Dw. Siemann, IN-VITRO CYTOTOXICITY AND CHEMOSENSITIZING ACTIVITY OF THE DUAL FUNCTION NITROIMIDAZOLE RB-6145, International journal of radiation oncology, biology, physics, 29(2), 1994, pp. 301-306
Citations number
24
Categorie Soggetti
Oncology,"Radiology,Nuclear Medicine & Medical Imaging
Purpose: To determine the cytotoxicity and chemosensitizing potential
of RB 6145 in mouse KHT/iv and human A549 tumor cells. Methods and Mat
erials: RSU 1069, the lead compound in a series of nitroimidazoles con
taining an alkylating aziridine function, has been shown to possess a
high degree of selective cytotoxicity for hypoxic cells in addition to
being a potent sensitizer of radiation and chemotherapy. Unfortunatel
y, preliminary clinical studies have revealed a dose-limiting gastroin
testinal toxicity for RSU 1069. Recently RB 6145, the ring-opened anal
ogue of RSU 1069, has been found to be less emetic than RSU 1069. In t
he present studies, we assessed both the differential hypoxic cell cyt
otoxicity of RB 6145 and its chemosensitizing potential when combined
concomitantly with variable doses of the activated form of cyclophosph
amide (4-hydroperoxy-cyclophosphamide, 4-OOH-CP) or the nitrosourea CC
NU. Results: As we had observed previously for RSU 1069, RB 6145 was f
ound to be less cytotoxic to human than rodent tumor cells. In additio
n, the degree of selective cytotoxicity toward hypoxic cells was (a) l
ess in A549 than in KHT/iv cells (factor of 9 vs. 80) but (b) comparab
le to that seen with RSU 1069. For both cell lines, inclusion of the s
ensitizer enhanced the cell killing of the chemotherapeutic agent 4-OO
H-CP by a factor of similar to 1.5-1.7-fold. When combined with CCNU,
RB 6145 increased the killing of A549 cells similar to 15-fold. Simila
r hypoxic cell preferential cytotoxicity and enhancement in anti-tumor
treatment efficacy were seen when A549 cells were exposed to the R en
antiomer of RB 6145 (PD 144872) either alone or in combination with CC
NU. Conclusion: These data support the notion that further considerati
on should be given to the clinical application of these bioreductive a
gents.