Overview and classification of chemotherapeutic agents and theory

Cancer chemotherapy

1. Overview and classification of chemotherapeutic agents Dr Saurabh Gupta DNB Trainee Rajiv Gandhi cancer institute

2. Chemotherapy ( CTX or CTx ) is a category of cancer treatment that uses one or more anti-cancer drugs( chemotherapeutic agents) as part of a standardized regimen. Paul Ehrlich Father of Chemotherapy Coined the term “Chemotherapy” in 1908 Sidney Farber -- the father of modern chemotherapy Introduced use of antifolates in ALL Sidney Farber 1903-1973

3. The era of cancer chemotherapy began in the 1940s with the first use of nitrogen mustards and folic acid antagonist drugs. Classically , anticancer drugs are grouped as chemotherapy, hormonal therapy and immunotherapy. Used in differerent modalities Neoadjuvant - Before definitive Surgery Adjuvant- After initial Local therapy (Surgery/RT) Palliative- Metastatic disease Concurrent Therapy- with RT/ Immunotherapy Currently nearly all regimen use combination chemotherapy. Introduction

4. ANTINEOPLASTIC DRUGS CHEMOTHERAPY IMMUNOTHERAPY TARGETTED THERAPY Cytotoxic agents which destroy or inhibit the growth and division of malignant cells in the treatment of cancer. Treatment of disease by inducing, enhancing, or suppressing an immune response A form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth

5. Chemical structure Alkylating agents , Antimetabolites , Antitumor antibiotics, Hormonal agents Plant derivatives Biochemistry or mechanism of action Block nucleic acid biosynthesis Direct influence the structure and function of DNA Interfere transcription and block RNA synthesis Interfere protein synthesis and function Influence hormone homeostasis Mitotic spindle inhibitors Cell cycle or phase specificity Cell cycle nonspecific agents ( CCNSA ) & Cell cycle specific agents ( CCSA ) Classification methods

6. Alkylating Agent: ◦ Nitrogen mustards : mechlorethamine , cyclophosphamide , ifosfamide , chlorambucil , Mephalan ◦ Ethylenimine : Thio -TEPA ◦ Alkyl sulfonate : Busulfan ◦ Nitrosoureas : Carmustine , Lomustine ◦ Triazine : Dacarbazine , Tremozolomide ◦ Methylhadrazine : Procarbazine ◦ Platinum: C isplatin , Carboplatin and Oxaliplatin Antimetabolites : ◦ Folate antagonist : Methotrexate ( Mtx ), Pemetrexed , Pralatrexate ◦ Purine antagonist : 6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG ), azathioprine , Fludrabine ◦ Pyrimidine antagonist : 5-Fluorouracil(5-FU) and cytarabine , Capecitabine , Gemcitabine Cytotoxic agents

7. Antitubulins ( mitotic spindle inhibitors ) Vinca alkaloids- Vincristine , Vinblastine Taxanes - Paclitaxel , Docetaxel , Eribulin Topoisomerase II inhibitors- Etoposide , Mitoxatrone , Anthracyclines ( doxorubicin, epirubicin , idarubicin ) Topoisomerase I inhibitors- Irinitecan , Topotecan Antibiotics - Bleomycin , Mitomycin C, Actinomycin D ( dactinomycin ), Anthracyclines Miscellaneous : Aldesleukin , Anagrelide , Arsenic trioxide Hydroxyurea , IFN alpha L- asparginase , Lanreotide , Linalidomide Tretinoin , Thalidomide,.

8. I mpair cell function by transferring alkyl groups to amino, carboxyl, sulfhydryl , or phosphate groups of biologically important molecules React with DNA bases to disrupt the DNA Most common target at the N7 position of guanine Interfere tumor cell growth by DNA cross linking. ALKYLATING AGENTS

9. NITROGEN MUSTARDS Mechlorethamine Cyclophosphamide Ifosphamide Melphalan Chlorambucil 2. ALKYL SULPHONATES Busulphan , Treosulphan 3. NITROSOUREAS Carmustine Lomustine Streptozocin Classification

10. 4. AZIRIDINE AND EPOXIDE ThioTEPA Mitomycin C 5. TRIAZENES P rocarbazine Dacarbazine 6. IMIDAZOTETRAZINES Temozolomide 7. Platinum Compounds Cisplatin Carboplatin Oxaliplatin

11. Myelosuppresion , alopecia Haemorragic cystitis, amenorrhoea, infertility- Cyclophosphamide , Ifofamide Pulmonary toxicity- Busulfan,cyclophosphamide Mucositis , stomatitis , diarrhoea- Melphalan , Thiotepa Renal toxicity- Platinols and nitrosoureas Ototoxicity - Platinum compounds Neurotoxicity, Teratogenecity Side effect profile

12. Busulfan – CML Cyclophosphamide - BREAST CANCER, NHL, CLL, Ovarian, Sarcomas, RMS, Neuroblastoma , Wilm’s tumor Carmustine - HL, NHL , Multiple myeloma, GLIOBLASTOMA MULTIFORME(impregnated wafer (GLIADEL ). Temozolamide - Newly diagnosed glioblastoma multiforme (GBM ), Malignant melanoma Mechlorethamine - HL Melphalan - Multiple myeloma, melanoma, Ovarian Ca Streptozocin - Islet cell tumors Dacarbazine - HL, Malignant melanoma Therapeutic Uses

13. Platinum derivatives Cisplatin Carboplatin TESTICULAR CANCER. OVARIAN CANCER. BLADDER CANCER. HEAD AND NECK CANCER. ESOPHAGEAL CANCER. SMALL CELL AND NON–SMALL CELL LUNG CANCER. NON-HODGKIN’S LYMPHOMA. TROPHOBLASTIC NEOPLASMS. OVARIAN CANCER. GERM CELL TUMORS. HEAD AND NECK CANCER. SMALL CELL AND NON–SMALL CELL LUNG CANCER. BLADDER CANCER. RELAPSED AND REFRACTORY ACUTE LEUKEMIA. ENDOMETRIAL CANCER

14. Oxaliplatin METASTATIC COLORECTAL CANCER EARLY-STAGE COLON CANCER(adjuvant) METASTATIC PANCREATIC CANCER . METASTATIC GASTRIC CANCER and GASTROESOPHAGEAL CANCER .

15. Antifolate compounds are tight-binding inhibitors of DHFR( dihydrofolate reductase ), enzyme in folate metabolism . inhibition of the synthesis of tetrahydrofolate (THF )-key one-carbon carrier for enzymatic processes involved indenovo synthesis of thymidylate , purine nucleotides Activity is greatest in the S phase of the cell cycle.(CCS) ANTIMETABOLITES

16. Antifolates Methotrexate Pemetrexed Pralatrexate Purine antagonists 6-Thiopurine(6-TP) 6-Mercaptopurine(6-MP) Fludarabine Cladribine Pyrimidine antagonist Gemcitabine Cytarabine Decitabine 5-Fluorouracil Capecitabine Others Hydroxyurea Azacitidine Classification

17. Methotrexate enhances the antitumor activity of 5-fluorouracil when given 24 hours before fluoropyrimidine treatment Leucovorin rescues the toxic effects of methotrexate and may also impair the antitumor activity. The active form of leucovorin is the L-isomer. Leucovorin is normally started 24 hours after methotrexate is given. This delay gives the methotrexate a chance to exert its anti cancer effects.

18. Methotrexate Dose-limiting myelosuppression Rescue with leucovorin ( folinic acid)-10mg/m2 every 6h fro 72 hrs Chronic demyelinating encephalopathy(children) and acute neurotoxicity (adults) with Intrathecal MTX Nephrotoxicity Self limitng interstitial pneumonitis Gastro-intestinal (GI) toxicity Acute elevations in hepatic enzyme levels and hyperbilirubinemia ( with high doses) Pemetrexed- Mucositis , skin rash (hand-foot syndrome) Needs VIT B12/FA supplementation Side effects

19. Clinical USES METHOTREXATE PRALATREXATE Breast cancer. Head and neck cancer. Osteogenic sarcoma. Acute lymphoblastic leukemia Non- hodgkin’s lymphoma Primary CNS lymphoma. Meningeal leukemia and carcinomatous meningitis. Bladder cancer. Gestational trophoblastic cancer Mesothelioma (with CISPLATIN) NSCLC Relapsed or refractory peripheral T-cell lymphoma PEMETREXED

20. GEMCITABINE Pancreatic cancer Non–small cell lung cancer Breast cancer Ovarian Ca Bladder Ca Soft tissue sarcoma. CAPECITABINE Metastatic breast cancer Metastatic colorectal cancer HYDROXYUREA - MPD, Refractory ovarian Ca, Sickle cell disease 6-MP - Acute lymphoblastic leukemia (maintenance) 6-TG - AML, ALL AZACITIDINE, DECITABINE- - MDS CLADRIBINE- Hairy cell leukemia CYTARABINE - Acute LL,NHL,HL, Leptomeningeal disease FLUDARABINE - CLL, Low grade Lymohoma

21. 5- Fluorouracil

22. Colorectal cancer—adjuvant setting and advanced disease. Breast cancer—adjuvant setting and advanced disease. GI malignancies, including anal, esophageal , gastric, and pancreatic cancer. Head and neck cancer. Ovarian cancer. Topical use in basal cell cancer of skin and actinic keratoses . Therapeutic uses(5FU)

23. TOPOTECAN IRINOECAN ETOPOSIDE TENIPOSIDE VINBLASTINE VINCRISTINE VINORELBINE PACLITAXEL DOCETAXEL CABAZITAXEL VINCA ALKALOIDS CAMPTOTHECINS DNA TOPOISOMERASE I INHIBITOR DNA TOPOISOMERASE II INHIBITOR MITOTIC SPINDLE INHIBITORS PODOPHYLLOTOXIN TAXANES PLANT ALKALOIDS

24. VINBLASTINE Hodgkin’s Lymphomas, Testicular Ca, Kaposi Sarcoma VINCRISTINE- With prednisone for remission of Acute Leukemia VINORELBINE non-small cell lung cancer Ovarian CA Lymphoma Common side effects Nausea,Vomiting Myelosupression , Alopecia, Extravasation Muscle weakness Peripheral neuritis VINCA ALKALOIDS

25. USES PACLITAXEL - Carcinomas of breast, ovary, lung, oesphagus . Nab- PACLITAXEL- Metastatic breast Ca, Pancreatic CA, NSCLC CABAZITAXEL - Hormone refractory Prostate CA previously treated with docetaxel regimen DOCETAXEL - Crcinoma Breast, Lung Stomach, Esophagus , HEAD and neck, Prostate Ca TAXANES

26. Paclitaxel Neutropenia , Alopecia (90%) Hypersensitivity( upto 40 %) Peripheral neuropathy(stocking glove) Docetaxel Bone marrow suppression Neurotoxicity Fluid retention GI upset Side effects

27. Nontaxane microtubule inhibtor ( G2-M phase) USES- Metastatic breast cancer LIPOSARCOMA SIDE EFFECTS Myelosuppresion , alopecia Peripheral neuropathy Vomiting, stomatitis , diarrhoea, hepatitis ERIBULIN

28. Etoposide Teniposide Semi-synthetic derivatives of podophyllotoxin extracted from the root of the mayapple Blocks cells in the late S-G 2 phase of the cell cycle through inhibition of topoisomerase II DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme Podphyllotoxins

29. Clinical uses Small cell carcinoma lung Testicular Ca Ewings sarcoma Kaposi's sarcoma lymphomas(HL/NHL) and malignant melanomas Side effects Alopecia, nausea, anorexia, diarrhea Metallic taste Hypotension if rapidly infused risk of development of preleukemic or leukemic syndrome ETOPOSIDE

30. TOPOTECAN IRINOTECAN Camptothecins

31. CCS drugs Side effects Severe diarrhea Myelosuppression Arthralgia Irinotecan - colo - rectal cancer, Lung cancer Topotecan - Metastatic ovarian cancer ( cisplatin -resistant) Cervical cancer with cisplatin Relapsed SCLC

32. Anthracyclines - Doxorubicin & Daunorubicin Dactinomycin Plicamycin Mitomycin Bleomycin Antitumor Antibiotics

33. Doxorubicin Daunorubicin Idarubicin Epirubicin Pirarubicin Valrubicin Anthracyclines

34. ANTHRACYCLINES- -CELL CYCLE NON SPECIFIC(CCNS) Various mechanisms are implicated for its cytotoxicity : DNA intercalation. Inhibition of topoisomerase II Formation of cytotoxic oxygen free radical. Inhibition of transcription through DNA dependent RNA polymerase PLICAMYCIN - Binds to DNA through an antibiotic-Mg 2+ complex DACTINOMYCIN Binds to double stranded DNA through intercalation between adjacent guanine-cytosine base pairs Inhibits all forms of DNA-dependent RNA synthesis MITOMYCIN - Bioreductive alkylating agent Mechanism of action

35. Dactiomycin - Wilms ’ tumors,Gestational choriocarinoma with MTX Plicamycin - Testicular cance,Hypercalcemia Mitomycin - Squamous cell carcinoma of the cervix, Adenocarcinomas of the stomach, pancreas, and lung,2 nd line in metastatic colon cancer Mitomycin Renal toxicity(HUS) Uses

36. The iron chelating agent dexrazoxane , reduce anthracycline induced oxygen radical production ; preventing cardiotoxicity .

37. Anthracyclines Myelosuppresion Alopecia Vesicant- Extravasation injury Mucositis (dose limiting) Cardiotoxicity -- Hyperpigmentation of nails , urticaria Red discoloration of urine RADIATION RECALL Liposomal analogues of anthracyclines have been developed to reduce drug toxicity while preserving antineoplastic effects SIDE EFFECTS

38. Acts through binding to DNA, which results in single and double strand breaks following free radical formation and inhibition of DNA synthesis The DNA fragmentation is due to oxidation of a DNA- bleomycin -Fe(II) complex and leads to chromosomal aberrations CCS drug that causes accumulation of cells in G 2 – M phase Side effects Lethal anaphylactoid reactions Blistering Pulmonary fibrosis Skin rash (Whiplash/Flagellate) BLEOMYCIN

39. Uses Testicular cancer Squamous cell carcinomas of the head and neck, cervix, skin, penis, and rectum Lymphomas Intracavitary therapy in ovarian and breast cancers ..cont

40. Asparaginase Hydroxurea Mitoxantrone Mitotane Retinoic Acid Derivatives Amifostine Miscellaneous Agents

41. Causes catabolic depletion of serum asparagine to aspartic acid and ammonia Resulting in reduced blood glutamine levels and inhibition of protein synthesis Neoplastic cells require external source of asparagine Treats childhood acute leukemia Can cause anaphylactic shock ASPARAGINASE

42. An analog of urea Inhibits the enzyme ribonucleotide reductase Resulting in the depletion of deoxynucleoside triphosphate pools Thereby inhibiting DNA synthesis S-phase specific agent Treats melanoma and chronic myelogenous leukemia HYDROXYUREA

43. Structure resembles the anthracyclines Binds to DNA to produce strand breakage Inhibits DNA and RNA synthesis Treats pediatric and adult acute myelogenous leukemia, non-Hodgkin’s lymphomas, and breast cancer Causes cardiac toxicity MITOXANTRONE

44. These drugs bind to hormone receptors to block the actions of hormones which results in inhibition of tumor growth Glucocorticoids Estrogens and estrogen receptor modulators : SERM - Tamoxifen , Raloxifene SERD : Fulvestrant Aromatase inhibitor : Letrozole and anastrazole , Exemestane Androgen antagonists : Flutamide, Bicalutamide, Abiraterone Progestogen e : Hydroxyprogesterone acetate GnRH analogue : Goserelin , Leuprolide GnRH antagonist : Degarelix 5-ɑ reductase inhibitors : Finasteride , Dutasteride Hormonal Agents

45. Glucocorticoids Component in combination regimens in lymphoproliferative disorders and plasma cell dyscrasia Lymphangitis carcinomatosis , Bronchial obstruction by tumor Painful liver metastasis Immune mediated cytopenias CINV Apetite stimulant and mood elevator Symptomatic brain mets , Spinal cord compression Clinical indications

46. GnRH Agonist/Antagonist, Estrogens Prostate and Breast Cancer Progestins Endometrial and Breast Ca Apetite stimulant Aromatase Inhibitors- Ca Breast (Postmenopausal) Antiandrogens - Prostatic Ca in combination with CT Androgens- Ca breast Ocreotide – Islet cell tumors

47. Prolonged use of the androgens and estrogens will cause masculinization and feminization, respectively Extended use of adrenocortical steroids can cause HTN, diabetes, and cushingoid appearance All of these agents can produce fluid retention through their sodium-retaining effects SIDE EFFECTS

48. Targeted therapy stops the action of molecules that are key to the growth of cancer cells. Thus, it affects cancer cells more so than normal cells Targetted Therapies

49. TKI 1 gen 2 gen 3 gen BCR-ABL Imatinib Dasatinib Nilotinib Bosutinib Ponatinib EGFR Erlotinib Geftinib Afatinib Neratinib Ocimertinib Rociletinib Oral agents Monoclonal antibodies Antibodies derivatives Sunitinib Sorafenib Lapatinib Axitinib Pazopanib Lenvatinib Cabozantinib Bevacizumab (AVASTIN) Ranibizumab Afibercept ANTI VEGF AGENTS

50. ALK( anaplastic lymphoma kinase ) inhibitors Alectinib , Ceretinib , Crizotinib BCL 2 inhibitors- Venetoclax BRAF, MEK inhibitors – Cobimetinib , Dabrafenib , Trametinib,Vemurafenib , CDK 4/6 inhibitors- Palbociclib HDAC inhibitors- Belinostat , Panabinostat Her-2 Inhibitors- Lapatinib , JAK inhibitors- Roxulitinib mTOR - Everolimus , Sirolimmus Proteasome inhibitors- Bortezomib , Carfilzomib ..cont

51. Immunotherapy

52. Monoclonal Antibodies- Rituximab , Transtuzumab , Cetuximab , Ramucirumab , Pertuzumab , Panitumumab , Brentuximab , Bevacizumab . Immune checkpoint inhibitors CTLA 4 inhibitors-IPILIMUMAB PDL1 inhibitors- Atezolizumab , Dorvalumab PD1 inhibitors- Nivolumab , Pembrolizumab Adoptive Cell transfer(ACT) therapy Chimeric antigen receptor(CAR T-cell therapy) TIL’s( tumor infiltrating lymphcytes ) Innate immune modulators Aldesleukin (recombinant IL-2)

53. Therapeutic BCG vaccie - intravescal for bladder Ca Oncophage ( Vitespen ) - RCC, Melanoma Sipuleucel -T (APC8015, trade name Provenge )- Hormone refractory prostate cancer BiovaxID - Follicular NHL (Phase III trial) Talimogene laherparepvec in melanoma (phase III) Gp100 vaccine- melanoma (PIII) Preventive HPV vaccine Hepatitis B vaccine Cancer vaccines