ZIB

Hits per page

hits 1 - 2 | 2 hits

Sorting

Electronic Resource

Sequential administration of temozolomide and fotemustine: Depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours (1999)

Gander, M. ; Leyvraz, S. ; Decosterd, L. ; [et al.]

Springer

Annals of oncology 10 (1999), S. 831-838

add to mindlist on the mindlist

Details

ISSN: 1569-8041

Keywords: melanoma ; pharmacodynamics ; pharmacokinetics ; temozolomide

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Background: The DNA repair protein O6-alkylguanine-DNA alkyl transferase (AT) mediates resistance to chloroethylnitrosoureas. Agents depleting AT such as DTIC and its new analogue temozolomide (TMZ) can reverse resistance to chloroethylnitrosoureas. We report the results of a dose finding study of TMZ in association with fotemustine. Patients and methods: Twenty-four patients with metastatic melanoma or recurrent glioma were treated with escalating dose of oral or intravenous TMZ ranging from 300 to 700 mg/m2, divided over two days. Fotemustine 100 mg/m2 was given intravenously on day 2, 4 hours after TMZ. AT depletion was measured in peripheral blood mononuclear cells (PBMCs) and in selected cases in melanoma metastases and was compared to TMZ pharmacokinetics. Results: The maximum tolerated dose (MTD) of TMZ was 400 mg/m2 (200 mg/m2/d) when associated with fotemustine the 2nd day with myelosuppression as dose limiting toxicity. The decrease of AT level in PBMCs was progressive and reached 34% of pretreatment values on day 2. There was however wide interindividual variability. AT reduction was neither dose nor route dependent and did not appear to be related to TMZ systemic exposure (AUC). In the same patients, AT depletion in tumour did not correlate with the decrease of AT observed in PBMCs. Conclusions: PBMCs may not be used as a surrogate of tumour for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therapy.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1008304032421

Permalink

Library	Location	Call Number	Volume/Issue/Year	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

Electronic Resource

Rationale for using TNFα and chemotherapy in regional therapy of melanoma (1994)

Lejeune, F. ; Liénard, D. ; Eggermont, A. ; [et al.]

New York, N.Y. : Wiley-Blackwell

Journal of Cellular Biochemistry 56 (1994), S. 52-61

add to mindlist on the mindlist

Details

ISSN: 0730-2312

Keywords: melanoma ; TNFα ; isolation perfusion ; melphalan ; interferon-γ ; Life and Medical Sciences ; Cell & Developmental Biology

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Biology , Chemistry and Pharmacology , Medicine

Notes: Recombinant tumor necrosis factor-alpha (rTNFα) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNFα is hampered by severe systemic side-effects. The maximum tolerated dose range from 350 to 500 mg/m2, which is at least 10-fold less than the efficient dose in animals. Isolation perfusion of the limbs (ILP) allows the delivery of high dose rTNFα in a closed system with acceptable side-effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNFα with chemotherapy, with interferon-y, and with hydperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we obtained a 91% complete response, compared with 52% after ILP with melphalan alone. Release of nanograms levels of TNFα in the systemic circulation was evident but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this prtocol is due to a dual targeting: rTNFα activates and electively lyses the tumor endothelial cells while melphalan is mainly cytoxic to the tumor cells. ILP with rTNFα appears to be a useful model for studying the biochemotherapy of cancer in man.

Additional Material: 2 Ill.