Fused pyrazine mono-n-oxides as bioreductive drugs. II Cytotoxicity in human cells and oncogenicity in a rodent transformation assay.
OBJECTIVE
To determine what structural moieties of the fused pyrazine mono-N-oxides are determining factors in their in vitro cytotoxicity and oncogenicity.


METHODS
A new series of experimental bioreductive drugs, fused pyrazine mono-N-oxides, was evaluated in vitro for aerobic and hypoxic cytotoxicity in the HT29 human colon adenocarcinoma cell line by using clonogenic assays. The relative oncogenicities of these compounds were also determined in aerobic cultures of C3H 10T1/2 mouse embryo fibroblasts by using a standard transformation assay.


RESULTS
Removal of the 4-methyl piperazine side chain from the parent compound, RB 90740, reduced the potency of the hypoxic cytotoxin. Reduction of the N-oxide function increased the aerobic cytotoxicity and eliminated most of the hypoxic/aerobic cytotoxic differential. The reduced N-oxide also had significant oncogenicity, consistent with a mechanism of genotoxicity following bioreduction of RB 90740.


CONCLUSIONS
This new series of bioreductive compounds may be effective in cancer therapy, particularly the lead compound RB 90740. The oncogenic potential of these compounds is similar to that for other cancer therapies. Further studies should include evaluation of these compounds in vivo and the development of analogs with reduced oncogenic potential and retention of the hypoxic/aerobic cytotoxicity differential.
Langmuir
V K
VK
SRI International, Menlo Park, CA 94025-3493, USA.
Laderoute
K R
KR
Mendonca
H L
HL
Sutherland
R M
RM
Hei
T K
TK
Liu
S X
SX
Hall
E J
EJ
Naylor
M A
MA
Adams
G E
GE
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D015687:Cell Hypoxia / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D011719:Pyrazines / Q000009:adverse effects*; D011853:Radiobiology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D011719:Pyrazines; C087409:RB 90740