Hyaluronic acid-paclitaxel: effects of intraperitoneal administration against CD44(+) human ovarian cancer xenografts.
OBJECTIVE
Hyaluronan (HA)-receptors (mainly CD44 and RHAMM) are overexpressed in a wide variety of cancers including ovarian tumors, and HA-bioconjugates have been developed to enhance selective entry of cytotoxic drugs into HA receptor-expressing cancerous cells. Here, we evaluated the potential application of a new HA-paclitaxel bioconjugate, ONCOFID-P, for intraperitoneal (IP) treatment of ovarian cancer.


METHODS
In vitro cytotoxic effect of ONCOFID-P was first assessed on CD44(+) OVCAR-3 and SKOV-3 human ovarian cancer cell lines. Studies were performed in female Balb/c athymic mice IP implanted with OVCAR-3 or SKOV-3 and treated with IP ONCOFID-P, and IP and intravenous (IV) free paclitaxel, at their maximum tolerated dose (MTD 168, 80 and 80 mg/kg, total dose, respectively). The potential detrimental effect of the IP ONCOFID-P and IP free paclitaxel on hematopoiesis was also assessed on peripheral blood, bone marrow and spleen.


RESULTS
Results show that ONCOFID-P cytotoxicity against both OVCAR-3 and SKOV-3 cell lines was somewhat less effective than free paclitaxel. Conversely, in in vivo experiments, IP treatment with ONCOFID-P was overall more effective than IV and IP free paclitaxel in inhibiting intra-abdominal tumor dissemination, abrogating ascites, prolonging survival and curing mice. ONCOFID-P and IP free paclitaxel were equivalent in terms of myelotoxicity, although the former was administered at a two-fold higher dose.


CONCLUSIONS
Present data strongly support the development of ONCOFID-P for locoregional treatment of ovarian cancer.
De Stefano
Ilaria
I
Department of Obstetrics and Gynaecology, Catholic University of the Sacred Heart, Largo A. Gemelli, 8, 00168 Rome, Italy.
Battaglia
Alessandra
A
Zannoni
Gian Franco
GF
Prisco
Maria Grazia
MG
Fattorossi
Andrea
A
Travaglia
Daniele
D
Baroni
Silvia
S
Renier
Davide
D
Scambia
Giovanni
G
Ferlini
Cristiano
C
Gallo
Daniela
D
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D018394:CA-125 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use* / Q000633:toxicity; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use* / Q000633:toxicity; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D018394:CA-125 Antigen; D018960:Hyaluronan Receptors; C560640:ONCOFID-P; D006820:Hyaluronic Acid; D017239:Paclitaxel