Anticancer Drugs

Dr Muhammad Raza

Cancer: Introduction
Cancer occurs after normal cells have been transformed into neoplastic cells through
alteration of their genetic material and the abnormal expression of certain genes. These changes lead to

Treatment options of cancer

Chemotherapy Radiotherapy

uncontrolled cell division and many result in the invasion of previously unaffected organs (metastasis)

Immunotherapy and Gene therapy

Surgery

Chemotherapy and proliferating cells

Tumor cells can be divided into 2 populations: 1. Proliferating cells (rapidly proliferating cells in the cell cycle) 2. Resting cells (G0) (can re-enter cell cycle) Chemotherapy targets proliferating tumor cells Normal cells, which are rapidly dividing, are also killed by chemotherapy; this leads to the common side effects of these agents Normal (untransformed) cells, which are rapidly dividing, are also killed by chemotherapy; this leads to the common side effects of these agents.

Subgroups of anticancer drugs

Others: Topoisomerase Inhibitors: Etoposide, teniposide,Irinotecan, topotecan Monoclonal Antibodies: Alemtuzumab, bevacizumab, cetuximab, gemtuzumab ozogamicin, rituximab, trastuzumab Tyrosine Kinase Inhibitors: Erlotinib, Imatinib (GLEEVEC) Cytokines and interferons: Aldesleukin, interferon

The Classification of Anticancer Drugs

According to chemical structure and resource
According to biochemical mechanisms of anticancer action

Alkylating Agents
Antimetabolite Antibiotics Plant Extracts Hormones

Others

(cis-platinum,

carboplatinlobaplatin)

Block nucleic acid (DNA, RNA) biosynthesis Directly destroy DNA and inhibit DNA reproduction Interfere transcription and block RNA synthesis Interfere protein synthesis and function Influence hormone homeostasis Others

The Classification of Anticancer Drugs

The cycle of cell replication includes:
MMitosisphase G1Gap1, period before Sphase SDNA synthesisphase G2Gap2,period after Sphase

Cell cycle specific agents and Cell cycle Non-specific agents

Cell Cycle Nonspecific Agents (CCNSA) Alkylating Agents Platinum Compounds Antibiotics Cell Cycle Specific Agents (CCSA)

drugs that are active throughout the cell cycle

drugs that act during a specific phase of the cell cycle

S Phase Specific Drug:
Vinca Alkaloids, Taxanes
Bleomycin

M Phase Specific Drug:

Antimetabolites, Topoisomerase Inhabitors

G2 Phase Specific Drug:

Cell cycle summary and site of action of Cellcycle specific antineoplastics

Podophyllotoxins

Vincrisine Vinblastine Taxanes

Steroids

Cell cycle effects of cytotoxic antineoplastic drugs

Block Nucleic Acid (DNA, RNA) Biosynthesis

drugs that are structural analogues of essential metabolites and that interfere with DNA synthesis

Interfere with Protein Synthesis

Bind tubulin, destroy spindle to produce mitotic arrest

Influence the Structure and Function of DNA

ANTIBIOTICS:

Interfere Transcription and Block RNA Synthesis

Adriamycin (Anthracyaline Antibiotics) that block the synthesis Mitomycin C (alkylates DNA and thereby causes strand
breakage and inhibition of DNA synthesis)

of DNA and RNA in S-Phase of cell cycle. used to treat acute leukemias, lymphoma, and a number of solid tumors

Bleomycin (Iron catalyzed free radical damage to DNA-strand

breakage in the G2 phase of the cell replication cycle. useful in Hodgkins and non-Hodgkins lymphomas, testicular cancer, and several other solid tumors; little myelosuppression. The serious toxicities are pulmonary and mucocutaneous reactions)

Actinomycin D (intercalates DNA and thereby prevents DNA

transcription and messenger RNA synthesis; treatment of trophoblastic (gestational) tumors and the treatment of pediatric tumors, such as Wilms tumor and Ewings sarcoma)

Influence Hormone Homeostasis

These drugs bind to hormone receptors to block the actions of the sex hormones which results in inhibition of tumor growth. Estrogens and estrogen antagonistic drug Androgens and androgen antagonistic drug Progestogen drug Glucocorticoid drug GnRH inhibitor: leuprolide, goserelin aromatase inhibitor: aminoglutethimide, anastrazole

Hormones to treat cancers

Classification of Alkylating Agents

CP: Chronic lymphocyctic leukemia, non-Hodgkins lymphomas, breast and ovarian cancer

CNS penetration, to treat brain tumors

active in bladder cancer
to treat chroic granulocytic leukemia and other myeloproliferative disorders

Resistance to Alkylating Agents

ed Membrane transport The drug may be bound by glutathione (GSH) via GSH-Stransferase or metallothioneins in the cytoplasm and inactivated. The drug may be metabolized to inactive species. Cross resistance

has several causes:

Adverse Effects of Alkylating Agents

Myelosuppression is the dose-limiting adverse effect for alkylating agents. Nausea and vomiting are common teratogenesis gonadal atrophy- variable, according to the drug, its schedule, and route of administration. Treatment also carries a major risk of leukemogenesis and carcinogenesis

Adverse effects shared by most cancer chemotherapeutic agents

Due to the effect of cancer chemotherapy on rapidly dividing cells Bone marrow depression: manifested as leucopenia (leading to immunosuppression and repeated infections) and thrombocytopenia (manifested as bleeding tendency) GIT: manifested as nausea and vomiting, diarrhea and ulceration of the mucous membrane of the mouth. Hair follicles leading to alopecia Amenorrhea and sterility due to decreased sperm count

Teratogenicity and carcinogenicity

Notable side effects of chemotherapeutic agents