Improvement of gemcitabine-based therapy of pancreatic carcinoma by means of oncolytic parvovirus H-1PV.
Pancreatic carcinoma is a gastrointestinal malignancy with poor prognosis. Treatment with gemcitabine, the most potent chemotherapeutic against this cancer up to date, is not curative, and resistance may appear. Complementary treatment with an oncolytic virus, such as the rat parvovirus H-1PV, which is infectious but nonpathogenic in humans, emerges as an innovative option.


OBJECTIVE
To prove that combining gemcitabine and H-1PV in a model of pancreatic carcinoma may reduce the dosage of the toxic drug and/or improve the overall anticancer effect.


METHODS
Pancreatic tumors were implanted orthotopically in Lewis rats or subcutaneously in nude mice and treated with gemcitabine, H-1PV, or both according to different regimens. Tumor size was monitored by micro-computed tomography, whereas bone marrow, liver, and kidney functions were monitored by measuring clinically relevant markers. Human pancreatic cell lines and gemcitabine-resistant derivatives were tested in vitro for sensitivity to H-1PV infection with or without gemcitabine.


RESULTS
In vitro studies proved that combining gemcitabine with H-1PV resulted in synergistic cytotoxic effects and achieved an up to 15-fold reduction in the 50% effective concentration of the drug, with drug-resistant cells remaining sensitive to virus killing. Toxicologic screening showed that H-1PV had an excellent safety profile when applied alone or in combination with gemcitabine. The benefits of applying H-1PV as a second-line treatment after gemcitabine included reduction of tumor growth, prolonged survival of the animals, and absence of metastases on CT-scans.


CONCLUSIONS
In addition to their potential use as monotherapy for pancreatic cancer, parvoviruses can be best combined with gemcitabine in a two-step protocol.
Angelova
Assia L
AL
Infection and Cancer Programme F010 and INSERM U701, German Cancer Research Center, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
Aprahamian
Marc
M
Grekova
Svitlana P
SP
Hajri
Amor
A
Leuchs
Barbara
B
Giese
Nathalia A
NA
Dinsart
Christiane
C
Herrmann
Alexia
A
Balboni
Ginette
G
Rommelaere
Jean
J
Raykov
Zahari
Z
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy* / Q000628:therapy; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D050504:Oncolytic Viruses / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000628:therapy; D017992:Parvovirus / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine