Anticancer drugs (I)

What is Cancer?

A disease of the body’s own cells, involving dynamic changes (i.e., mutations) in the genome

Loss of normal control mechanisms

• Proliferation

• Differentiation

• Programmed death (apoptosis)

Proliferation

cancer cells - uncontrolled growth, but NOT always grow faster than normal cells​

Differentiation

cancer cells de-differentiated (immature), but in different degree

Programmed death (apoptosis)

cancer cells resistant to apoptosis, but in different degree

Tumorigenesis (malignant transformation)

• Initiation, promotion, and progression

• Due to the accumulation of genetic alterations (mutations)

• Metastases arise from the spread of cancer cells from the primary site and the formation of new tumors in distant sites

Normal vs. Cancer cells (Structural differences)

Normal Cells:

• DNA is functioning in a normal way.

• Divide in an orderly way to produce more cells only when the body needs them

Cancer cells:

• Carry mutations including abnormal gene structure or numbers of chromosomes

• Continue to be created without control or order. A mass of tissue or tumor is formed

Normal vs. Cancer cells (Differences in Energy Use)

Normal cells:

• 70% of their energy from the Krebs cycle

• Only 20% of their energy from glycolysis

Cancer cells:

• Have a defective Krebs cycle and derive little or no energy from it

• Almost all their energy from glycolysis

• Glycolysis even in the presence of oxygen (aerobic glycolysis)

Glycolysis of Cancer cells

How is High aerobic glycolysis utilized to diagnose and monitor treatment responses of cancers?

High aerobic glycolysis by malignant tumors is utilized to diagnose and monitor treatment responses of cancer by imaging uptake of 2-18F-2 deoxyglucose

Normal vs. Cancer cells (Differences in Blood Vessels)

Normal cells:

• Have a built-in blood vessel system

Cancer cells:

• Do not have a build-in blood vessel system. They require some chemical stimulation to build one, because tumor growth depends on development of new blood supply (angiogenesis)

Normal vs. Cancer cells (Differences in Growth Factors)

Normal Cells:

• Produce a balanced amount of growth factors

• Normal level of activity

Cancer Cells:

• Overproduce growth factors

• Thus, cells are overactive

Normal vs. Cancer cells (Functional Differences)

Normal Cells:

• Produce enzymes and hormones in a balanced manner

Cancer Cells:

• The enzymes and hormones are either overactive or underactive

Cancer Classification

Carcinomas - solid tumor

Sarcomas - solid tumor

Lymphoma - solid tumor

Leukemia

Carcinomas

From epithelial cells (line some organs and skin)​

Sarcomas

From connective or other deeper tissues​

Lymphoma

Cancer of the lymphatic system​

Leukemia

Cancer of the blood

Cancer Staging symptoms

• describe how far cancer has spread anatomically (i.e.metastasis)​

• This is not applicable to leukemia because the blood is not localized.​

For solid tumors there are two staging systems

1. The overall stage grouping system​

2. The tumor, nodes, and metastases (TNM) system​

The Overall Stage Grouping System: 5 Stages

Stage 0 and I: Small localized cancers that are usually curable.​

Stages II and III: Locally advanced and/or involvement of local lymph nodes. ​

Stage IV: Inoperable or metastatic cancer.​

The TNM Systen

• Each tumor (T), lymph node (N), or metastasis(M) is classified with anumber.​

• T classifies the extent of the primary tumor: in situ (T0) or extensive invasion(T4) to other organs.​

• N classifies the amount of regional lymph node involvement: no (N0) or extensive (N4).​

• M0: no metastasis

• M1: metastasis

Ex: T1N2M0

Relative early stage of cancer

Tumor Grading

• Measure of how abnormal cells appear underthe microscope

• Gx = grade cannot be assessed (leastaggressive)​

• G1 = well differentiated

• G2 = moderately differentiated​

• G3 = poorly differentiated​

• G4 = undifferentiated (most aggressive andfast growing)

Cancer Etiology

• Tobacco - environmental exposure

• Alcohol - environmental exposure

• Radiation - environmental exposure

• Dietary Habits - environmental exposure

• Chemicals - environmental exposure

• Viruses - environmental exposure

• Hereditary (germline or somatic)

Tobacco

• 30% of all cancer deaths in the USA

• 90% of lung cancer are due to smoking

• Associated with upper respiratory tract, lung, esophageal, bladder, and pancreatic cancers​

• Lung cancer = smoking

Alcohol

• Ethanol is not a carcinogen per se.​

• Can cause cancer in upper GI tract by increasing permeability of mucosa to carcinogens.​

• Strong evidence that consuming alcohol increases the risk of esophageal cancer, hepatocellular carcinoma, pancreatic cancer, etc.

Radiation

Solar:​

• Skin cancer such as squamous and basal cell carcinoma and melanoma​

• Whitest skin, highest risk​

Ionizing Radiation:​

• Associated with development of leukemia and thyroid cancer

Dietary Habits

Foods associated with increased risk of developing cancer such as colon, prostate, and breast​

• high fat, high calories intake​

• alcohol​

• salt cured, smoked or charred foods​

• nitrates and nitrites additives in processed meats​

Foods associated with decreased risk of developing cancer.​

• high-fiber foods​

• high content of vegetables, fruits, and whole grain cereal​

Chemicals

• Aflatoxin → hepatoma (liver cancer)​

Aflatoxin and hepatoma

• Aflatoxins are highly toxic compounds produced by certain fungi that contaminate crops especially in warm/humid conditions​

• Cause liver cancer​

• Prevention strategies: Proper food storage; dietary interventions; regular screening for liver cancer in high-risk populations

Viruses

10-15% of cancers worldwide are linked to infections,e.g, ​

• Epstein-Barr virus → Non-Hodgkin’s lymphoma and nasopharyngeal cancer​

• HIV → Kaposi’s sarcoma and lymphoma​

• HTLV1 → Cutaneous T-cell lymphoma​

• Human papilloma virus → Cervical cancer​

• Hepatitis B virus → Liver cancer

Two main categories of genetic changesthat lead to cancer

• The activation of proto-oncogenes to oncogenes​

• The inactivation of tumor suppressor genes

Proto-Oncogenes​

• Proto-oncogenes are normal genes whose protein products stimulate growth and viability of cells. ​

• Also include genes that contribute to tumor growth by inhibiting cell death (inhibiting apoptosis)(“Do not die”) (BCL2). ​

• Example: growth factors and their receptors,e.g. HER2, EGFR, K-RAS, B-RAF, BCL2 (anti-apoptotic)…

Oncogenes

• Oncogenes are mutated or damaged genes that contribute to tumor growth (oncogenes are abnormal proto-oncogenes)​

Activation of proto-oncogenes by

• Mutation or amplification (increased # of gene copies); chromosome abnormality (“Driver mutations”)​

• Increase of protein expression (epigenetics-changes that alter gene activity without changingDNA sequences)

Tumor Suppressor Genes​

• Genes whose protein products can directly or indirectly prevent cell division or lead to cell death. ​

• E.g, P53 - “guardian of the genome”, mutated in ~50% of human solid tumors

Inactivation of tumor suppressor genes by

• Mutation or deletion​

• Decrease of protein expression (epigenetics)