In vitro and in vivo antitumor activity of the novel derivatized polyvinyl alcohol-based polymer P10(4).
OBJECTIVE
The major limitation to successful chemotherapy of neuroblastoma is the toxicity of traditional antitumor drugs. Hence, less toxic and more effective drugs are to be found, and novel formulations of conventional compounds allowing a more favorable biodistribution should be sought for. In an attempt to pursue this task, we recently synthesized an amphiphilic polymer based on a polyvinyl alcohol backbone [P10(4)].


METHODS
The cytotoxic activity of P10(4) was evaluated both in vitro on neuroblastoma and melanoma cell lines and in vivo in pseudometastatic neuroblastoma models. Apoptosis was assessed by morphology, cytofluorimetric analysis of DNA content, and DNA fragmentation assay. Caspases activation was investigated by kits specific for caspase-1, caspase-2, caspase-3, caspase-4, caspase-6, caspase-7, caspase-8, caspase-9, caspase-10, and caspase-13. Colony formation was evaluated by soft agar assay.


RESULTS
P10(4) exerted a potent cytotoxic activity on different neuroblastoma and melanoma cell lines through induction of both extrinsic and intrinsic caspase cascades and subsequent apoptosis. Moreover, the clonogenic potential of cells that survived P10(4) treatment was strongly reduced. Next, we tested the effects of P10(4) in nude mice injected with both a human and a murine neuroblastoma cell lines i.v. P10(4) significantly increased the life span and the long-term survival of treated mice over controls. No side effects were observed, even at doses higher than those used for therapeutic purposes.


CONCLUSIONS
Our data suggest that P10(4) holds promise as an anticancer compound and, because of its lack of interaction with DNA, is unlikely to give rise to drug resistance.
Raffaghello
Lizzie
L
Laboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy.
Zuccari
Guendalina
G
Carosio
Roberta
R
Orienti
Isabella
I
Montaldo
Paolo G
PG
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy* / Q000556:secondary; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology*; D011142:Polyvinyl Alcohol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C524134:poly(vinyl alcohol-co-vinyloleyl ether-co-polyethylene glycol vinyl ether); D011092:Polyethylene Glycols; D011142:Polyvinyl Alcohol