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Introduction
Changes in normal cells
Neoplastic transformation Expression of specific surface antigens Signs of immaturity Qualitative or quantitative chromosomal abnormalities Loss of contact inhibition ~ uncontrolled proliferation ~ migration to distant sites ~ clonogenic
Causes
Genetic Environmental (azo dyes, aflatoxins, asbestos, benzene, and radon) Virus through oncogenes/tumor suupressors
Treatment Avenues
3 main settings for indication of chemo
Primary induction treatment
For advanced cancer with no alternative options Goals ~ Palliation ~ prolong tumor progression Curative for small percentage
Neoadjuvant
For patients with localized (Alternate available)
Adjuvant
Adj to local treatments chances of local & systemic recurrence ~ improve survival
Classification I
Cell Cycle-Specific (CCS) Agents
Antimetabolites (S phase)
Capecitabine, Cladribine, Clofarabine, Cytarabine (ara-C), Fludarabine, 5-Fluorouracil (5-FU), Gemcitabine, 6Mercaptopurine (6-MP), Methotrexate (MTX), 6-Thioguanine (6-TG)
Taxanes (M Phase)
Albumin-bound paclitaxel, Docetaxel, Paclitaxel
Classification II
Cell Cycle-Specific (CCS) Agents Contd
Vinca Alkaloids (M Phase)
Vinblastine, Vincristine, Vinorelbine
Classification III
Cell CycleNonspecific (CCNS) Agents Contd
Anthracyclines
Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone
Antitumor Antibiotics
Dactinomycin, Mitomycin
Platinum analogs
Carboplatin, Cisplatin, Oxaliplatin
Resistance
Fundamental problem ~ inherent (p53, mismatch repair enzymes) & acquired Specific to one agent or several (MDR1)
Toxicity
Killing rapidly dividing cancer cells
buccal mucosa, bone marrow, gastrointestinal (GI) mucosa, and hair
Common ADR
Severe vomiting, stomatitis, bone marrow suppression, and alopecia Cardiotoxicity with doxorubicin and pulmonary fibrosis with bleomycin Variable duration
Induced tumors
acute nonlymphocytic leukemia (Alkylating agents)
Terms I
Lymphoma
Any neoplasm of lymphoid tissue; in general use, synonymous with malignant lymphoma.
Sarcoma
A connective tissue neoplasm, usually highly malignant, formed by proliferation of mesodermal cells.
Carcinoma
Any of various types of malignant neoplasm derived from epithelial cells.
Leukemia
Progressive proliferation of abnormal leukocytes found in hemopoietic tissues, other organs, and usually in the blood in increased numbers. Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia (CML), Acute Lymphocytic Leukemia (ALL), and Acute Myeloid Leukemia (AML)
Terms II
Myeloma
A tumor composed of cells derived from hemopoietic tissues of the bone marrow
Insulinoma
An insulinoma is a tumor in the pancreas that produces too much insulin
Malenoma
Skin cancer
Wilms tumor
a malignant renal tumor of young children
Terms III
Rhabdomyosarcoma
A malignant neoplasm derived from skeletal (striated) muscle, occurring in children or, less commonly, in adults
Choriocarcinoma
Uterine Cancer
Kaposis Sarcoma
Kaposi's sarcoma is a cancerous tumor of the connective tissue, and is often associated with AIDS.
Ewings Sarcoma
Ewing's sarcoma is a malignant bone tumor that affects children.
Cyclophosphamide
Ovarian, breast carcinoma, Hodgkins and nonHodgkins lymphoma & All types of leukemias. Also used as immunosuppressant in transplantation
Melphalan
Ovarian carcinoma & multiple myeloma
Streptozocin
Pencreatic insulinoma
Carboplatin
Ovarian carcinoma
Busulfan
CML
Dacarbazine
Hodgkins lymphoma & Malenoma
Procarbazine
Hodgkins
Antibiotics
Drugs
Doxorubicin, Daunorubicin
MOA
Bind to adjacent nucleotides along the sugar-phosphate bond ~ block DNA & RNA synthesis Disrupt cell membrane Generate free radicals (oxygen) that cause single-strand breaks in DNA
ADR
Irreversible cardiac toxicity
Other Antibiotics
Bleomycin
+Fe complex + O2 Free radicals Strand scission Used for testicular & Hodgkins Pulmonary toxicity
Mitomycin
Reduced to Alkylating agent Used for carcinoma of cervix, lung, bladder & colon
Dactinomycin
Forms complex with DNA RNA polymerase inhibited+ Single strand break Used for Wilms tumor, rhabdomyosarcoma, choriocarcinoma & Kaposis Sarcoma
Plicamycin
Same MOA as Dactinomycin Highly toxic but used for testicular cancer
Antimetabolites: Methotrexate
Folate Antagonist DHFA to THFA inhibited Thymidylate inhibited AA, neucleotide synthesis inhibited Used for Breast cancer, head and neck cancer, osteogenic sarcoma, primary central nervous system lymphoma, non-Hodgkin's lymphoma, bladder cancer, choriocarcinoma
5-Fluorouracil
Inhibits TS Used for Colorectal cancer, anal cancer, breast cancer, gastroesophageal cancer, head and neck cancer, hepatocellular cancer Neurotoxicity
Other Antimetabolites
6-Mercaptopurine
Used for AML
6-Thioguanine
ALL, AML
Capecitabine
Breast cancer, colorectal cancer, gastroesophageal cancer, hepatocellular cancer, pancreatic cancer
Cytarabine
AML, ALL, CML
Tamoxifen
Antiestrogen that inhibits estradiol and estrogen Breast cancer
Leuprolide
Inhibits FSH & LH Prostate cancer
Plant Alkaloids
Vinca alkaloids~ bind to tubulin~ prevent assembly of microtubules Vincristine
Hodgkins, Wilms, Ewings Sarcoma
Vinblastin
Hodgkins & testicular Cancer
Others
Etoposide
Topoisomerase II inhibitor ~ Single stranded DNA break Small cell lung carcinoma, Kaposis Sarcoma, NonHodgkins
Paclitaxel
Interferes with microtubules ~ arrest the cells in mitosis Used for ovarian and breast cancer
Monoclonal Antibodies
Trastuzumab for Breast cancer Rituximab for Lymphomas and CLL Bevacizumab for metastatic colorectal cancer with 5-FU Cetuximab for colorectal cancer Gemtuzumab and Ozogamicin for AML Alemtuzumab for CLL I131-tositumomab for (relapsed) non-Hodgkins