Lowering of tumor interstitial fluid pressure specifically augments efficacy of chemotherapy.
Chemotherapy of solid tumors is presently largely ineffective at dosage levels that are compatible with survival of the patient. Here, it is argued that a condition of raised interstitial fluid pressure (IFP) that can be observed in many tumors is a major factor in preventing optimal access of systemically administered chemotherapeutic agents. Using prostaglandin E1-methyl ester (PGE1), which is known transiently to reduce IFP, it was shown that 5-fluorouracil (5-FU) caused significant growth inhibition on two experimental tumors in rats but only after administration of PGE1. Furthermore, timing experiments showed that only in the period in which IFP is reduced did 5-FU have an antitumor effect. These experiments uniquely demonstrate a clear and, according to the starting hypothesis, logical, synergistic effect of PGE1 and 5-FU that offers hope for better treatment of many tumors in which raised IFP is likely to be inhibiting optimal results with water-soluble cancer chemotherapeutic agents.
Salnikov
Alexei V
AV
Department of Medical Biochemistry, Uppsala University, BMC, Sweden.
Iversen
Vegard V
VV
Koisti
Markus
M
Sundberg
Christian
C
Johansson
Lars
L
Stuhr
Linda B
LB
Sjöquist
Mats
M
Ahlström
Håkan
H
Reed
Rolf K
RK
Rubin
Kristofer
K
D000527:Alprostadil / Q000627:therapeutic use*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001794:Blood Pressure; D002277:Carcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division; D004357:Drug Synergism; D005110:Extracellular Space / Q000187:drug effects; D005472:Fluorouracil / Q000627:therapeutic use*; D008954:Models, Biological; D011312:Pressure; D051381:Rats
D000964:Antimetabolites, Antineoplastic; D000527:Alprostadil; D005472:Fluorouracil