Table 2.
Modifications of the gemcitabine molecule and their outcome in pancreatic cancer.
| Position | Target Moiety | Prodrug | Experimental Model | Outcomes | References |
|---|---|---|---|---|---|
| 4-(N) | Acyl derivative (stearoyl) | GemC18 | AsPC-1 and PANC-1 cells, murine BxPC-3 tumor xenografts | Inhibition of RRM1 and increased dFdCTP levels, enhanced anti-tumor activity | [105,106,107] |
| Polyethylene glycol (PEG) | PEG–NHS | MIA PaCa-2 and PANC-1 cells | Prolonged circulation in murine plasma, improved cytotoxicity and apoptosis | [108] | |
| PEG-PCC | MIA PaCa-2 and L3.6 cells, murine MIA PaCa-2 tumor xenografts | High anti-tumor activity and increased apoptosis | [109] | ||
| Vitamin E succinate (VES) | VES-dFdC | BxPC-3 cells | High anti-tumor activity, enhanced cellular uptake | [110] | |
| D-ɑ-tocopheryl PEG succinate | TPGS/VES-dFdC | BxPC-3 cells and murine BxPC-3 tumor xenografts | High anti-tumor activity, resistant to CDA induced deamination and superior cytotoxicity | [111,112] | |
| 1,1′,2-tris-nor-squalenoic acid (squalene) | SQ-dFdC/SQ-dFdCMP | BxPC-3, Capan-1, PANC-1 cells; murine BxPC-3, MIA PaCa-2 and PANC-1 tumor xenografts | High anti-proliferative and cytotoxic effects, reduced tumor growth and prolonged survival | [113] | |
| 5′-OH | Cardiolipin | NEO6002 | BxPC-3 cells and murine BxPC-3 tumor xenografts | High cytotoxicity independent of NT activity and high tumor growth inhibition | [114,115] |
| Elaidic acid | CP-4126 (CO-101) | Murine MIA PaCa-2, PANC-1 tumor xenografts | Transport independent of hENT1, equally effective to gemcitabine | [116,117] | |
| Phosphoramidate | Mono-phosphate | Cell lines with dCK-deficient variants: AG600 and CEM-dCK | ~4-fold more effective than gemcitabine | [118] | |
| Phosphoramidate ProTide | NUC-1031 (ProTide 6f) | BxPC-3, MIA PaCa-2, PANC-1 cells; murine MIA PaCa-2, tumor xenografts | Resistant to CDA mediated deamination and directly generates dFdCMP intracellularly; reduced tumor volume | [119,120] | |
| Other | D-amino modifications | - | AsPC-1 cells | High plasma concentration superior enzymatic stability | [121] |
| Dipeptide monoester prodrugs | - | PANC-1, and AsPC-1 cells | Enhanced uptake and anti-proliferation activity | [122] |