摘要:

The incidence of malignant melanoma continues to rise exponentially and it is estimated that 7000 people will die of metastatic malignant melanoma annually. Conventional chemotherapy, immunological and/or biological therapies and novel combinations are being studied intensively in an effort to improve the dismal outcome for patients with this disease. This review deals with recently published studies and the state of the art of the treatment available for metastatic malignant melanoma.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

This study provides the first evidence that treatment of human pancreatic adenocarcinoma is markedly improved by the intratumoral administration of chemotherapeutic agents in a novel drug delivery system. The effect of chemotherapeutic agents delivered in a sustained-release, protein-based, injectable gel was evaluated on the growth of human pancreatic adenocarcinoma cell line, BxPC-3.In vitrochemosensitivity of BxPC-3 cells exposed for 24 or 72 h to fluorouracil (0.01–5 mM), cisplatin or doxorubicin (0.1–50 μM) and floxuridine, vinblastine, mitomycin or paclitaxel (1.0–100 μM) was compared with that of untreated cells.In vitrochemosensitivity was also studied with fluorouracil and mitomycin in the poorly differentiated PANC-1, human pancreatic cancer cell line. Survival was determined after 7–10 days. All drugs decreased cell growth in a dose-dependent fashion. The efficacy of fluorouracil, cisplatin and doxorubicin increased with prolonged exposure, rendering these drugs most appropriate for a sustained-release preparation. Forin vivostudies, athymic nude mice bearing BxPC-3 xenografts were treated either with fluorouracil, cisplatin or doxorubicin in the therapeutic injectable gel containing epinephrine or with vehicle alone administered intratumorally on days 1 and 4. After 28 days, the mice were sacrificed and tumors dissected and weighed. Tumors in mice treated with the injectable gel decreased in size by 72–79% compared with tumors in untreated controls and tumors treated with vehicle alone. Intratumoral injection of drug solution and intraperitoneal injection of drug in the injectable gel did not change tumor size compared with controls. In a drug-retention study, mice were injected intratumorally with [3H]fluorouracil either in the injectable gel or in solution. Sustained radioactivity was observed in tumors injected with the gel, and, conversely, greater radioactivity was detected in the liver and kidneys in mice receiving the radiolabeled solution. hese results suggest that the therapeutic injectable gel chemotherapy, when given intratumorally, may improve tumor response with less systemic toxicity in comparison with conventional systemic chemotherapy.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Multidrug resistance in cancer cells, in cell culture and in the clinic, is often associated with a membrane protein (the multidrug resistance pump or P-glycoprotein) that pumps out anti-cancer drugs as fast as they enter the cell. This pump is blocked by a range of well-known pharmaceuticals that reverse drug resistance. We have investigated whether effective reversal of drug resistance could be achieved by using many reversers together, each at a low dose relative to its maximal tolerated plasma level. We measured in cell culture, using resistant P388 cells in suspension, the extent of reversal of the accumulation of two labeled cytotoxins (vinblastine and daunomycin). We fitted the data to a modified Michaelis–Menten equation and extracted the half-inhibition constants for 18 reversers acting on the pump. We measured also the reversal of resistance in a cell growth assay using incorporation of labeled thymidine. We showed that these drugs in groups of up to 18 together, each drug being at a low dose, in many cases well-tolerated in humans, had additive effects so that the combination was as effective as any of the drugs present singly. This was the case both for reversal of cell accumulation and for the effects of cytotoxins on cell growth. Our data show that a low-dose multidrug approach to saturation reversal of the multidrug pump is feasible in cell culture and provide the initial experimental basis for the development of an effective regime of such combination reversal therapy.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Multiple myeloma is a plasma cell malignancy which is generally incurable in spite of a high initial response to chemotherapy. Relapsing disease commonly heralds an increase in the incidence of drug resistance which is often mediated by the product of theMDR-1 gene, P-glycoprotein (Pgp). One approach to modulating drug resistance due to Pgp overexpression has involved the use of agents known as chemomodulators which inhibit its function. We have developed a human xenograft model of multiple myeloma using the SCID mouse to evaluate the efficacy and toxicities of new MDR-1 chemomodulators. Cyclosporin A (CsA) is a widely used immunosuppressant which has been demonstrated to be a potent inhibitor of Pgpin vitroat concentrations which are clinically achievable. Preliminary studies revealed an acute toxicity in our SCID model which was associated with the combination of CsA and doxorubicin, and which was not observed with either drug alone, nor with cremaphor, the vehicle for CsA. In the current study, non-tumor bearing SCID mice were dosed with doxorubicin or the combination of doxorubicin with cremaphor, verapamil or CsA. Animals were sacrificed and tissues harvested for morphologic examination and for HPLC analysis of doxorubicin levels. In all tissues examined, there was a marked increase in tissue levels of doxorubicin when combined with CsA. Results also revealed a higher incidence and severity of myocardial damage in those animals receiving the combination of doxorubicin and CsA than in those receiving other combinations. The elevations in tissue levels observed with doxorubicin and CsA may contribute to the acute toxicities observed in the SCID mouse model.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Ether lipids in general are accumulated in tumor tissue with a favorable tumor/healthy tissue ratio. The uptake of the boron-containing analograc-1-(9-o-carboranyl)nonyl-2-methyl-glycero-3-phosphocholine (B-Et-11-OMe) was studied in C3H mice bearing the murine mammary carcinoma AT17 and in BALB/c mice bearing an osteosarcoma. Boron concentrations of tumor, blood, liver and kidney were followed up to 48 h by inductively coupled plasma emission spectrometry and inductively coupled plasma mass spectrometry. Boron concentration in AT17 mamma carcinoma rose up to 2 mg/kg and the tumor/blood ratio rose to 0.5. The bulk was taken up by the liver. Osteosarcoma did not take up B-Et-11-OMe. This result constitutes a significant contrast to the behavior of published (non-boron-containing) analogs. It is interpreted in terms of critical micellar concentration (CMC). Whereas earlier work with ether lipids was done well below CMC, this study was undertaken above. Further studies will concentrate on syntheses of high CMC analogs.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

We have measured the cytotoxic effect of 1 h exposure to doxorubicin (DOX) on a panel of tumor cell lines. Cellular effects were measured by monolayer colony-forming assay and a colorimetric cytotoxicity assay. As parameters of chemosensitivity we used two different end-points: the dose of DOX that reduces to 50% the number of colonies (ID50) and the dose of DOX that reduces the final optical density to 50% of the control value (IC50). There was a significant correlation between both chemosensitivity indices (r= 0.886,p= 0.0034). DOX-induced DNA doublestrand breaks (dsb) were evaluated using pulsed-field gel electrophoresis (PFGE) and compared with cellular effects, P-glycoprotein expression (P-170) and intracellular glutathione (GSH) levels. Our results showed a relationship between the slope of DNA dsb dose–response curves and the percentage of cells that express P-170 (r= −0.957,p= 0.0002). Our study also detects a positive relationship between cellular chemosensitivity parameters and GSH content [ID50versus GSH (r= 0.794,p= 0.0186), IC50versus GSH (r= 0.790,p= 0.0198)] in our panel of cell lines.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Micronuclei (MN) induction by carboplatin, cis-diammine-1, 1-cyclobutane decarboxylate platinum (II) (CBDCA), in B and T lymphocytes was studied by the MAC (morphology/antibody/chromosome) method which allows the immunologic identification of different cell lineages. An increased frequency of MN in B and T lymphocytes in CBDCA-treated cultures compared with controls was observed (p

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The cell growth inhibitory activity, antitumor activity and toxicity of M-16 and M-18, the major metabolites of a new mitomycin C (MMC) derivative KW-2149, in mouse and human were compared with those of KW-2149 or MMCin vitroandin vivo.The growth inhibitory activity of M-18, a symmetrical disulfide dimer, against human uterine cervix carcinoma HeLa S3cells was almost equivalent to that of KW-2149 and their IC50values were about 10-fold smaller than that of MMC. The activity of M-16, a methyl sulfide form, was almost equivalent to that of MMC. The cell-killing activity of MMC and M-16 was augmented in the hypoxic condition, whereas that of KW-2149 and M-18 was reduced. M-16 also exhibited almost equivalent activities to MMCin vivoin terms of many biological profiles, i.e. antitumor activity against murine P388 leukemia, ascitic or solid B16 melanoma or human lung carcinoma xenograft L-27, and bone marrow toxicity in mice. Thesein vitroandin vivoresults indicate that the antitumor activity and toxicity of KW-2149 might not be mediated by M-16 in mice. On the other hand, M-18 exhibited almost equivalent activities to KW-2149 in these regards, suggesting the involvement of M-18 in the biological activities of KW-2149. However, the small values of the area under the curve of M-18 in mice make this unlikely. Thus the biological activities of KW-2149 in mice are not explained by the M-16 or M-18 concentration in plasma and are postulated to be manifested by KW-2149 itself.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Cyclophosphamide, an alkylating agent, is currently being used for the treatment of various types of cancer, either alone or in combination with other cytostatic drugs. However, cyclophosphamide has a detrimental effect on lipid metabolism and causes hyperlipidemia in patients. Since α-tocopherol is known to reduce hyperlipidemia, we have investigated the effects of adding α-tocopherol to the cyclophosphamide treatment. Our study, carried out on fibrosarcoma-bearing rats, shows that α-tocopherol markedly reduces cyclophosphamide-induced hyperlipidemia and brings lipid metabolism down to values observed in untreated controls.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Side effects of cisplatin and carboplatin include nausea, vomiting, peripheral neuropathy, nephrotoxicity, hearing loss, bone marrow depression, and rarely Lhermitte's sign and allergic reactions. A unique case of idiosyncrasy related to carboplatin administration was observed in a young woman treated for ovarian cancer. Symptoms and signs included skin rash, shortness of breath, and redness of face and upper trunk, without drop in blood pressure or change in heart rate, and were resolved within a short time following administration of hydrocortisone and promethazine.

ISSN:0959-4973    

出版商:OVID    

年代:1995

数据来源: OVID