Synergetic bitherapy in mice with xenografts of human prostate cancer using a methional mimic (METLICO) and an aldehyde dehydrogenase 3 inhibitor (MATE): systemic intraperitoneal (IP) and targeted intra-tumoral (IT) administration.
An intraperitoneal (IP) monotherapy in nu/nu mice with subcutaneous xenografts of a human prostate epithelial cancer cell line:DU145 was undertaken with an aldehyde dehydrogenase 3 inhibitor MATE, that is a potent apoptogen on (DU145) in culture but not on their human prostate epithelial normal counterparts [13] . Tumour growth was slowed down but treatment had to be done 5days/week. To try to potentiate the action of MATE in vivo, a bitherapy was undertaken based on the synergetic apoptotic effect that had been observed previously in culture on DU145 treated with a methional mimic METLICO and DIMATE, an inhibitor of ALDH1 and ALDH3 [19]. The bitherapy with METLICO/MATE administered IP was as effective as the monotherapy with MATE alone by IP, but at a 2-fold lower dose of MATE and at a dose of METLICO that had no growth-inhibitory effect as a monotherapy . Hence there was definite synergism with bitherapy. To try to increase the efficacy of bitherapy, it was administered by the intra-tumoral (IT) route using the recently developed 20-bars-pressurized microinjection system from CERMA [16, 17]. IT administration of the bitherapy was indeed more effective than that by IP as regards tumour volumes are concerned. Histopathological analysis of IT-treated tumours confirmed that there were many necrotized zones but intact cells were still present. Approaches for treating a wider zone of tumour tissue by IT-bitherapy are discussed.
CERMA, BioPark d'Archamps, F-74160, France.
E
E
Hiltbrand
G
G
Fournet
J-P
JP
Giliberto
M-J
MJ
Paret
J
J
Chantepie
D
D
Morel
J
J
Goré
U
U
Reichert
H
H
Mehier
M-E
ME
Rochedix
G
G
Quash
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000447:Aldehydes / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use; D000818:Animals; D032701:Biomimetics; D003131:Combined Modality Therapy; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D015552:Injections, Intralesional; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000737:chemistry / Q000627:therapeutic use*; D047368:Tumor Burden
C541792:6,8-bis(3-(methylthio)-1-oxopropylthio)-1-oxooctyloxy-N,N,N-trimethylethanaminium; D000447:Aldehydes; D004791:Enzyme Inhibitors; D009025:Morpholines; D011799:Quinazolines; C008390:methional; D000444:Aldehyde Dehydrogenase