Preclinical Auger and gamma radiation dosimetry for fluorodeoxyuridine-enhanced tumour proliferation scintigraphy with [123I]iododeoxyuridine

Abstract

Animal experiments have shown that short blocking of thymidine (dThd) synthesis with fluorodeoxyuridine (FdUrd) results in significantly increased DNA incorporation of [(125)I]iododeoxyuridine ([(125)I]IdUrd) in tumour and rapidly cycling tissues. Based on these results, we give an Auger and gamma radiation dosimetry estimate for a scintigraphy study in glioblastoma patients using [(123)I]IdUrd. The Auger radiation dosimetry calculated for patients is based on measurement of DNA-incorporated [(125)I]IdUrd in rapidly dividing tissues in nude mice xenografted with human glioblastoma. Further data obtained 0.5, 6 and 24 h after injection of [(125)I]IdUrd allowed calculation of the additional gamma radiation exposure using MIRDOSE3.1. High gradients of radioactivity concentration between dividing and non-dividing tissues were observed 6 and 24 h after injection of [(125)I]IdUrd combined with FdUrd pretreatment. While the estimated Auger radiation absorbed doses of [(123)I]IdUrd in six rapidly cycling normal tissues in patients are low, the equivalent doses become significant with application of the recommended preliminary radiation weighting factor (W(R)) of 20 for stochastic effects of DNA-associated Auger radiation. Using the latter W(R), extrapolation of the animal results to the proposed patient injection with 300 MBq [(123)I]IdUrd combined with FdUrd pretreatment indicates that the effective dose will be 5.42 mSv, including 1.67 mSv from Auger and 3.75 mSv from gamma radiation. The predicted Auger radiation effective dose for patients undergoing [(123)I]IdUrd scintigraphy will be significant if the enhancement of DNA incorporation that is achieved by means of FdUrd pretreatment is similar to that obtained in animals.

Auger radiation targeted into DNA: a therapy perspective

“…For the estimation of the risk of long-term stochastic effects, a W R of 20 may then be applied for nuclearassociated Auger radiation [39]. This may provide a radiation dose risk estimate for a patient exposed to Auger radiation in a nuclear medicine diagnostic procedure [61]. As a best approximation, this dosimetry was based on biodistribution and DNA incorporation measurements performed in mice [61].…”

“…This may provide a radiation dose risk estimate for a patient exposed to Auger radiation in a nuclear medicine diagnostic procedure [61]. As a best approximation, this dosimetry was based on biodistribution and DNA incorporation measurements performed in mice [61]. Measurement of all these parameters in individual patients would be impossible.…”

Highly efficient DNA incorporation of intratumourally injected [125I]iododeoxyuridine under thymidine synthesis blocking in human glioblastoma xenografts

“…Such conditions would be promising for therapy experiments. In fact, it has been shown by different groups that radio‐IdUrd, once incorporated in DNA, remained there for prolonged times without significant loss over 24 hr 13, 16, 17. Loco‐regional delivery of radio‐IdUrd under TS inhibition has been reported previously 18.…”

“…The 5 hr delay postinjection of radio‐IdUrd was chosen for biodistribution analysis because recent experiments using dThd competition had shown that high and specific tumour uptake was observed 6 hr post‐i.v. injection of radio‐IdUrd 11, 13. Tumour and normal tissues including a cleaned femoral bone and the entire carcass were dissected, weighed and counted in a γ‐counter with a standard sample of injected activity.…”

Dual addressing of thymidine synthesis pathways for effective targeting of proliferating melanoma

“…This is due to the efficient incorporation of ITdU into the DNA, where the cytotoxic effect of the Auger emitter is the highest. The bone marrow dose for a mouse was calculated based on two previous preclinical studies using a nucleoside analog to be 60.5 μ Gy/MBq. Applying the weighting W R factor for human the bone marrow cells would be 605 μ Gy/MBq, which would allow applying up to 3.3 GBq 123 I‐ITdU combined with FdUrd in patients resulting in an equivalent bone marrow radiation absorbed dose of just below the maximal tolerated dose of 2 Gy.…”