Supplementary table 1. Summary of FDA-approved anticancer cytotoxic drugs at May 2019. Classification Targets Name Indication Detox pathway Known off-targets Resistance mechanisms References Substrate of Overexpression and lower CYP3A4, phosphorylation of CDC2, enhanced DNA Busulfan CML GSTA1, GSTA2, Unclear [1–3] stress response, inactivating mutations in GSTM1, GSTP1, the mismatch repair system (in vitro) MGST2. Alkylsulfonate DNA Altretamine Ovarian Unclear Unclear Unclear [3] Anal, bladder, breast, cervical, gastric, lip, mesothelioma, Substrate of DNA Mitomycin Unclear Overexpression of ABC transporters [3,4] NSCLC, oral cavity, POR pancreas, peritoneum, and Ethyleneimine pharynx Breast, ovarian, Substrate of Inhibitor of BCHE, DNA Thiotepa Enhanced activity of GST [3,5] bladder CYP3A4 CYP2B6 Synthetic drugs Synthetic Alkylating Agents Alkylating DNA, HL, Substrate of Inactivating mutations in the mismatch MAOA, Procarbazine oligodendrogliomas, Unclear [6,7] CYP1B1, XDH repair system (in vitro) MAOB PCNSL Methylhydrazine Substrate of DNA Bendamustine CLL, NHL Unclear Overexpression of CD69 (in vitro) [8] CYP1A2 Nitrogen mustard derivative mustard Nitrogen SUPPLEMENTARY TABLE 1. SUMMARY OF FDA-APPROVED ANTICANCER CYTOTOXIC DRUGS AT MAY 2019 (CONTINUATION) Classification Targets Name Indication Detox pathway Known off-targets Resistance mechanisms References CLL, lymphomas (HL, NHL, giant Substrate of Overexpression of GST isoenzymes and DNA Chlorambucil Unclear [3,9] folicular and GSTP1 ABCC1 lymphosarcoma) ALL, brain, breast, leukemias, malignant Increased levels of glutathione and increased DNA Cyclophosphamide lymphomas, Unclear NR1I2 [3,10,11] activity of GST and ALDH1 multiple myeloma, ovarian, retinoblastoma Substrate of CYP2A6, CYP2B6, CYP2C8, NR1I2; inducer of TP53 silencing, increased GST and ALDH1 Lymphomas, CYP2C9, CYP2C8, inhibitor activities, increased DNA repair, DNA Ifosfamide sarcomas, [3,12] CYP2C18, and inducer of overexpression of thioredoxin reductase (in testicular CYP2C19, CYP3A4 vitro) CYP3A4, CYP3A5, Synthetic drugs Synthetic Alkylating Agents Alkylating PTGS1 Nitrogen mustard derivative mustard Nitrogen Bronchogenic carcinoma, CML/CLL, lymphomas (lymphosarcoma , mycosis fungoides, polycythemia DNA Mechlorethamine vera, palliation Unclear Inhibitor of GSR Overexpression of GST isoenzymes [3,13,14] on HL III and IV). Also for the palliative treatment of metastatic carcinoma resulting in effusion. SUPPLEMENTARY TABLE 1. SUMMARY OF FDA-APPROVED ANTICANCER CYTOTOXIC DRUGS AT MAY 2019 (CONTINUATION) Classification Targets Name Indication Detox pathway Known off-targets Resistance mechanisms References Multiple myeloma, DNA Melphalan Unclear Inhibitor of SLC22A3 Bcl-X expression [3,15,16] ovarian Nitrogen mustard derivative mustard Nitrogen Anaplastic astrocytoma, DNA, Substrate of Carmustine glioblastoma Inhibitor of GSR Overexpression of MGMT [3,17–20] RNA CYP1A2 multiforme, multiple myeloma Glioma, STMN4, inhibitor of DNA Lomustine medulloblastoma, Unclear Overexpression of MGMT [3,21] CYP2D6, CYP3A4 lymphoma Nitrosurea Synthetic drugs Synthetic Alkylating Agents Alkylating SLC2A2 ligand, antagonist of Beta-n- Pancreas and acetylglucosaminida DNA Streptozocin carcinoid Unclear Overexpression of MGMT [22] se, MGEA5, inducer syndrome of ABCB1, CYP1A1, CYP1A2, CYP2E1. Substrate of Overexpression of MGMT, Bcl-2 expression, DNA, Melanoma, Dacarbazine CYP1A1, Inhibitor of PGD AKT activation, NF-kB activation, VEGFR-1 [3,23] POLA2 lymphomas CYP1A2, CYP expression Triazenes Anaplastic Overexpression of MGMT, Bcl-2 expression, Temozolomide astrocytoma, DNA Unclear Inducer of CYP3A4 AKT activation, NF-kB activation, VEGFR-1 [23,24] (Oral dacarbazine) glioblastoma expression multiforme SUPPLEMENTARY TABLE 1. SUMMARY OF FDA-APPROVED ANTICANCER CYTOTOXIC DRUGS AT MAY 2019 (CONTINUATION) Classification Targets Name Indication Detox pathway Known off-targets Resistance mechanisms References Substrate of ABCC2, ABCG2, Lung, ovarian ATP7A, ATP7B, Upregulation of P-type ATPases, and squamous GSTM1, GSTT1, SOD1, inducer of overexpression of MRP2, enhanced activity of DNA Carboplatin [3,25,26] cell head and GSTP1, MT1A, MPO, XDH, NER and overexpression of BRCA2, mutation neck MT2A, NQO1, and downregulation of RAD52 (repair gene) SLC31A1, SLC31A2 Bladder, cervical, Substrate of esophageal, ABCB1, ABCC6, A2M, ATOX1, MPG gastric, germ cell ABCG2, ATP7A, and TF. Inhibitor of tumours ATP7B, GSTM1, BCHE, CYP2B6, (including GSTP1, GSTT1, CYP2C9, nat, Upregulation of P-type ATPases, adducts testicular), DNA Cisplatin MT1A, MT2A, PTGS2 and overexpression of MRP2, enhanced activity of [3,25,27] mesothelioma, NQO1, SLC22A2. Inducer of NER and overexpression of BRCA1 NSCLC, SLC22A2, ABCC2, ABCC3, osteosarcoma, SLC31A1, ABCC5, CYP4A11, based agents based - ovarian, SCLC, SLC31A2 and MPO and XDH. and squamous SOD1. cell head and Synthetic drugs Synthetic neck Platinum Alkylating Agents / DNA / DNA Agents Alkylating Substrate of ATP7A, ATP7B, ABCC2, ABCG2, CYP1A1, CYP1B1, CYP2E1, CRC, Alterations in the mitochondrial apoptotic GSTM1, GSTT1, DNA Oxaliplatin esophageal and Unclear pathway, enhanced autophagy, increased GSH [3,28–30] GSTP1, MPO, gastric levels, SRBC hypermethylation (in vitro) MT1A, MT2A, NQO1, SLC22A2, SLC22A3, SLC31A1 and SOD1. SUPPLEMENTARY TABLE 1. SUMMARY OF FDA-APPROVED ANTICANCER CYTOTOXIC DRUGS AT MAY 2019 (CONTINUATION) Classification Targets Name Indication Detox pathway Known off-targets Resistance mechanisms References Substrate of ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCC11, ABCG2, AOX1, CYP3A4, Acute leukemias, DHFR, FPGS, bladder, brain, FOLR1, GGH, breast, Inhibitor of ABCC1, MTHFR, SLC16A1, Overexpression of ABC transporters, gestational ABCC2, ABCC3, SLC19A1, SLC22A6, downregulation of RFC, overexpression of DHFR Methotrexate trophoblastic ABCC4, ABCC10, [3,31,32] SLC22A7, SLC22A8, DHFR, loss of function of FPGS, disease, head PGD, SLC22A8, SLC22A11, overexpression of TS and neck, lung, SLC46A1 SLC46A1, NHL, SLCO1A2, osteosarcoma SLCO1B1, SLCO1B3, SLCO1C1, SLCO3A1, SLCO4C1, TYMS Antifolates Overexpression of ABC transporters, DHFR, Malignant Substrate of ATIC, inducer of downregulation of RFC, overexpression of GART, Pemetrexed mesothelioma [33] SLC22A8 DCK, SLC29A1 DHFR, loss of function of FPGS, TYMS and NSCLC Antimetabolite overexpression of TS Synthetic drugs Synthetic DHFR, T-cell Substrate of FPGS, decreased RFC-1 expression and increased Pralatrexate Unclear [34] TYMS Lymphoma SLC19A1 MDR1 expression DNA, RNA, 5-Azacitidine Leukemias Substrate of cytidine Unclear Mutations in TET2, overexpression of BCL2 [3,35] DNMT1 deaminase (CDA) analogs Nucleoside and precursor precursor and Nucleoside SUPPLEMENTARY TABLE 1. SUMMARY OF FDA-APPROVED ANTICANCER CYTOTOXIC DRUGS AT MAY 2019 (CONTINUATION) Classification Targets Name Indication Detox pathway Known off-targets Resistance mechanisms References ABCC3, ABCC4, ABCC5, ABCG2, CYP1A2, Anal, breast, CYP2A6, CRC, gastric, CYP2C8, DPYD, Overexpression of ABC transporters, DNA, RNA, 5-Fluorouracil head and neck, MTHFR, PPAT, Inhibitor of CYP2C9 overexpression of TS, enhanced activity of [3,36] TYMS esophageal and SLC22A7, DPD pancreas SLC29A1, TYMP, TYMS, UMPS, UPP1, UPP2 DNA, MGMT, PNP, POLA1, Hairy cell POLE2, leukemia, Substrate of Decreased expression of hENT1, reduced POLE3, Cladribine chronic DCK, ABCG2, Unclear activity of dCK, overexpression of 5'- [3,37] POLE4, lymphocytic SLC28A3. nucleotidase (in vitro) POLE, RRM1, leukemia RRM2, RRM2B. Acute lymphoblastic DNA, POLA1, Substrate of Clofarabine leukemia and Unclear Reduced activity of dCK [3,38] RRM1 DCK, ABCG2 acute myeloid leukemia Antimetabolite Acute myeloid Synthetic drugs Synthetic leukemia, acute lymphoblastic leukemia, Nucleoside and precursor analogs precursor and Nucleoside chronic myeloid leukemia, Substrate of Downregulation of dCK, downregulation of DNA, POLB Cytarabine lymphomas, CDA, CYP3A4, Unclear [3,39] hENT1 transporter progressive DCTD, NT5E multifocal leucoencephalop athy and meningeal leukemia Myelodysplastic syndrome, sickle cell anaemia (orphan), acute Substrate of Mutations in TET2, higher activity of CDA DNA, DNMT1 Decitabine Unclear [40,41] myeloid DCK combined with decreased activity of dCK leukemia and chronic myeloid leukemia. SUPPLEMENTARY TABLE 1. SUMMARY OF FDA-APPROVED ANTICANCER CYTOTOXIC DRUGS AT MAY 2019 (CONTINUATION) Classification Targets Name Indication Detox pathway Known off-targets Resistance mechanisms References Metastatic GI Floxuridine TYMS adenocarcinoma TYMP Inhibitor of CYP2C9 Amplification of TS and/or deletion of OPRTase [42–44] (5-FU analog) and gastric Acute myeloid leukemia, chronic DNA, lymphocytic Substrate of POLA1, Fludarabine leukemia, NHL SLC28A3, Agonist of DCK Mutations in TP53, overexpression of MYC [3,45,46] RRM1 and SLC29A1 Waldenstrom macroglobulinae mia. Bladder, breast, Substrate of nasopharyngeal, CDA, DCK, Antimetabolite Synthetic drugs Synthetic DNA, non-small cell ABCB1, RRM1, lung, ovarian ABCC10, Low expression of hENT1, higher dCDA Gemcitabine Unclear [3,47] TYMS, and pancreas, SLC28A1, expression, enhanced activity of dCK CMPK1 lymphomas and SLC28A3, Nucleoside and precursor analogs precursor and Nucleoside inflammatory SLC29A1, bowel disease. SLC29A2 Acute Substrate of lymphoblastic AOX1, TPMT, leukemia, acute HPRT1, XDH, SLC22A8, promyelocytic PPAT, ABCC4, ABCC5, Overexpression of ABC transporters, activating Mercaptopurine leukemia, Unclear [3,48] IMPDH1, SLC28A2, mutations in NT5C2 lymphoblastic IMPDH2 SLC28A3, lymphoma