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The enzyme that nicks one DNA strand to relieve twisting while DNA is copied. Camptothecins and the payloads of several antibody-drug conjugates trap it on the DNA so the nick becomes a permanent break when the cell replicates.
Topoisomerase I relaxes supercoiled DNA by cutting one strand, letting it rotate and resealing it. Camptothecin derivatives such as irinotecan, topotecan, SN-38, DXd and exatecan bind the enzyme-DNA complex and stop the reseal step, so replication forks collide with the trapped complex and create double-strand breaks. The same chemistry is the payload of sacituzumab govitecan, trastuzumab deruxtecan and datopotamab deruxtecan, which explains their shared toxicities of neutropenia and diarrhoea and the cross-resistance seen when one topoisomerase I antibody-drug conjugate follows another.
In plain words · The enzyme that nicks one DNA strand to relieve twisting while DNA is copied. Camptothecins and the payloads of several antibody-drug conjugates trap it on the DNA so the nick becomes a permanent break when the cell replicates.
The enzyme that nicks one DNA strand to relieve twisting while DNA is copied. Camptothecins and the payloads of several antibody-drug conjugates trap it on the DNA so the nick becomes a permanent break when the cell replicates.
Type IB topoisomerase that relieves torsional stress during replication and transcription; trapped as a covalent cleavage complex by camptothecins.
1 product aims at Topoisomerase I (TOP1): small molecules. Inhibitors are shaped to fit the enzyme's active site so the reaction the cancer relies on stops.
Broadly expressed or essential: HPA lists TOP1 among essential proteins and finds the RNA at low tissue specificity; the 4 medicines aimed at it (Irinotecan (and liposomal irinotecan), Topotecan, Sacituzumab govitecan and more) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA TOP1: RNA low tissue specificity; high antibody staining in 27 normal tissues; highest cancer staining head and neck cancer (4 of 4 high). Distribution: 3 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Colorectal cancer, Lung cancer (all types), Breast cancer (all types)); approvals of single-target medicines aimed at it also list Bladder & urothelial cancer, Gastric & gastro-oesophageal junction cancer, Oesophageal cancer, Salivary gland cancers and more, not counted; Open Targets associates it with 7 specific cancer types at or above 0.5 (small cell lung carcinoma, breast cancer, non-small cell lung carcinoma, cervical cancer, colorectal cancer, ovarian cancer and more). Tissue-agnostic: Trastuzumab deruxtecan US 2024: "HER2 IHC3+ solid tumours (tumour-agnostic)". (Rule 7 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas TOP1 tissue; Open Targets ENSG00000198900 associations
First described 1988. Earliest sequence paper UniProt cites for the protein: D'Arpa et al, Proc. Natl. Acad. Sci. U.S.A, 1988, "cDNA cloning of human DNA topoisomerase I: catalytic activity of a 67.7-kDa carboxyl-terminal fragment". Source.
Type IB topoisomerase that relieves torsional stress during replication and transcription; trapped as a covalent cleavage complex by camptothecins.
RNA: low tissue specificity, detected in all normal tissues.
Medium: Breast, Cervix, Fallopian tube, Kidney, Liver, Lung, Pancreas, Parathyroid gland.
HPA TOP1 tissue · HPA TOP1 pathology · HPA protein class: Essential proteins, FDA approved drug targets
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Metastatic cancer | all% | Housekeeping enzyme present in every dividing cell (DNA unwinding during replication); not a selection marker, which is why these drugs are given by cancer type rather than by test. |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
HR070803 is an experimental small-molecule drug from Jiangsu HengRui Medicine in phase 3 trials for colorectal cancer, with its target not yet stated publicly.
Query for this target: (TITLE:"Topoisomerase I" OR ABSTRACT:"Topoisomerase I" OR TITLE:"TOP1" OR ABSTRACT:"TOP1") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Topoisomerase I (TOP1), not a curated reading list.
Shares HR070803, Colorectal cancer.
Shares Topotecan, Sacituzumab govitecan, Small-cell lung cancer.
Shares Irinotecan (and liposomal irinotecan), Small-cell lung cancer, Colorectal cancer.
Shares Sacituzumab govitecan, Trastuzumab deruxtecan, Triple-negative breast cancer (TNBC).
Shares Topotecan, Small-cell lung cancer.
Shares Trastuzumab deruxtecan, HER2-positive breast cancer, Triple-negative breast cancer (TNBC).
Shares Irinotecan (and liposomal irinotecan), Sacituzumab govitecan, Small-cell lung cancer, Triple-negative breast cancer (TNBC).
Shares Topotecan, Small-cell lung cancer.