Preclinical studies of steroid-linked nitrosoureas in murine pancreatic adenocarcinoma PANO2.
OBJECTIVE
In earlier studies, this laboratory carried out research on the synthesis and anticancer evaluation of hybrid compounds, which combine two molecules in one such as homo-aza-steroidal esters (HASE) of carboxylic derivatives of N, N-bis (2-chloroethyl) aniline. In this combination, steroidal hormones are employed as carriers for transporting the alkylating agents to specific targeted tissues. Aiming to continue our research, we used alkylating agents, as nitrosoureas, instead of nitrogen mustards. In this work the N-[N- (2-chloroethyl)-N-nitroso-carbomoyl]-L-alanine (CNC-ala) has been used and was bound to 7 newly synthesized modified steroidal esters (carrier molecule) of nitrosourea and the hybrid molecules were tested for antitumor activity against PANO2 murine pancreatic adenocarcinoma.


METHODS
PANO2 adenocarcinoma was used in this study. C57Bl mice were used for chemotherapy evaluation. The activity was assessed from the inhibition of tumor growth and the oncostatic parameter T/C %.


RESULTS
The antitumor activity displayed by 7 hybrid steroidal esters of nitrosourea was quite interesting. It was able to discern 4 of 7 compounds that exhibited considerable antitumor activity, increasing the lifespan of the tumor-bearing mice by inhibiting the tumor growth.


CONCLUSIONS
The comparative study of 7 newly synthesized hybrid steroidal esters of nitrosourea shows that the antitumor effects of compound 7, which has an enlarged (7 carbon atoms) A-lactamic ring and nitrosourea esterified at the position 17, which seems to be the most appropriate for the connection of a DNA cross-linking amino acid derivative is superior.
Symeonidion Research Center, Theagenio Cancer Hospital, 2 Al.Symeonidis Street, Thessaloniki, Greece. geromchem@yahoo.gr
A
A
Papageorgiou
Th
T
Lialiaris
E
E
Stergiou
I
I
Stergiou
C
C
Tsigris
A
A
Kourti
G
G
Geromichalos
P
P
Stravoravdi
D
D
Trafalis
A E
AE
Athanassiou
A
A
Pitsas
Ch
Ch
Camoutsis
D000230:Adenocarcinoma / Q000188:drug therapy / Q000556:secondary; D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000556:secondary; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009588:Nitrogen Mustard Compounds / Q000737:chemistry; D009607:Nitrosourea Compounds / Q000138:chemical synthesis / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology*; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D009607:Nitrosourea Compounds; D013256:Steroids; C058788:N-(2-chloroethyl)-1-nitrosocarbamoylalanine; D000409:Alanine