Development of dextran derivatives with cytotoxic effects in human urinary bladder cancer cell lines.
BACKGROUND
In a previous study we reported on a new approach describing intravesical instillation of charged dextran in patients with superficial bladder carcinoma. The cationic derivative showed a strong tumor-selective accumulation. To develop this approach, the present study investigates the cytotoxic effect of cationic dextran derivatives on two urinary bladder cancer cell lines (J82 and 5637).


METHODS
The dextran conjugates were prepared by periodate activation and subsequent coupling by reductive amination. A fluorimetric cytotoxicity assay (FMCA) was used for the cytotoxicity assay. The tumor cells were seeded into 96-well microtiter plates and different cationic dextran derivatives were added and incubated for 72 hours.


RESULTS
The results showed that cationic epirubicin-dextran had a clear inhibitory effect on the growth in both cell lines (40-95% growth inhibition). The corresponding values for epirubicin (the reference) was 90-100% inhibition. Interestingly, cationic dextran had, by itself, a growth inhibitory effect. This cytotoxic effect could be strongly enhanced to be almost equal to the reference by changing the cationic sidegroup to aminohexane. Dextran alone showed no effect.


CONCLUSIONS
The finding that cationic dextran by itself can be made cytotoxic, together with its capacity to accumulate in superficial bladder cancer, suggests possibilities for new therapeutic constructs. Cationic dextran with different cationic side-groups and in combination with cytotoxic drugs will be studied further. The cytotoxic mechanism needs to be elucidated.
Marquez
Marcela
M
Karolinska Institute, Cancer Center Karolinska, Stockholm, Sweden.
Du
Jin
J
Edgren
Maliha
M
Nilsson
Sten
S
Lennartsson
Lena
L
Hiltunen
Jukka
J
Westlin
Jan-Erik
JE
Tammela
Teuvo
T
Raitanen
Mika
M
Laato
Matti
M
Jönsson
Gun
G
Holmberg
Anders R
AR
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000633:toxicity*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D003911:Dextrans / Q000138:chemical synthesis / Q000633:toxicity*; D015251:Epirubicin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000633:toxicity; D005470:Fluorometry; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000138:chemical synthesis; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; D003911:Dextrans; D015251:Epirubicin; D008239:Lysine