Treatment of chemotherapy-resistant human ovarian cancer xenografts in C.B-17/SCID mice by intraperitoneal administration of Clostridium perfringens enterotoxin.
Ovarian cancer remains the most lethal gynecologic malignancy in the United States. Although many patients with advanced-stage disease initially respond to standard combinations of surgical and cytotoxic therapy, nearly 90% develop recurrence and inevitably die from the development of chemotherapy-resistant disease. The discovery of novel and effective therapy against chemotherapy-resistant/recurrent ovarian cancer remains a high priority. Using expression profiling, we and others have recently found claudin-3 and claudin-4 genes to be highly expressed in ovarian cancer. Because these tight junction proteins have been described as the low- and high-affinity receptors, respectively, for the cytotoxic Clostridium perfringens enterotoxin (CPE), in this study we investigated the level of expression of claudin-3 and/or claudin-4 in chemotherapy-naive and chemotherapy-resistant primary human ovarian cancers as well as their sensitivity to CPE treatment in vitro. We report that 100% (17 of 17) of the primary ovarian tumors tested overexpress one or both CPE receptors by quantitative reverse transcription-PCR. All ovarian tumors showed a dose-dependent cytotoxic effect to CPE in vitro. Importantly, chemotherapy-resistant/recurrent ovarian tumors were found to express claudin-3 and claudin-4 genes at significantly higher levels when compared with chemotherapy-naive ovarian cancers. All primary ovarian tumors tested, regardless of their resistance to chemotherapeutic agents, died within 24 hours to the exposure to 3.3 microg/mL CPE in vitro. In addition, we have studied the in vivo efficacy of i.p. CPE therapy in SCID mouse xenografts in a highly relevant clinical model of chemotherapy-resistant freshly explanted human ovarian cancer (i.e., OVA-1). Multiple i.p. administration of sublethal doses of CPE every 3 days significantly inhibited tumor growth in 100% of mice harboring 1 week established OVA-1. Repeated i.p. doses of CPE also had a significant inhibitory effect on tumor progression with extended survival of animals harboring large ovarian tumor burdens (i.e., 4-week established OVA-1). Our findings suggest that CPE may have potential as a novel treatment for chemotherapy-resistant/recurrent ovarian cancer.
Santin
Alessandro D
AD
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199, USA. santin.alessandrod@uams.edu
Cané
Stefania
S
Bellone
Stefania
S
Palmieri
Michela
M
Siegel
Eric R
ER
Thomas
Maria
M
Roman
Juan J
JJ
Burnett
Alexander
A
Cannon
Martin J
MJ
Pecorelli
Sergio
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D062465:Claudin-3; D062506:Claudin-4; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004768:Enterotoxins / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy; D023041:Xenograft Model Antitumor Assays
C568122:CLDN3 protein, human; C568157:CLDN4 protein, human; D062465:Claudin-3; D062506:Claudin-4; C568123:Cldn3 protein, mouse; C568158:Cldn4 protein, mouse; D004768:Enterotoxins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; C035598:enterotoxin, Clostridium