Me. Richardson et Dw. Siemann, TUMOR-CELL HETEROGENEITY - IMPACT ON MECHANISMS OF THERAPEUTIC DRUG-RESISTANCE, International journal of radiation oncology, biology, physics, 39(4), 1997, pp. 789-795
Citations number
22
Categorie Soggetti
Oncology,"Radiology,Nuclear Medicine & Medical Imaging
Purpose: The aim of these studies was to determine whether chemotherap
y-resistant tumor cell sublines derived from a single starting cell po
pulation with identical treatment protocols, have the same mechanism o
f resistance. Methods and Materials: Twelve cyclophosphamide-resistant
sublines were derived from KHT-iv murine sarcoma cells by repeated ex
posures to 2, 4, or 8 mu g/ml doses of 4-hydroperoxycyclophosphamide (
4-OOHCP), To investigate possible mechanisms of resistance, glutathion
e (GSH) levels, glutathione S-transferase (GST) activity, and aldehyde
dehydrogenase (ALDH) activity were determined, In addition, studies w
ith the GSH depletor buthionine sulfoximine (BSO) and the ALDH inhibit
or diethylamino-benzaldehyde (DEAB) were undertaken. Results: Resistan
t factors to 4-OOHCP, assessed at 10% clonogenic cell survival, ranged
from 1.5-7.0 for the various cell lines, Crossresistance to melphalan
and adriamycin also were commonly observed, Increased GSH levels, GST
activity and ALDH activity were detected in the sublines but not all
exhibited the same pattern of biochemical alterations. The response to
GSH and ALDH inhibitors also varied among the sublines; the resistanc
e being reversible in some cell lines but not others. Conclusion: The
present results indicate that when resistant sublines are derived simu
ltaneously from the same starting cell population, the observed mechan
isms of resistance may not be the same in each of the variants, These
findings support the hypothesis that preexisting cellular heterogeneit
y may affect mechanisms of acquired resistance. (C) 1997 Elsevier Scie
nce Inc.