Table 2.

The role of different radioisotopes in inducing DNA damage, activating DNA repair pathways, and their biological effects.

Radioisotopes	Emitting	Labeled	Mechanism of DNA Damage	DNA Repair Pathways	Biomarkers	Ref.
223Ra	α-emitter	-	DNA DSB and clustered DNA damage	NHEJ	❖Up-regulation of 53BP1 and γ-H2AX	[52,53,54,58]
212Pb	α-emitter	-	DNA DSB	HR	❖Down-regulation of Rad51 protein, inhibit Chk1 phosphorylation ❖Cell cycle arrest (G2-M and S-phase) ❖Alterations in protein levels associated with p73/GADD45 signaling pathway	[59,60,61]
		HER2
		TCMC
213Bi	α-emitter	E-cadherin	-	-	❖Up-regulation of TNF, SPHK1, STAT5A, p21, MYT1, and SSTR3 mRNA ❖Down-regulation of SPP1, CDC25 phosphatases mRNA	[62,63,64]
		CD20			❖Activation of caspase 2, 3, 8, and 9 proteins ❖Cell cycle arrest in G2/M-phase ❖Downregulation of XIAP and Bcl-x proteins
		CD45	Irreversible DNA DSB	NHEJ	❖Activation of caspase 2, 3, 8, and 9 proteins ❖PARP cleavage
125I	AE	-	DNA DSB	-	-	[100,108,109]
		CEA	DNA DSB and ROS-mediated pathway	-	Enhanced formation of 53BP1 and γ-H2AX foci
111In	AE	γH2AX	Lethal DNA DSB damage	-	Enhanced formation of ɤ-H2AX foci	[103,104,106,107]
		Anti-CD33
		anti-HER2	Induced significant DNA DSBs
99mTc	AE	HYNIC-DAPI	Induced SSBs and DSBs via a direct interaction with DNA	-	-	[99]
177Lu	β-emitter	DOTATATE	Induction of indirect DNA damage through ROS generation and formation of SSBs	-	Slightly increased γH2AX and pATM	[137]
		DOTATATE and DOTATOC	time- and dose-dependent induction of DNA-DSBs		Enhanced formation of γ-H2AX and 53BP1 nuclear foci	[126,135,136]
		PSMA
		HER2	DNA DSBs	NEHJ	❖Activating caspase-3-mediated apoptosis ❖Interfering with DNA-PK gene expression ❖Downregulation of various genes involved in DDR, including BRCA1, EXO1, FEN1, MSH2, NBN, PRKDC, and RAD51	[138]
		DOTA-JR11, SSTR antagonist DOTA-octreotide, SSTR agonist	Reversable DNA DSBs	-	Enhanced the formation of 53BP1 and γ-H2AX foci	[132]
		EDTMP and DOTMP	-		❖Downregulation of bcl-2 protein ❖Cleavage of PARP protein, which serves as a substrate for active caspase-3 during cell death	[143]
		Minigastrin analog	-	Activation of DNA damage response by p53	-	[145]
90Y	β-emitter	-	Induction of indirect DNA damage through ROS generation and formation of SSBs	NEHJ	-	[68,123]
131I	β-emitter	-	Induction of indirect DNA damage through ROS	--	❖Activation of initiator caspases-2, -8, -9, and effector caspase-3, along with the cleavage of PARP ❖Down and up-regulating mRNA level of Bcl-2 and Fas, respectively ❖Up-regulation of GADD45 mRNA, leading to G2/M phase arrest through a p53-independent pathway ❖Variations in the expression of DNA repair genes, RAD51 and P21	[153,154]
89Sr	β-emitter	-	-	-	❖Up-regulation of Fas acceptor and P53 mRNA ❖Down-regulation of Bcl-2 mRNA	[141,151]

HR: homologous recombination, NHEJ: non-homologous end joining, SSB: single-strand break, DSB: double-strand break, β: beta, α: alpha, ²²³Ra: rhodium-223, AEs: Auger electrons, ²¹²Bi: bismuth-212, ¹²⁵I: iodine-125, ¹¹¹In: indium-111, ^99mTc: technetium-99m, ¹⁷⁷Lu: lutetium-177, ¹³¹I: iodine-131, ⁹⁰Y: yttrium-90, ⁸⁹Sr: strontium-89, γ-H2AX: gamma-H2AX, 53BP1: p53-binding protein 1, CEA: carcinoembryonic antigen, DAPI: 4,6-diamidino-2-phenylindole, HYNIC (6-hydrazinonicotinic), FasL: CD95 ligand, FasR: CD95 receptor, bcl-2: B-cell lymphoma 2, EDTMP: ethylenediamine tetramethylene phosphonic, GADD45: growth arrest and DNA damage-45, PARP: poly(ADP-ribose) polymerase.