deproteinization with 5% perchloric acid-methanol (1:1, v/v), which results in the conversion of the carboxylate into the lactone form. The lower limits of quantitation were 50 pg/ml and 100 pg/ml for 9AC lactone and 9AC total, respectively. The within-run precisions at four tested concentrations were < or = 6.3% for 9AC lactone and < or = 5.3% for 9AC total. The between-run precisions were < or = 8.9% and < or = 5.6%, respectively. The assays were developed to enable pharmacological analysis of 9AC in a bioavailability and oral phase I study in patients with solid tumors.

Antineoplastic Agents↗