Enhanced anticancer activity of glutamate prodrugs of all-trans retinoic acid.
OBJECTIVE
All-trans retinoic acid (ATRA), an active metabolite of vitamin A, is widely used in the treatment of acute promyelocytic leukaemia and myelodysplastic syndrome. However, its high lipophilicity is thought to be responsible for the slow dissolution and low bioavailability following oral administration. In order to obtain compounds with better solubility characteristics to improve the transportation and bioavailability of ATRA, derivatives of ATRA containing glutamic acid or its sodium salt were synthesised.


METHODS
The ATRA derivatives synthesised - all-trans retinoyl glutamate (RAE) and all-trans retinoyl sodium glutamate (RAENa(2)) - were characterised in terms of melting point, optical rotation, mass spectrometry, NMR and partition coefficient. A liposomal preparation formed from RAE was characterised by particle size and zeta potential. The anti-tumour activity of RAE and RAENa(2) was compared with that of ATRA in mice bearing S(180) tumours and their effects on the cell cycle were determined in human pro-myelocytic leukaemia HL-60 cells.


RESULTS
RAE and RAENa(2) were more active than ATRA against tumour growth. Flow cytometry indicated that RAE and RAENa(2) induced HL-60 cell cycle arrest, similar to ATRA. DNA fragmentation studies suggested that apoptosis may be one of the mechanisms responsible for the anti-tumour activities.


CONCLUSIONS
The two derivatives of ATRA, RAE and RAENa(2), exhibited improved aqueous solubility and were more effective in mice bearing S(180) tumours.
Cui
Chunying
C
School of Chemical Biology and Pharmaceutical Sciences, Capital Medical University, Beijing, China.
Zhang
Yunwei
Y
Wang
Lili
L
Liu
Hu
H
Cui
Guohui
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D005971:Glutamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage; D051379:Mice; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects*
D000970:Antineoplastic Agents; D005971:Glutamates; D008081:Liposomes; D011355:Prodrugs; C546472:retinoyl glutamate; D014212:Tretinoin