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

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

• Treatment options of cancer Chemotherapy

Radiotherapy

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 α

The Classification of Anticancer Drugs According to chemical structure and resource

Alkylating Agents

Antimetabolite

Antibiotics

Plant Extracts

Hormones

Others (cis-platinum,

carboplatin，lobaplatin)

According to biochemical mechanisms of anticancer action

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: M（Mitosis）phase

G1（Gap1, period before S）phase

S（DNA synthesis）phase

G2（Gap2,period after S）phase

Cell cycle specific agents and Cell cycle Non-specific agents

Cell Cycle Nonspecific Agents (CCNSA)

drugs that are active throughout the cell cycle Alkylating Agents Platinum Compounds Antibiotics

Cell Cycle Specific Agents (CCSA) drugs that act during a specific phase of the

cell cycle S Phase Specific Drug:

Antimetabolites, Topoisomerase Inhabitors

M Phase Specific Drug: Vinca Alkaloids, Taxanes

G2 Phase Specific Drug: Bleomycin

Cell cycle summary and site of action of Cell-cycle specific antineoplastics

Vincrisine Vinblastine Taxanes

Steroids

Podophyllotoxins

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

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

Mitomycin C (alkylates DNA and thereby causes strand

breakage and inhibition of DNA synthesis)

Bleomycin (Iron catalyzed free radical damage to DNA-strand

breakage in the G2 phase of the cell replication cycle. useful in Hodgkin’s and non-Hodgkin’s 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 Ewing’s 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

Resistance to Alkylating Agents has several causes:

ed Membrane transport The drug may be bound by glutathione (GSH) via GSH-S-

transferase or metallothioneins in the cytoplasm and inactivated. The drug may be metabolized to inactive species. Cross resistance

CNS penetration, to treat brain tumors

to treat chroic granulocytic leukemia and other myeloproliferative disorders

active in bladder cancer

CP: Chronic lymphocyctic leukemia, non-Hodgkin’s lymphomas, breast and ovarian cancer

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