Table 4.
Chronological summary of the pre-clinical studies about radioprotective effects on the normal bladder.
| Reference | Animal model (strain) | Set-up | Endpoint (method) | Toxicity timing after RT | Findings |
|---|---|---|---|---|---|
| Edrees et al. (66) |
Female mouse (C3H) | 13–25 Gy in 1 fr. delivered by 250 kV X-ray machine + Cy | Micturition frequency (cystometry), incidence of haematuria | 5 months (rad) 1 week (Cy) Early and 9–12 month (rad+Cy) |
Cy administered up to 9 months before or after irradiation induced more severe bladder damage than X-rays alone |
| Malkinson et al. (67) |
Male mouse (B6D2F1) | 2–4.5 Gy/fr. x 10–15 fr. after PGs administration | Murine hair loss | Immediately after the fractionated RT | PGs may provide protection of tissue as bladder mucosa |
| Horsman et al. (68) |
Female mouse (CDFl and C3H) | Nicotinamide injected after local irradiation delivered by 250 kV X-ray irradiator | i) Moist desquamation ii) Reservoir function (transurethral cystometry) | i) 11–30 daysii) 9 months | Best radiosensitization with minimal effect on normal tissues (bladder) at time of nicotinamide peak plasma drug concentrations |
| Kanai et al. (69) |
Female rat (Sprague-Dawley) | 35 Gy in 1 fr. delivered by 6 MeV linac + MnSOD transgene injection 24 h before RT | Transepithelial resistance and permeability damage on detrusor function | 1, 48, and 96 h 7 and 24 days 6 months |
MnSOD transgene allows transepithelial resistance and permeability to recover within 4 weeks and shows baseline pressures and more stable voiding patterns after 6 months |
| Jaal et al. (70) |
Female mouse (C3H/Neu) | Graded radiation doses delivered by Seifert Isovolt 320/20 X-ray machine + rHuKGF | Reservoir function (transurethral cystometry) | Early phase response: 1–30 days Late phase response: 60–360 days |
Early: ED50 from 20 to 27 Gy Late: ED50 from 16 to 22 Gy rHuKGF administration before irradiation modified early and late radiation effects |
| Dinçbaş et al. (71) |
Male rat (Wistar) | 25 Gy in 5 fr. delivered by Co60 teletherapy unit + AF + GEM | Bladder fibrosis (H&E) | 4 months | AF may have a beneficial effect in limiting the radio-sensitizing effect of GEM |
| Rocha et al. (72) |
Rat (sex n.a.) (Wistar) | 11.64 Gy in 1 fr. delivered by 6 MeV linac + L-glutamine | Amount of collagen (Masson's trichrome, Picro Sirius Red) Immuno-histochemistry |
15 days | L-glutamine seems to prevent bladder wall damage |
| Costa et al. (73) |
Male rat (Wistar) | 10 Gy in 1 fr. delivered by 10 MeV linac + L-arginine | Morphologic change of blood vessels in the wall (H&E, expression of VEGF and FGF) | 16 days | L-arginine was radioprotective |
| Rajaganapathy et al. (51) | Female rat (Sprague-Dawley) | 40 Gy in 1fr. delivered by SARRP unit + liposomal tacrolimus | Micturition frequency(cystometry) Morphological changes (H&E) |
2 and 6 weeks | Lipo-tacrolimus treated rats show an increased post- irradiation IMI and minimal edematous changes |
| Horsman et al. (74) |
Male and Female Mice (CDF1) | Graded radiation doses + VDA(CA4P) | Reservoir function (transurethral cystometry) | 9 months | ED50 = 14 Gy for bladder VDA has no effect on the early (skin) or late (bladder and lung) tissues responding to radiation |
| Oscarsson et al. (75) | Female rat (Sprague-Dawley) | 20 Gy in 1 fr. delivered by 6 MeV linac + with and without 20 sessions of HBOT | Oxidative stress and pro-fibrotic factors | 28 days | HBOT may prevent radiation-induced changes |
| Sarsarshahi et al. (76) | Female mouse (C3H/Neu) | 14-24 Gy in 1 fr. delivered by YXLON Maxishot device + bortezomib | Reservoir function (transurethral cystometry) | Acute response: 6–9 days Late response: 21–24 days |
Daily bortezomib injections between days 0–15 resulted in a significant decrease in responders |
Several agents were tested in combination with radiation and the effect was measured using various techniques.
RT, radiotherapy; Cy, Cyclophosphamide; PGs, prostaglandins; MnSOD, Manganese superoxide dismutase gene therapy; VEGF, vascular endothelial growth factor; FGF, Wbroblast growth factors; AF, amifostine; GEM, gemcitabine; H&E, hematoxylin & eosin; rHuKGF, palifermin; HBOT, hyperbaric oxygen therapy; CA4P, combretastatin A-4 phosphate; VDA, vascular disrupting agents; SARRP, small animal radiation research platform; IMI, inter- micturition intervals IMI.