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(1/7975) Tumour ablation and hepatic decompensation rates in multi-agent chemoembolization of hepatocellular carcinoma.

Thirty-seven cirrhotic patients with 62 hepatocellular carcinoma (HCC) foci--most Child-Pugh class B or C and/or with large, inoperable tumours--underwent 148 sessions of transcatheter arterial chemoembolization (TACE) using lipiodol, doxorubicin and cisplatin. Treatment efficacy was assessed by serial hepatic arteriography in 34/37 (91.9%) patients and abdominal CT scanning in 3/37 (8.1%) patients. Child-Pugh status was determined prior to each treatment session. Varying degrees of control of tumour neovascularity occurred for a median 390 days (range 90 to > 1680 days) in 33/34 (97.1%) patients in whom progress hepatic arteriography was performed. Ablation of tumour neovascularity occurred in 6/6 (100%), 4/12 (33.3%) and 6/16 (37.5%) patients with HCC diameters < 4 cm, 4-7 cm and > 8 cm, respectively (p < 0.02). Significantly more sessions were required for ablation of larger tumours (p < 0.05). Recurrent HCC was detected in 50% of patients after a median 240 days (range 60-1120 days). Deterioration in Child-Pugh status followed a session of TACE on 19/148 (12.8%) occasions but resulted in unscheduled hospitalization on only 4/148 (2.7%) occasions, the highest incidence (8.3%) in Child-Pugh C patients. Actuarial survival was 27/36 (75.0%) at 6 months, 17/34 (50.0%) at 12 months, 14/34 (41.2%) at 18 months, 9/31 (29.0%) at 24 months and 4/27 (14.8%) at 36 months. Multi-agent TACE with lipiodol, doxorubicin and cisplatin provides a useful anti-tumour effect, even in cirrhotic patients with large HCCs. The incidence of clinically significant deterioration in hepatic function due to ischaemia of non-tumorous liver is acceptably low, even in Child-Pugh C patients.  (+info)

(2/7975) Intensive weekly chemotherapy is not effective in advanced pancreatic cancer patients: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

Twenty-two patients, with locally advanced unresectable and/or metastatic pancreatic carcinoma, received weekly administration of cisplatin 40 mg m(-2), 5-fluorouracil 500 mg m(-2), epidoxorubicin 35 mg m(-2), 6S stereoisomer of leucovorin 250 mg m(-2) and glutathione 1.5 mg m(-2), supported by a daily administration of lenograstim at a dose of 5 microg kg(-1). Nineteen patients were men and three were women. Median age was 63 years (range 47-70). At study entry, pain was present in 15 out of 22 patients (68%) with a mean value of Scott-Huskisson scale of 27.6+/-23.8, whereas a weight loss >10% was present in 15 patients. After eight weekly treatments, three partial responses were achieved for a response rate of 13% (95% CI 0-26%), five patients had stable disease and 14 progressed on therapy. Pain was present in 9 out of 22 patients (40%) with a mean value of Scott-Huskisson scale of 12.3+/-18.4. Eight patients (36%) (three partial response and five stable disease) had a positive weight change. Toxicity was mild: WHO grade III or IV toxicity was recorded in terms of anaemia in 7 out of 188 cycles (3.7%), of neutropenia in 9 out of 188 cycles (4.7%) and of thrombocytopenia in 3 out of 188 cycles (1.5%). Median survival of all patients was 6 months. The outcome of this intensive chemotherapy regimen does not support its use in pancreatic cancer.  (+info)

(3/7975) Role of dexamethasone dosage in combination with 5-HT3 antagonists for prophylaxis of acute chemotherapy-induced nausea and vomiting.

Dexamethasone (20 mg) or its equivalent in combination with 5-HT3 antagonists appears to be the gold-standard dose for antiemetic prophylaxis. Additional to concerns about the use of corticosteroids with respect to enhanced tumour growth or impaired killing of the tumour cells, there is evidence that high-dosage dexamethasone impairs the control of delayed nausea and emesis, whereas lower doses appear more beneficial. To come closer to the most adequate dose, we started a prospective, single-blind, randomized trial investigating additional dosage of 8 or 20 mg dexamethasone to tropisetron (Navoban), a 5-HT3 receptor antagonist, in cis-platinum-containing chemotherapy. After an interim analysis of 121 courses of chemotherapy in 69 patients, we have been unable to detect major differences between both treatment alternatives. High-dose dexamethasone (20 mg) had no advantage over medium-dose dexamethasone with respect to objective and subjective parameters of acute and delayed nausea and vomiting. In relation to concerns about the use of corticosteroids in non-haematological cancer chemotherapy, we suggest that 8 mg or its equivalent should be used in combination with 5-HT3 antagonists until further research proves otherwise.  (+info)

(4/7975) MycN sensitizes neuroblastoma cells for drug-induced apoptosis.

Amplification of the MYCN gene is found in a large proportion of neuroblastoma and considered as an adverse prognostic factor. To investigate the effect of ectopic MycN expression on the susceptibility of neuroblastoma cells to cytotoxic drugs we used a human neuroblastoma cell line harboring tetracycline-controlled expression of MycN. Neither conditional expression of MycN alone nor low drug concentrations triggered apoptosis. However, when acting in concert, MycN and cytotoxic drugs efficiently induced cell death. Apoptosis depended on mitochondrial permeability transition and activation of caspases, since the mitochondrion-specific inhibitor bongkrekic acid and the caspase inhibitor zVAD-fmk almost completely abrogated apoptosis. Loss of mitochondrial transmembrane potential and release of cytochrome c from mitochondria preceded activation of caspase-8 and caspase-3 and cleavage of PARP. CD95 expression was upregulated by treatment with cytotoxic drugs, while MycN cooperated with cytotoxic drugs to increase sensitivity to CD95-induced apoptosis and enhancing CD95-L expression. MycN overexpression and cytotoxic drugs also synergized to induce p53 and Bax protein expression, while Bcl-2 and Bcl-X(L) protein levels remained unchanged. Since amplification of MYCN is usually associated with a poor prognosis, these findings suggest that dysfunctions in apoptosis pathways may be a mechanism by which MycN-induced apoptosis of neuroblastoma cells is inhibited.  (+info)

(5/7975) A novel trinuclear platinum complex overcomes cisplatin resistance in an osteosarcoma cell system.

Multinuclear platinum compounds have been designed to circumvent the cellular resistance to conventional platinum-based drugs. In an attempt to examine the cellular basis of the preclinical antitumor efficacy of a novel multinuclear platinum compound (BBR 3464) in the treatment of cisplatin-resistant tumors, we have performed a comparative study of cisplatin and BBR 3464 in a human osteosarcoma cell line (U2-OS) and in an in vitro selected cisplatin-resistant subline (U2-OS/Pt). A marked increase of cytotoxic potency of BBR 3464 in comparison with cisplatin in U2-OS cells and a complete lack of cross-resistance in U2-OS/Pt cells were found. A detailed analysis of the cisplatin-resistant phenotype indicated that it was associated with reduced cisplatin accumulation, reduced interstrand cross-link (ICL) formation and DNA platination, microsatellite instability, and reduced expression of the DNA mismatch repair protein PMS2. Despite BBR 3464 charge and molecular size, in U2-OS and U2-OS/Pt cells, BBR 3464 accumulation and DNA-bound platinum were much higher than those observed for cisplatin. In contrast, the frequency of ICLs after exposure to BBR 3464 was very low. The time course of ICL formation after drug removal revealed a low persistence of these types of DNA lesions induced by BBR 3464, in contrast to an increase of DNA lesions induced by cisplatin, suggesting that components of the DNA repair pathway handle the two types of DNA lesions differently. The cellular response of HCT116 mismatch repair-deficient cells was consistent with a lack of influence of mismatch repair status on BBR 3464 cytotoxicity. Because BBR 3464 produces high levels of lesions different from ICLs, likely including intra-strand cross-links and monoadducts, the ability of the triplatinum complex to overcome cisplatin resistance appears to be related to a different mechanism of DNA interaction (formation of different types of drug-induced DNA lesions) as compared with conventional mononuclear complexes rather than the ability to overcome specific cellular alterations.  (+info)

(6/7975) Testicular cancer: an oncological success story.

Testicular cancer has become a model for a curable neoplasm. Our studies with cisplatin combination chemotherapy allow us to conclude that: (a) short-duration intensive induction therapy with the most active agents in optimal dosage is more important than maintenance therapy; (b) modest dose escalation increases toxicity without improving therapeutic efficacy; (c) it is possible to develop curative salvage therapy for refractory germ cell tumors; and (d) preclinical models predicting synergism, such as vinblastine + bleomycin or cisplatin + etoposide have clinical relevance. Finally, testicular cancer has also become a model for new drug development. Cisplatin was approved by the Food and Drug Administration for testis and ovarian cancer, and etoposide and ifosfamide were approved for refractory germ cell tumors. The success of these studies confirms the importance of the continued search for new investigational drugs in all solid tumors.  (+info)

(7/7975) Multimodality therapy for locally advanced and limited stage IV breast cancer: the impact of effective non-cross-resistance late-consolidation chemotherapy.

To determine the effectiveness of non-cross-resistant late-consolidation chemotherapy in locally advanced breast cancer (LABC) and stage IV breast cancer, we review our experience with two regimens. Between 1985 and 1991, we enrolled 56 patients with LABC, who were treated with a doxorubicin-based adjuvant regimen, followed by a late-consolidation non-cross-resistant regimen containing methotrexate, 5-fluorouracil, cisplatin, and cyclophosphamide. Between 1985 and 1996, a total of 45 patients with limited stage IV breast cancer underwent surgical excision of all evaluable disease, making them metastatic (stage IV) with no evaluable disease. Surgery was followed by a doxorubicin-containing regimen and then a late-consolidation non-cross-resistant regimen, which was either methotrexate, 5-fluorouracil, cisplatinum, and cyclophosphamide or 5-fluorouracil, mitomycin, etoposide, and cisplatin. Twenty-four patients with limited bone metastases that were unresectable were treated with a doxorubicin-containing regimen, radiation therapy to all sites of disease, and then one of the two late non-cross-resistant regimens. With a median follow-up of 84 months, 78% of patients with LABC are alive, and 68% are free of disease. After a median follow-up of 44 months, 53% of patients with stage IV with no evaluable disease are alive and free of disease. The use of non-cross-resistant late-consolidation chemotherapy is an effective strategy in the treatment of patients with LABC and selected patients with limited stage IV breast cancer.  (+info)

(8/7975) Modification of non-conservative double-strand break (DSB) rejoining activity after the induction of cisplatin resistance in human tumour cells.

The induction of collateral radioresistance after the development of cisplatin resistance is a well-documented phenomenon; however, the exact processes that are responsible for the cisplatin-induced radioresistance remain to be elucidated. There was no obvious difference in the level of radiation-induced DNA double strand breaks (DSBs), in DSB rejoining rates, or the level of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) in the cisplatin- and radiation-sensitive 2780/WT and cisplatin-resistant 2780/CP cell lines. However, there was a significantly (P < 0.01) lower level of DSB misrejoining activity within nuclear protein extracts derived from the cisplatin- and radiation-sensitive 2780/WT and OAW42/WT tumour cell lines than in similar extracts from their cisplatin- (and radiation-) resistant 2780/CP and OAW42/CP counterparts. All of the DSB misrejoining events involved deletions of between 134 and 444 bp that arose through illegitimate recombination at short repetitive sequences, such as those that arise through non-homologous repair (NHR). These data further support the notion that the radiosensitivity of DSB repair proficient human tumour cell lines may be partly determined by the predisposition of these cell lines to activate non-conservative DSB rejoining pathways. Furthermore, our data suggest that the induction of acquired cisplatin resistance is associated with a two- to threefold decrease in the activity of a non-conservative DSB rejoining mechanism that appears to be a manifestation of NHR.  (+info)