Medium-term culture of primary oral squamous cell carcinoma in a three- dimensional model: effects on cell survival following topical 5-fluororacile delivery by drug-loaded matrix tablets.
Since the activity of several conventional anticancer drugs is restricted by resistance mechanisms and dose-limiting side-effects, the design of formulations for local application on malignant lesions seems to be an efficient and promising drug delivery approach. In this study, the effect of locally applied 5-FU on cell death was evaluated both in a SCC4/HEK001 model and in a newly proposed 3D outgrowth model of oral squamous cell carcinoma (OSCC). Initially, the optimal drug dose was established by delivery of solutions containing different amounts of 5-FU. The solution containing 1% (w/v) of 5-FU resulted effective in inducing cell death with complete eradication of cell colonies. Buccal tablets were designed to deliver 5-FU locoregionally to the cancer lesions of the oral cavity. Tablets were prepared using a drug loaded matrix of acrylic/methacrylic acid copolymer containing 1% (w/w) of 5-FU and applied on 3D outgrowths. The drug release from tablets appeared to be sufficient to induce cell death as confirmed by transmission electron microscopy and enzymatic assay (TUNEL). After 120 h of treatment, when about 90% of the drug had been discharged from the tablets into the culture environment, 5-FU caused loss of cell-cell communications and apoptotic cell death. After 192 h, a complete disaggregation of the 3D oral outgrowths and the death of all the cells was observed. Buccal matrix tablets could be considered a promising new approach to the locoregional treatment of OSCC. Risks of systemic toxicity are avoided since very low drug doses are delivered.
Dipartimento di Discipline Chirurgiche ed Oncologiche, Università di Palermo, Italy.
Giuseppina
G
Campisi
Libero Italo
LI
Giannola
Alberto
A
Fucarino
Antonella
A
Marino Gammazza
Alessandro
A
Pitruzzella
Vito
V
Marciano
Viviana
V
De Caro
Maria Gabriella
MG
Siragusa
Giulia
G
Giandalia
Domenico
D
Compilato
Stephen T
ST
Holgate
Donna E
DE
Davies
Felicia
F
Farina
Giovanni
G
Zummo
Carlo
C
Paderni
Fabio
F
Bucchieri
D000179:Acrylates / Q000737:chemistry; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005079:Excipients / Q000737:chemistry; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D008689:Methacrylates / Q000737:chemistry; D046529:Microscopy, Electron, Transmission; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013607:Tablets
D000179:Acrylates; D000964:Antimetabolites, Antineoplastic; D005079:Excipients; D008689:Methacrylates; D013607:Tablets; C008384:methacrylic acid; C036658:acrylic acid; D005472:Fluorouracil