Inhibition of intracellular Ca2+ signalling, cytotoxicity and antitumor activity of the herbicide oryzalin and its analogues.
OBJECTIVE
Studies were conducted on oryzalin (3,5-dinitro-N,N-di(n-propyl)sulfanilamide), a widely used dinitroaniline sulfonamide herbicide, which was identified from plant extracts as an inhibitor of mitogen- and growth factor-mediated intracellular free Ca2+ ([Ca2+]i) signalling in mammalian cells.


RESULTS
Oryzalin inhibited vasopressin, bradykinin and platelet-derived growth factor [Ca2+]i signalling in Swiss 3T3 fibroblasts with IC50 values of 14, 16 and 18 microM, respectively. 45Ca2+ uptake into nonmitochondrial stores of saponin-permeabilized Swiss 3T3 cells was inhibited by oryzalin with an IC50 of 34 microM. Oryzalin inhibited colony formation of HT-29 colon carcinoma cells with an IC50 of 8 microM and inhibited the growth of a number of other cancer cell lines and primary human tumors in vitro with IC50 values in the range 3 to 22 microM. A number of oryzalin analogues were studied and an association was found between the ability to inhibit [Ca2+]i signalling and inhibition of the growth of HT-29 human colon cancer cells (P = 0.001) and of CCRF-CEM human leukemia cells (P = 0.016). Oryzalin at doses up to 600 mg/kg administered orally or subcutaneously daily to mice for 3 to 10 days beginning a day after tumor inoculation inhibited the growth of murine B16 melanoma by 63% but showed no appreciable activity when administered subcutaneously or intraperitoneally to mice beginning a number of days after tumor inoculation against a variety of human tumor xenografts. The peak plasma concentration of oryzalin following repeated subcutaneous administration of oryzalin at 600 mg/kg per day to mice was 37 microM and of its major metabolite N-depropyl oryzalin was 53 microM.


CONCLUSIONS
It is unlikely that the absence of significant antitumor activity of oryzalin is a result of the inability to achieve adequate plasma concentrations.
Powis
G
G
Arizona Cancer Center, University of Arizona, Tucson 85724-5024, USA.
Gallegos
A
A
Abraham
R T
RT
Ashendel
C L
CL
Zalkow
L H
LH
Dorr
R
R
Dvorakova
K
K
Salmon
S
S
Harrison
S
S
Worzalla
J
J
D016475:3T3 Cells / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects*; D002296:Carcinosarcoma / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000473:pathology; D004136:Dinitrobenzenes / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D005347:Fibroblasts / Q000502:physiology; D006540:Herbicides / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D006801:Humans; D066298:In Vitro Techniques; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology; D008545:Melanoma / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D015398:Signal Transduction / Q000187:drug effects*; D013424:Sulfanilamides
D015220:Calcium Channels; D004136:Dinitrobenzenes; D006540:Herbicides; D013424:Sulfanilamides; C012465:oryzalin; D002118:Calcium