Anticancer Agents

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

Log Kill Hypothesis

Relationship of tumor cell no. to time of diagnosis, symptoms, treatment, and survival.
A. Infrequent/ unplanned/Late ~ Survival benefits but B. Combination therapy (acute leukemia, testicular cancers, and Hodgkin's lymphoma) C. Tumor resection+ Adjuvant therapy

Cell Cycle & Cancer

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)

Epipodophyllotoxin (topoisomerase II inhibitor) (G1S phase)

Etoposide

Taxanes (M Phase)
Albumin-bound paclitaxel, Docetaxel, Paclitaxel

Classification II
Cell Cycle-Specific (CCS) Agents Contd
Vinca Alkaloids (M Phase)
Vinblastine, Vincristine, Vinorelbine

Antimicrotubule inhibitor (M phase)

Ixabepilone

Antitumor antibiotics (G2-M phase)

Bleomycin

Cell CycleNonspecific (CCNS) Agents

Alkylating Agents
Altretamine, Bendamustine, Busulfan, Carmustine, Chlorambucil, Cyclophosphamide, Dacarbazine, Lomustine, Mechlorethamine, Melphalan, Temozolomide, Thiotepa

Classification III
Cell CycleNonspecific (CCNS) Agents Contd
Anthracyclines
Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone

Antitumor Antibiotics
Dactinomycin, Mitomycin

Camptothecins (topoisomerase I inhibitors)

Irinotecan, Topocetan

Platinum analogs
Carboplatin, Cisplatin, Oxaliplatin

Using Drug Combinations

Advantages
Maximal killing (in therapeutic conc.) Broader range of interaction b/w drugs & tumors Prevention/slowing resistance

Dosage & Resistance

Dosage Factors
Effective dosing ~ conventional Sigmoidal with threshold, a linear phase, and a plateau phase Toxicity hampers ~ dose or time interval Strategies Dose escalation Interval reduction

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

Hodgkins Lymphoma & Non-Hodgkins Lymphoma

Reed-Sternberg cell are present in Hodgkins.

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.

Regression, Remission, Relapse

Uses of Alkylating agents: Nitrogen Mustards

Mechlorethamine
Hodgkins disease

Cyclophosphamide
Ovarian, breast carcinoma, Hodgkins and nonHodgkins lymphoma & All types of leukemias. Also used as immunosuppressant in transplantation

Melphalan
Ovarian carcinoma & multiple myeloma

Uses of Alkylating agents: Nitrosoureas

Lomustine & Carmustine
Brain tumor, malenoma, GI cancers ADRs pulmonary fibrosis & renal failure (high doses)

Streptozocin
Pencreatic insulinoma

Uses of Alkylating agents: Miscellanous

Cisplatin
Testicular, bladder, lung and ovarian carcinomas Nephro- and ototoxic

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

Uses and Adverse Effects

Uses
Doxo ~ AML, ALL, breast, endometrium, ovary, thyroid and lung cancer Dauno ~ AML, ALL

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

Hormones & Related Agents I

Flutamide
Nonsteroidal Antiandrogen that inhibits translocation of androgen receptors Prostate cancer

Tamoxifen
Antiestrogen that inhibits estradiol and estrogen Breast cancer

Leuprolide
Inhibits FSH & LH Prostate cancer

Hormones & Related Agents II

Glucorticoids
Prednisone & Hydrocortisone Hodgkins, Non-Hodgkins, ALL, Myeloma

Plant Alkaloids
Vinca alkaloids~ bind to tubulin~ prevent assembly of microtubules Vincristine
Hodgkins, Wilms, Ewings Sarcoma

Vinblastin
Hodgkins & testicular Cancer

Cause peripheral neuropathies

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