The Prostaglandin E 1 Analog, Misoprostol, a Normal Tissue Protector, Does Not Protect Four Murine Tumors In Vivo from Radiation Injury

Abstract

The clinical development of radioprotectors, such as misoprostol, to protect normal tissue during cancer treatment must proceed with the assurance that tumors are not protected similarly or significantly. To provide data on this critical question, radiation-induced growth delay with or without the presence of misoprostol was measured in four murine tumors grown in the flanks of mice: the Lewis lung carcinoma, M-5076 ovarian sarcoma, FSA and NFSA. The effect of misoprostol on the tumor control dose (TCD50) of radiation was measured in FSA-bearing mice with or without prior treatment with the nonsteroidal anti-inflammatory agent, indomethacin. Misoprostol did not influence the in vivo growth of any of the four tumors, nor did it protect any of the tumors from radiation-induced growth delay. Likewise, there was no increase in the radiation TCD50 to treat the FSA in vivo in control or indomethacin-treated tumor-bearing mice. To measure any possible influence of tumor burden on the protective effect of misoprostol on normal tissue in mice, the protective effect of misoprostol on the survival of intestinal clonogenic cells was measured in M-5076-bearing mice and found to be the same as in non-tumor-bearing mice. These data suggest that misoprostol protects normal tissue in mice without protecting at least four experimental murine tumors. The data support the contention that misoprostol can achieve therapeutic gain by protecting normal tissues without protecting tumors.

Radiosensitivity Enhancement by Celecoxib, a Cyclooxygenase (COX)-2 Selective Inhibitor, via COX-2–Dependent Cell Cycle Regulation on Human Cancer Cells Expressing Differential COX-2 Levels

“…Reports regarding prostaglandin treatment for the modulation of cancer cell radiosensitivity have not been consistent. PGE 1 , PGE 2 , and their analogues have been shown to protect normal tissues from radiation but not cancer cells (27,28). Some prostaglandins have been shown, in fact, to potentiate radiation toxicity in cancer cells (29,30).…”

Use of topical misoprostol to reduce radiation‐induced mucositis: Results of a randomized, double‐blind, placebo‐controlled trial

“…A clear understanding of the mechanism of these properties is lacking, although it appears that free‐radical scavenging does not occur. Importantly, limited animal studies have failed to show any tumour protection with the use of misoprostol perhaps because of the lack of prostaglandin receptors on the surface of tumours 26 . We have not reported on patient outcome (loco‐regional control/survival) as this was not the aim of the study.…”

Novel radioprotectant drugs for sparing radiation‐induced damage to the physis

“…MISO is the most promising of the eicosanoid class of radioprotectants with a demonstrated selective radioprotection to other tissues in mice (Hanson et al 1995) and humans as well as an additive effect when administered in combination with amifostine. Eicosanoids bind to G-protein receptors to induce signal transduction via adenyl cyclase, cAMP and a cascade of kinases (Hanson 1997).…”

“…Interleukin 1a (IL-1), an immune system cytokine and demonstrated haematopoietic radioprotectant, might act by stimulating post-irradiation inflammatory and repair processes (Neta et al 1988). Misoprostol (MISO), a prostaglandin E1 analogue, has shown selective radioprotection to other tissues in mice (Hanson et al 1995) and humans, and an additive effect has been demonstrated when it is administered in combination with amifostine (Steel et al 1988).…”