摘要:

This study evaluates the degree of kidney damage during cisplatin/ifosfamide-based combination chemotherapy and its possible prevention by amifostine. Thirty-one patients with solid tumors stratified according to pretreatment were randomized to receive cisplatin/ifosfamide-based chemotherapy with or without amifostine (1000 mg absolute) given as a short infusion prior to cisplatin. Chemotherapy consisted of cisplatin (50 mg/m2), ifosfamide (4 g/m2) and either etoposide (500 mg/m2) (VIP regimen) or paclitaxel (175 mg/m2) (TIP regimen) repeated at 3 weekly intervals. For all patients the glomerular filtration rate (GFR) measured by creatinine clearance, serum creatinine, electrolytes and differential urinary protein excretion were determined prior to, during and after each treatment cycle. A total of 62 cycles of chemotherapy were evaluable. In the amifostine arm the GFR was almost completely maintained after application of two cycles of chemotherapy (121 to 108 ml/min), whereas in the control group a 30% reduction of the GFR (105 to 80 ml/min) was observed. In both groups marked increases of glomerular and tubular marker profiles peaking at day 3 after chemotherapy were found with a nearly complete reversibility of these changes prior to the next chemotherapy cycle. Patients receiving amifostine had a lower degree of hypomagnesemia, as well as a lower urinary excretion ofN-acetyl-glucosaminidase and albumin, indicating less tubular damage compared to the control patients. Treatment with 1000 mg amifostine resulted in an almost complete preservation of GFR. This corresponded to a slightly reduced excretion of tubular marker proteins and a lower incidence of hypomagnesemia during chemotherapy in amifostine patients compared to controls. This dose of amifostine may be sufficient for nephroprotection in patients without pre-existing risk factors for renal damage who undergo a restricted number of chemotherapy cycles.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The objective of this study was to evaluate a regimen of full doses of docetaxel and cisplatin, using an alternating schedule, as first-line therapy for patients with inoperable non-small cell lung cancer (NSCLC). The standard concomitant schedule does not allow full doses of both drugs to be administered. We wanted to see if there was an advantage to be gained by administering full doses of both docetaxel and cisplatin, using a different schedule. Docetaxel 100 mg/m2was given once every 6 weeks from week 1 and cisplatin (120 mg/m2for two doses and 100 mg/m2thereafter) once every 6 weeks from week 4, for six cycles (three docetaxel and three cisplatin). Thirty-six of the 44 patients enrolled were evaluable for efficacy. Forty-eight percent of the patients had good (KPS 90-100%) performance status. A median of five cycles was administered, for which no dose reductions were necessary. There were 13 of 36 partial responses (36%; 95% CI 21-54%) and 15 of 36 patients achieved stable disease (42%). The median duration of response was 10.5 months, the median time to progression was 4.5 months and the median survival was 9 months. The 1 and 2 year survival rates were 39 and 16%, respectively. The most frequent grade 3-4 toxicities were nausea (23% of patients), vomiting (18%) and neutropenia (77%). Infections were also common, but not severe. The alternating schedule produced response, toxicity and survival figures that compared favorable with those using the concomitant schedule. This study could serve as a model for future studies of non-cisplatin-containing regimens, in which full doses of docetaxel could alternate with full doses of other new agents active against NSCLC.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Gemcitabine is a deoxycytidine analog with broad antitumor activity. Its main toxicities include myleosuppression, flu-like symptoms, bronchospasms and mild skin rash. We report three cases, in which the patients developed time- and dose-limiting erysipeloid skin reactions confined to areas of impaired lymphatic drainage after application of gemcitabine. Three patients with metastatic tumors (breast cancer, endometrial cancer and non-small cell lung cancer) received weekly infusions of gemcitabine (1000 mg/m2). All patients suffered from lymphedema of different origin and developed an erysipeloid erythema 40-48 h after chemotherapy within their pre-existing lymphedema. Genuine erysipela was ruled out by laboratory tests and clinical observation. The skin reaction was repeatedly observed and faded after 14 days without specific treatment. Although the pathogenesis of the observed reaction is unclear, it is suspected that the skin symptoms were caused by gemcitabine or its metabolites. Gemcitabine is usually metabolized fast and excreted renally. In areas with impaired lymphatic drainage pharmakocinetics might be altered: inactivation happens slower and the drug might accumulate in the s.c. and cutaneous tissue, thus increasing local toxicity. Clinical judgement and biochemical parameters can help to tell apart genuine erysipela and the erysipeloid reaction.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

A new semi-synthetic podophyllotoxin derivative, 4′-O-demethyl-4β-(2′′-nitro-4′′-fluoroanilino)-4-desoxypodophyllotoxin (compound 1), an analog of GL-331 (compound 2), is a potent and broad-spectrum inhibitor of cultured human cancer and drug-resistant cell growth. In general, 4′-demethylepipodophyllotoxin analogs, including 2, exert anti-tumor activity by targeting the nuclear enzyme DNA topoisomerase II, but 1 is not an enzyme inhibitor. Unlike the cytotoxic activity of compound 2, cell killing by 1 is dose-limiting and a significant fraction of cells (30-40%) survive treatment. As an approach to investigate mechanism of action, 1-resistant A549 (human lung cancer) sub-lines were selected and characterized. Results of the work show that 1-resistant cells: (i) are moderately cross-resistant (2- to 3-fold) to various cytotoxic drugs via a P-glycoprotein-independent mechanism, (ii) have an altered growth habit, (iii) are deficient in normal attachment on plastic and collagen substrata, and (iv) have an altered plasma membrane protein composition including several proteins in the 140->200 kDa molecular mass range and a doublet of phosphoserine-containing proteins of about 135 kDa. Since 1 treatment of cells affects neither cellular attachment or membrane-protein phosphorylation, the changes observed in 1-resistant cells are interpreted as a survival response to drug action.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

It is well known that the anti-cancer drug cisplatin has an ototoxic property; however, the details are not yet evident. In this study, the expression of inducible nitric oxide synthase (iNOS/NOS II) in the vestibule of guinea pigs after i.p. injections of cisplatin was examined immunohistochemically. Three days after the injection of cisplatin (10 mg/kg) or placebo, animals were sacrificed. Then the temporal bones were removed and subjected to immunohistochemical studies for iNOS. In the cisplatin group, iNOS was detectable, whereas the tissue in the control group was negative for iNOS. The vestibule, the wall of blood vessels and the vestibular ganglion cells showed immunoreactivity for iNOS. It is known that iNOS catalyzes an inadequate quantity of NO under pathological conditions. Increased NO levels lead to inner ear dysfunction. Therefore, our results indicate that iNOS could also mediate the vestibulo-toxicity of cisplatin.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Thein vivoantitumor activity and toxicity of a newly synthesized polymeric prodrug of cisplatin was investigated and also compared with plain cisplatin. The prodrug included a dicarboxymethyl-dextran conjugate of cisplatin (DCM-Dex/CDDP). DCM-Dex/CDDP was i.v. injected in mice bearing s.c. Colon 26 mouse colon cancer cells. The tissue distribution of platinum was thereafter determined by flameless atomic absorption spectrophotometry. The platinic concentration of the organs showed a high rate of retention at 24 h after injection in the DCM-Dex/CDDP-treated mice. No biochemical or hematologically adverse effects were observed. In addition, DCM-Dex/CDDP showed a significantly higher antitumor activity than cisplatin alone. These results indicate that DCM-Dex/CDDP may therefore be a potentially effective cancer chemotherapy.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Anticancer agents effect tumor cell killing bothin vivoandin vitrothrough the induction of apoptosis. Endonuclease-mediated internucleosomal DNA fragmentation, the most widely used biochemical marker of apoptosis, has been shown to play a central role in apoptosis in many experimental systems. In the present investigation, we report that activation of endonuclease(s) leading to oligonucleosomal DNA fragmentation is common and an essential event in apoptosis, induced by different anticancer drugs, adriamycin, etoposide and cisplatin. The endonuclease inhibitors aurintricarboxylic acid and zinc ion prevented apoptotic cell death in human monocytic leukemic cell line U937, as documented by DNA fragmentation, morphological and nuclear alterations, and cell viability assay. Additional studies suggest endonuclease(s)-mediated DNA fragmentation may not play a central role in apoptosis in the same cell line in response to other inducers such as heat shock and cells may undergo cell death showing all morphological features of apoptosis even in the absence of DNA fragmentation.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The antitumor activity of cinnamamide (CNM), an agent acting on matrix metalloproteinase (MMP), was investigated in the present study. CNM displayed low cytotoxicity. By the MTT assay the IC50(50% inhibitory concentration) values of CNM on cell proliferation ranged from 1.29 to 1.94 mM in human oral epidermoid carcinoma KB cells, human hepatoma BEL-7402 cells and human fibrosarcoma HT-1080 cells. Moreover, the IC50for human fetal lung 2BS cells reached 4.33 mM. The administration of CNM in the range of 50-150 mg/kg (i.p. or p.o.) showed moderate antitumor effects in mice. When administered i.p. or p.o., CNM (150 mg/kg) inhibited the growth of transplanted hepatoma 22 by 48.8 or 40.5%, respectively. At the dose of 100 mg/kg, CNM inhibited the growth of colon 26 carcinoma by 39.0% and that of Lewis lung carcinoma by 53.9%. In the Lewis lung carcinoma model, CNM at the dose of 100 mg/kg (i.p.) also reduced the lung metastasis by 59.1%. Gelatine zymography revealed that CNM was able to decrease the level of MMP-2 in conditioned medium of HT-1080 tumor cells in a concentration-dependent manner. These results indicate that CNM is an antitumor agent with low cytotoxicity acting on MMP and may serve as a lead compound in the development of antitumor drugs.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The present study was performed to evaluate the adverse effects of KR-30035, a multidrug-resistance modulator, on the cardiovascular systemin vivo, along with its effect on paclitaxel-induced cell cycle arrest in cultured cancer cells. In anesthetized rats, KR-30035 was about 10-fold less potent than verapamil in lowering blood pressure (i.v. ED20: 0.320±0.052 and 0.034±0.005 mg/kg, respectively) and in producing electrocardiogram changes. In conscious spontaneously hypertensive rats, verapamil caused a significant antihypertensive effects at the doses tested (p.o. ED20, 7.8±4.0 mg/kg), whereas KR-30035 did not significantly change either the blood pressure or the heart rate at any doses tested (up to 100 mg/kg). The estimated i.v. LD50values in mice were 5.9 and 48.9 mg/kg for verapamil and KR-30035, respectively. In the presence of 10 μM KR-30035, paclitaxel (1 μM) when added to cultures of HCT15/CL02 human cancer cells greatly shifted the cell population from the G0/G1phases towards G2/M phases (from 42.4, 30.3 and 27.3 to 14.6, 21.5 and 63.9% for the G0/G1, S and G2/M phases, respectively), with a similar magnitude to that of 10 μM verapamil (14.0, 15.7 and 70.3%, respectively). These results suggest that KR-30035 has weakerin vivoeffects on the cardiovascular system compared with verapamil, while potentiating the G2/M arresting effect of paclitaxel on the cell cycle.

ISSN:0959-4973    

出版商:OVID    

年代:2000

数据来源: OVID