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O Rixe

Publications and source records attributed to O Rixe.

At least 19 recordsLinked to original sources
PubMed2006

[Choroidal metastasis revealing pulmonary adenocarcinoma].

Lung cancer is the first cause of choroidal metastasis in man. Generally, its discovery is made at end-stage of the disease. It can be uncommonly the presenting sign as in our case. We report a case of a 28-year-old patient with no prior medical history. He presented with visual decrease and metamorphopsia that lead to the diagnosis of a metastatic adenocarcinoma of the lung (bone, liver, choroid, nodles). Chemotherapy permitted to improve visual acuity, in parallel with disappearance of choroidal metatasis. Discovery of choroidal tumor should evoke in first line metastasis. Chemotherapy can improve visual acuity and the quality of life.

Adenocarcinoma↗
PubMed2006

[Skin signs associated with epidermal growth factor inhibitors].

BACKGROUND: Inhibitors of epidermal growth factor receptors (EGFR) constitute a new alternative treatment for patients presenting certain advanced stage solid cancers (bowel, breast, ovary). Adverse cutaneous effects of these drugs are now starting to be described. OBSERVATIONS: Our study involved 2 men and 2 women with no previous history of acne included in a treatment protocol comprising EGFR inhibitors. Mean age was 52 years. The primary cancers were breast, ovary, bowel and unidentified. The EGFR inhibitors used were gefitinib (ZD1839) (2 cases), carnetinib (Cl1033) and cetuximab (IMC-C225). Skin lesions appeared after 7 days and included erythematous papules and follicular pustules of the face, back and upper chest. No comedons were seen, and there were no nodules or cysts. The severity of the rash resulted in discontinuation of treatment in 2 patients with complete disappearance of skin lesions in both cases. In one patient, reduction of the dosage of gefitinib (IMC-C225) led to gradual resolution of the rash. Histological examination of papules and pustules concluded on an acute suppurative folliculitis. Smears and cultures ofa nasal lesion and pustules revealed coagulase-positive Staphylococcus aureus in 2 patients. Combined doxycycline 100 mg daily and benzoyl peroxide was prescribed for 3 months and a favourable outcome was achieved after a mean 2 weeks. DISCUSSION: EGFR inhibitors act by inhibiting mechanisms oftumour proliferation in certain cancers at advanced stages or refractory to other treatments. Our findings in these four patients are similar to the published cases in terms of rapid onset of monomorphous, papulopustular, follicular eruption without comedons. Rapid response to cyclines and benzoyl peroxide is also reported in literature. This treatment must be instituted rapidly and patients must be informed about the cutaneous side-effects of EGFR inhibitors before the start of therapy. The pathophysiology of these eruptions is still unknown. Skin signs are probably due to interaction with EGFR functions, including overexpression of EGFR in keratinocytes and hair follicles.

Adult↗
PubMed2005

Epidermal growth factor receptor signaling in colorectal cancer: preclinical data and therapeutic perspectives.

Epidermal growth factor receptor (EGFR) belongs to a family of receptors known as the ErbB family (ErbB tyrosine kinase receptors) which comprises four proteins encoded by the c-erbB proto-oncogene. EGFR is known to activate a cascade of multiple signaling pathways that facilitate tumor growth process. EGFR has been shown to be overexpressed in colorectal cancer patient populations but its prognostic value in colorectal cancer progression remains unclear. The development of a panel of EGFR inhibitors could reduce the proliferation of tumor cells when used alone or in combination with cytotoxic drugs or radiation. This review focuses on the potential role of EGFR signaling in the survival of colorectal tumor cells and the possible modulation of such signaling pathways by EGFR inhibitors so as to increase tumor control or render tumor cells more sensitive to conventional therapy.

Cell Proliferation↗
PubMed2005

Comparison of the efficacy and safety of combinations of metopimazine or ondansetron with methylprednisolone in the prevention of delayed emesis in patients receiving chemotherapy.

BACKGROUND: Delayed emesis following chemotherapy in cancer patients remains an important challenge for treatment and contributes to poor quality of life and treatment compliance. OBJECTIVES: To compare the efficacy and tolerability of associations of metopimazine and ondansetron with methylprednisolone for the prevention of delayed chemotherapy-induced nausea and emesis. METHODS: A randomised, open-label, observational, cross-over design was used to compare two treatment strategies following two consecutive sessions of chemotherapy separated by at least 1 week. Patients were randomised to treatment with sublingual metopimazine (15 mg tid) or ondansetron lyophilisate (8 mg bid) for 5 days. All patients received oral methylprednisolone (48 mg). Patients reported episodes of nausea and emesis in a diary, and completed the Functional Living Index Emesis quality of life questionnaire. Adverse events were also evaluated. RESULTS: Ninety-nine patients were included in the study, 79.5% of whom were women, with a mean age of 52.7 years. Breast cancer was the most common individual cancer and most patients were receiving combinations of cytotoxic drugs. Treatment was successful at preventing delayed emesis in 73.6% of patients during treatment with the metopimazine-methylprednisolone association and 57.5% during the ondansetron-methylprednisolone association. Analysis of discordant pairs revealed a significant benefit in favour of the methopimazine-methylprednisolone association (p = 0.006). No significant difference was observed between treatments for the overall quality of life score. The incidence of gastrointestinal disorders, particularly constipation, was significantly higher during ondansetron-methylprednisolone treatment (p = 0.0112). CONCLUSION: Methopimazine is an effective and well-tolerated alternative to setrons for the treatment of delayed nausea and emesis in patients undergoing chemotherapy.

Adult↗
PubMed2004

Dose-finding study of weekly 24-h continuous infusion of 5-fluorouracil associated with alternating oxaliplatin or irinotecan in advanced colorectal cancer patients.

PURPOSE: To determine maximum tolerated dose, safety and efficacy of weekly 24 h infusional 5-fluorouracil (5-FU) combined alternately with oxaliplatin and irinotecan. PATIENTS AND METHODS: Advanced colorectal carcinoma patients in first- or second-line chemotherapy received increasing doses of 5-FU (weekly 24 h continuous intravenous infusion without leucovorin) on days 1, 8, 15 and 22, irinotecan days 1 and 15; and oxaliplatin days 8 and 22, every 35 days. RESULTS: Thirty-four patients received 175 cycles. The median age was 64 years (range 47-78). Eighteen per cent of patients had the primary tumor in the rectum, with a median of one disease site (range one to three), and liver involvement in 88% and lung in 38%. Six (18%) patients had chemotherapy for prior advanced disease. The most frequent grade 3-4 toxicity was neutropenia (41% of patients), but the regimen was well tolerated clinically, with febrile neutropenia in two patients and grade 4 neutropenia lasting >7 days in one; grade 3-4 diarrhea, nausea and vomiting in 6% of patients; grade 3-4 peripheral neuropathy in 9% of patients. Seventeen patients had a partial response (50%; 95% confidence interval 33%-67%), 13 had stable disease and one had progressive disease. Five patients underwent metastatic surgical resection after tumor shrinkage. Median response duration was 14 months (range 4.7-29.2+) and median time to progression was 11.3 months (range 1.1+-30.7+). CONCLUSIONS: This combination three-drug regimen is feasible and well tolerated without toxicity overlap. Preliminary antitumor activity compares well with standard double combinations, with an unusually long median time to progression. The recommended dose is 5-FU 3000 mg/m(2), weekly for 4 weeks, irinotecan 100 mg/m(2) days 1 and 15, oxaliplatin 80 mg/m(2) days 8 and 22. Further assessment of antitumor activity and safety is warranted.

Aged↗
PubMed2003

Multicentre phase II study and pharmacokinetic analysis of irinotecan in chemotherapy-naïve patients with glioblastoma.

BACKGROUND: To assess the antitumour activity and safety profile of irinotecan and its pharmacokinetic interactions with anticonvulsants in patients with glioblastoma multiforme. PATIENTS AND METHODS: This multicentre phase II and pharmacokinetic study investigated the effects of irinotecan 350 mg/m(2) given as a 90-min infusion every 3 weeks either prior to (group A) or after relapse following radiotherapy (group B) in chemotherapy-naïve patients with glioblastoma. Preferred concomitant medication for seizure prevention was valproic acid. Pharmacokinetic analysis of irinotecan and its main metabolites (SN-38, SN-38-G, APC and NPC) was performed during cycle 1. An independent panel of experts reviewed the activity data. RESULTS: Fifty-two patients (25 patients in group A and 27 patients in group B) received a total of 191 cycles of irinotecan. Forty-six patients (22 patients in group A and 24 patients in group B) were evaluable and externally reviewed for activity. According to external review, one partial response (group B), seven minor responses (three in group A and four in group B), 12 disease stabilisations (seven in group A and five in group B) were observed. This resulted in an overall response rate of only 2.2% (95% confidence interval 0.2% to 6.5%). The median time to tumour progression was 9 weeks in group A and 14.4 weeks in group B. Six-month progression-free survival rates were 26% in group A and 43% in group B. Grade 3-4 toxicities (percentage of patients in groups A and B) consisted of neutropenia (12.5% and 25.9%), diarrhoea (8.3% and 7.4%), asthenia (12.5% and 7.4%) and vomiting (0% and 7.4%). The clearance of irinotecan was 12.4 and 14.4 l/h/m(2) in two patients who received no anticonvulsant. In patients receiving valproic acid, the clearance of irinotecan was 17.2 +/- 4.4 l/h/m(2). CONCLUSIONS: Irinotecan given at the dose of 350 mg/m(2) every 3 weeks has limited clinical activity as a single agent in patients with newly diagnosed and recurrent glioblastoma after radiotherapy. The toxicity profile and plasma disposition of irinotecan and SN-38 were not strongly influenced by anticonvulsant valproic acid therapy. Although the response rate of irinotecan as a single agent was limited, it remains an attractive drug for combination studies in patients with glioblastoma.

Adult↗
PubMed2003

Metastatic malignant melanoma.

Malignant melanoma is one of the most worrisome tumors in terms of epidemiology, and incidence is increasing. The estimated lifetime risk in the United States is 1 in 75 people. As soon as the first distant metastasis appears, the disease becomes one of the most aggressive and chemoresistant tumors: 90-95% of patients do not survive more than 3 years. Results with chemotherapy are disappointing as few drugs have demonstrated an impact on survival. Drug combinations provide only a slightly higher response rate and do not overcome the natural chemoresistance of this tumor. Tamoxifen, which was widely investigated in the late 1980s and 1990s, has not added any benefit in terms of response rate or survival. Since their description as immunomodulating molecules, the cytokines interferon-alpha and interleukin-2 (IL-2) have been extensively tested in malignant melanoma. They seem to achieve higher response rates and survival rates than chemotherapy but undoubtedly lead to more long-term unmaintained remissions. Their combination with chemotherapeutic drugs, "chemoimmunotherapy", has been tested using various doses and schedules (one or two cytokines, single drug or combination chemotherapy). The combination of cisplatin and IL-2 plays a key role in this strategy. However, because of its higher toxicity, the real benefit of chemoimmunotherapy on patient survival still needs to be proven.

Antineoplastic Agents↗
PubMed2002

[Acute alveolo-interstitial pneumopathies in HIV-negative patients treated with antineoplastic chemotherapy].

INTRODUCTION: Treatment of malignant tumors can delay some opportunistic infections. In this paper, we report three cases of alveolo-interstitial pneumonia among HIV negative patients who received chemotherapy. EXEGESIS: All three patients received corticotherapy for a long time. In two cases, it was pneumocystis-tuberculosis coinfection. Evolution was favourable for two patients with sulfaméthoxazole-triméthoprime (one with corticotherapy). CONCLUSION: The possible role of chemotherapy, corticotherapy and malignant tumor in the pathogenesis of opportunistic infections will be discussed.

Acute Disease↗
PubMed2002

Oxaliplatin plus vinorelbine in advanced non-small-cell lung cancer: final results of a multicenter phase II study.

BACKGROUND: Oxaliplatin and vinorelbine are both active agents against non-small-cell lung cancer (NSCLC). In a previous phase I trial, we showed that oxaliplatin (130 mg/m2, day 1) and vinorelbine (26 mg/m2/day, days 1 and 8) can be safely combined when given every 21 days. We completed the evaluation of this new platinum-based doublet in advanced NSCLC patients in a multicenter phase II study. PATIENTS AND METHODS: Twenty-eight chemotherapy-naïve patients (22 men and six women: median age 58 years, range 33-70), including 20 with stage IV disease, received this out-patient combination, with 5-hydroxytryptamine-3-receptor agonists as the only prophylactic measure. RESULTS: A total of 117 cycles were given, for a median of three per patient (range 1-8). Of 26 eligible patients, nine achieved a partial response (WHO criteria), giving an objective response rate of 35% [95% confidence interval (CI) 17% to 56%]. The median progression free survival was 5.0 months (95% CI 3.1 to 6.9), median overall survival was 9.8 months (95% CI 2.2 to 17.5) and the 1-year survival rate was 37%. Neutropenia was the principal toxicity, grade 4 occurring in 11 patients (39%) and 25 cycles (22%). Four patients (14%) experienced one episode of febrile neutropenia each. Acute oxaliplatin-related neurosensory toxicity was prevalent, but was mild to moderate in the majority of patients (82%) and reversible. Grade 1/2 vomiting (65% of patients) and diarrhea (32% of patients) were easily managed. CONCLUSIONS: The oxaliplatin-vinorelbine doublet is a safe and active out-patient combination. It may represent an interesting alternative in the management of patients with NSCLC, and serve as a new doublet to which other active agents could be added.

Adult↗
PubMed2001

Randomized multicenter phase II study comparing a combination of fluorouracil and folinic acid and alternating irinotecan and oxaliplatin with oxaliplatin and irinotecan in fluorouracil-pretreated metastatic colorectal cancer patients.

PURPOSE: To assess antitumor activity and safety of two regimens in advanced colorectal cancer (CRC) patients with proven fluorouracil (5-FU) resistance in a randomized phase II study: 5-FU/folinic acid (FA) combined with alternating irinotecan (also called CPT-11) and oxaliplatin (FC/FO tritherapy), and an oxaliplatin/irinotecan (OC) combination. PATIENTS AND METHODS: Sixty-two patients were treated: arm FC/FO (32 patients) received, every 4 weeks, FA 200 mg/m(2) followed by a 400-mg/m(2) 5-FU bolus injection, then a 600-mg/m(2) continuous infusion of 5-FU on days 1 and 2 every 2 weeks administered alternately with irinotecan (180 mg/m(2) on day 1) and oxaliplatin (85 mg/m(2) on day 15). Arm OC (30 patients) received oxaliplatin 85 mg/m(2) and irinotecan 200 mg/m(2) every 3 weeks. RESULTS: In an intent-to-treat analysis, two partial responses lasting 10.7 and 16 months were observed with the tritherapy regimen, and seven (median duration, 11 months; range, 10.6 to 11.4 months) were observed with the bitherapy regimen. Median progression-free and overall survival times were 8.2 and 9.8 months, respectively, in the FC/FO arm and 8.5 and 12.3 months, respectively, in the OC arm. Main grade 3/4 toxicities were, respectively, neutropenia, 53% and 47%; febrile neutropenia, 13% and 3%; diarrhea, 19% and 10%; vomiting, 6% and 13%; and neurosensory toxicity, 3% and 3%. No treatment-related deaths occurred. CONCLUSION: The every-3-weeks OC combination is safe and active in advanced 5-FU-resistant CRC patients. The lower activity data seen with the tritherapy regimen may be related to the lower dose intensities of irinotecan and oxaliplatin in this schedule.

Adult↗
PubMed2001

Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma.

BACKGROUND: Currently, there is no gold standard for the treatment of patients with metastatic breast carcinoma who have experienced failure with anthracyclines and taxanes. A biologic rationale suggests that the mechanism of taxane resistance could be because of an excess of depolymerized tubulin that could enhance sensitivity to vinorelbine. The objective of the study was to assess the tolerance and efficiency of weekly vinorelbine in metastatic breast carcinoma after failure with taxanes. METHODS: Patients with measurable disease, a World Health Organization performance status of less than 3 and a life expectancy longer than 3 months were eligible. Persistent taxane-induced neuropathy higher than Grade 1 was an exclusion criterion. The initial planned dose was 30 mg/m(2)/week on an outpatient basis without granulocyte colony-stimulating factor (G-CSF). Neutrophil and platelet counts of 1.0 and 80 g/L, respectively, were required before each new injection; otherwise vinorelbine was delayed for 7 days with a dose reduction of 5 mg/m(2) at the second episode. The dose also was reduced if Grade 3 or 4 toxicity occurred. If the adverse event persisted or if the delay exceeded 14 days between 2 injections given at a dose of 20 mg/m(2), vinorelbine was definitively discontinued. RESULTS: Between November 1997 and March 1999, 40 patients with a median age of 49 (range, 39-69) were enrolled. All of them had previously received anthracyclines and taxanes. Because of the delays in neutrophil recovery, the median dose intensity did not exceed 22.5 mg/m(2)/week (range, 11.25-30), and the initial planned dose of 30 mg/m(2)/week appeared unfeasible without G-CSF. The starting dose therefore was 25 mg/m(2)/week after the first 6 patients. Neutropenia led to fever in only three patients. Other severe toxicities were Grade 2-3 neuropathy (n = 5), Grade 2-3 ileus (n = 7), Grade 3 anemia (n = 4), and Grade 3 sepsis (n = 1). Objective responses were observed in 10 of 40 patients (25%), 7 of whom had visceral metastases and 4 who were refractory to taxanes (including 2 patients with liver involvement > 50%). The median time to failure was 6 months (range, 4-12) for responding patients. Disease stabilization was achieved in 9 patients (23%) for a median duration of 5 months (range, 4-6). The median survival duration for the whole population was 6 months (range, 2-18+). CONCLUSIONS: Weekly vinorelbine is an active salvage therapy for metastatic breast carcinoma after failure with anthracyclines and taxanes, even in patients with taxane-refractory metastatic breast carcinoma. This confirms that vinorelbine and taxanes are not cross-resistant.

Adult↗
PubMed2001

A phase I and pharmacokinetic study of the novel aza-anthracenedione compound BBR 2778 in patients with advanced solid malignancies.

BBR 2778 is a novel aza-anthracenedione with no cardiotoxicity in preclinical models. This Phase I dose escalation trial of BBR 2778 was conducted to determine the maximum tolerated dose, the dose-limiting toxicity, and the pharmacokinetic profile of BBR 2778 in patients with advanced solid tumors. BBR 2778 was given in three consecutive weekly 30-min i.v. infusions over a 4-week cycle (cy). Thirty patients (pts) were treated with BBR 2778 at doses ranging from 5 to 150 mg/m2/week. The dose levels 5, 10, 16.5, 25, 37.5, 75, 112.5, and 150 mg/m2/week were investigated in 4 pts (9 cy), 3 pts (3 cy), 3 pts (5 cy), 6 pts (9 cy), 1 pt (1 cy), 4 pts (9 cy), 6 pts (18 cy), and 3 pts (4 cy), respectively. The dose-limiting toxicity was neutropenia, typically occurring at day 14. Other toxicities were mild to moderate and were principally thrombocytopenia, lymphopenia, alopecia, nausea, and vomiting and blue coloration of the skin and urine. No significant cardiac toxicity was observed. The plasma dose concentration curve fitted a biexponential profile, with a rapid distribution phase followed by a prolonged elimination phase (mean t1/2,z, 12 h). BBR 2778 displayed a large volume of distribution (range, 9.7-29.7 l/kg) with a high plasma clearance rate (0.75-1.31 l/h/kg). Less than 10% of the dose was recovered in urine as unchanged drug. The maximum tolerated dose was 150 mg/m2/week for 3 weeks, every 4 weeks. On the basis of this study, the recommended dose for Phase II studies is 112.5 mg/m2/week days 1 and 8 with individual optional administration at day 15, every 4 weeks. Antitumor activity was observed in patients with breast, small cell lung carcinoma, and facial cylindroma. This trial showed that BBR 2778 has a manageable toxicity profile on a weekly schedule. This lead compound of the aza-anthracenedione family shows promising antitumor activity and deserves Phase II investigation in patients with high risk of cumulative cardiotoxicity, such as anthracycline-pretreated breast cancer patients.

Adult↗
PubMed2001

[Quantification of hepatic arterial and portal venous flow using ultrasound contrast agents for early detection of liver metastases of colorectal cancers].

PURPOSE: To quantify liver blood flow using US contrast agents and to evaluate arterial and portal changes in control patients and patients with liver metastases. MATERIALS AND METHODS: Twenty eight patients were included in this study, 8 controls (M0) and 20 patients with liver metastases from colon carcinoma (M+). Hepatic blood flow from hepatic artery and portal vein were determined using quantification of enhancement after contrast injection using Power Doppler US. The ratio of enhancement rise from artery and vein allows calculation of Contrast Enhanced Doppler Perfusion Index (CEDPI) as previously described for Doppler Perfusion Index (DPI). RESULTS: A significant difference was noted for CEDPI between controls (0.49 +/- 0.07) and liver with metastases (0.70 +/- 0.12). CONCLUSION: This functional method of evaluation of liver blood flow was easy to perform, and would be valuable for early detection of overt micro-metastases before anatomical changes observed by conventional imaging. This is helpful for accurate staging of colon carcinoma.

Adult↗
PubMed2000

Phase I and pharmacokinetic study of the camptothecin analog DX-8951f administered as a 30-minute infusion every 3 weeks in patients with advanced cancer.

PURPOSE: DX-8951f is a totally synthetic derivative of camptothecin with greater cytotoxicity and more potent topoisomerase I inhibition than SN-38, topotecan, and camptothecin in preclinical studies. This phase I study aimed to describe the toxicity and to determine the maximum-tolerated dose (MTD) and pharmacokinetics of DX-8951f given as a 30-minute intravenous infusion every 3 weeks. PATIENTS AND METHODS: Twelve patients with refractory solid malignancies were treated with DX-8951f at dose levels ranging from 4 to 7.1 mg/m(2). All but one patient had received previous chemotherapy, and eight patients were considered heavily pretreated. Total DX-8951f plasma concentrations were assayed using high-performance liquid chromatography. RESULTS: Thirty-six cycles of DX-8951f were administered. Neutropenia was the dose-limiting toxicity, and it was dose-related, reversible, and noncumulative. Other toxicities included nausea and vomiting, alopecia, asthenia, fever, and anemia. Grade 1 or 2 diarrhea was observed in seven patients but was transient and resolved without requiring treatment. Pharmacokinetic analysis showed that DX-8951f had a half-life of 7.15 hours and a clearance rate of 1.65 L/h.m(2). The DX-8951f area under the plasma-concentration curve increased linearly with the dose. We defined the MTD of DX-8951f administered as a 30-minute intravenous infusion every 3 weeks as 7.1 mg/m(2). CONCLUSION: The dose-limiting toxicity of DX-8951f is neutropenia. The recommended dose for phase II studies is 5.33 mg/m(2) every 3 weeks in patients previously treated with chemotherapy.

Adult↗
PubMed2000

Transactivation of the metallothionein promoter in cisplatin-resistant cancer cells: a specific gene therapy strategy.

BACKGROUND: Cisplatin (cis-diamminedichloroplatinum) is one of the most active agents against a broad range of malignancies, including ovarian cancer. Cisplatin resistance appears to be associated with several molecular alterations, including overexpression of metallothionein, a metal-binding protein. In the present study, we attempted to take advantage of metallothionein overexpression to overcome cisplatin resistance. METHODS: Using a virus-free system (liposomes), we sought to express the suicide gene, thymidine kinase (TK), driven by the promoter of the human metallothionein IIa (hMTIIa) gene using the pMT-TK plasmid. We used cisplatin-resistant human ovarian carcinoma cells as a model. RESULTS: We first analyzed metallothionein expression using a ribonuclease protection assay. In comparison to parental cells, the cisplatin-resistant cells were found to have increased expression of metallothionein messenger RNA (mRNA). Metallothionein overexpression in these cells was not associated with an increased copy number of the hMTIIa gene or with different transfection efficiencies. Furthermore, we showed by reverse transcription-polymerase chain reaction analysis that transfection of the pMT-TK plasmid results in a 56-fold higher expression of thymidine kinase mRNA in cisplatin-resistant cells compared with parental cells, consistent with increased metallothionein promoter-mediated transactivation in the cisplatin-resistant cells. Transfection of resistant cells with pMT-TK or a control plasmid (pCD3-TK) resulted in a marked sensitization to ganciclovir, with a 50% cell growth-inhibitory concentration (IC(50)) of 20 microg/mL and 9 microg/mL, respectively. Transfections of the cisplatin-sensitive cells resulted in no sensitization to ganciclovir with pMT-TK (IC(50) 200 microg/mL) and a high sensitization with pCD3-TK (IC(50) = 6 microg/mL). CONCLUSION: These studies suggest that pMT-TK gene therapy may provide an alternative treatment for cisplatin-refractory ovarian tumors.

Cisplatin↗
PubMed2000

A dose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies.

PURPOSE: Gemcitabine and vinorelbine are active drugs with broad spectrum of activity and manageable toxicity in clinical trials. The aims of this study were to describe the toxicity, to determine the dose-limiting toxicity, and to define the doses of gemcitabine and vinorelbine to be recommended for phase II studies in patients with advanced cancers. PATIENTS AND METHODS: Drugs were given as 30-min infusions on day 1 and 8 (vinorelbine before gemcitabine) every 3 weeks. Thirty-six patients (male:female ratio 25:11; mean age 54, PS > 60) were treated including 1 retroperitoneal sarcoma, 7 head and neck, 10 lung, 4 thyroid, 6 pancreatic, 1 bladder, 2 ovary, 2 gastric, 1 rectum, 1 unknown primary, and 1 renal cell carcinoma. Doses of gemcitabine/vinorelbine ranged from 800/20 mg/m2 to 1500/30 mg/m2. RESULTS: The dose-limiting toxicity was neutropenia. A transient grade 2-3 elevation of transaminases was frequently observed at several dose-levels, although this toxicity did not appear to be dose dependant and was reversible at day 21 before the next cycle. Other toxicities were mild and easily manageable, consisting of fatigue and flu-like syndromes. Since the MTD was not reach at the higher dose-level, the recommended dose level of the gemcitabine-vinorelbine combination was 1500/30 mg/m2. One toxic death due to hematologic toxicity was reported in a heavily pretreated patient who underwent prior chemotherapy and pelvic radiotherapy. A total of 12 patients were treated at the recommended dose level which was associated with grade 3-4 neutropenia in 3 of 12 patients and in 22.9% of cycles. CONCLUSIONS: This study estimates that the recommended dose for phase II studies of gemcitabine-vinorelbine is 1500/30 mg/m2 at day 1 and 8 every three weeks. A careful monitoring of the hematologic toxicity is recommended in heavily pretreated patients and in patients who received pelvic radiotherapy. Partial responses observed in a patient with an advanced cisplatin-5-fluorouracil-resistant pancreatic adenocarcinoma and in a patient with mesothelioma support further evaluation of this combination in patients with tumors refractory to classical antitumor agents.

Adult↗
PubMed2000

Inhibition of glioma cells in vitro and in vivo using a recombinant adenoviral vector containing an astrocyte-specific promoter.

Gene therapy using the herpes simplex virus thymidine kinase (HSV-TK) gene in combination with the drug ganciclovir (GCV) is a promising approach for the treatment of cancer-inducing gliomas, a tumor with a poor prognosis. In an attempt to limit the toxic effects on normal tissues, we constructed a recombinant adenoviral vector, Adgfa2TK, in which the HSV-TK gene is driven by the promoter for the gene encoding glial fibrillary acidic protein, an intermediate filament protein expressed primarily in astrocytes. Infection by Adgfa2TK of a glial cell line (C6) and a non-glial cell line (MDA-MB-231) revealed markedly increased expression of HSV-TK in glial cells as determined by Western blot. In comparison, high HSV-TK protein levels were produced in both cell lines after infection with a control virus, AdCMVTK, in which the constitutive cytomegalovirus viral promoter was used to direct HSV-TK expression. Infection of two glial cell lines (C6, U251) and two non-glial cell lines (HepG2, MDA-MB-231) with Adgfa2TK followed by GCV treatment revealed high toxicity in glial cell lines (50% growth inhibitory concentration: <2 microg/mL of GCV) with little or no toxicity (50% growth inhibitory concentration: >75 microg/mL) in the non-glial cell lines. In vivo, injection of Adgfa2TK into C6 tumors grown in nude mice followed by intraperitoneal GCV treatment significantly repressed tumor growth compared with the controls. Adgfa2TK may be useful for directing expression of the HSV-TK gene to gliomas.

Adenoviridae↗