( I ) Chemotherapy
Ih-Jen SU
STUST Lecture
October 8, 2015

九十五年臺灣地區主要死亡原因
順位 死亡原因
所有死亡原因
1
2
3
4
5
6
7
8
9
惡性腫瘤
腦血管疾病
心臟疾病
糖尿病
事故傷害
肺炎
慢性肝病 / 肝硬化
腎臟疾病
自殺
高血壓性疾病 10
* 每十萬人口
死亡人數 死亡率 * %
135,071 591.8 100.00
37,998 166.5 28.1
12,596 55.2 9.3
12,283
9,690
8,011
5,396
5,049
4,712
4,406
1,816
53.8
42.5
35.1
23.6
22.1
20.6
19.3
8.0
3.5
3.3
1.3
9.1
7.2
5.9
4.0
3.7

Loss of Normal Growth Control


Fundamental to the origin of all neoplasms is loss of responsiveness to normal growth control.

• Benign: expansion with fibrous capsule
• Malignant: invasion and infiltration without capsule

Benign tumor

Malignant tumor

Arsenic skin cancer in Southwestern Taiwan:
Multiple at different stages

• Benign neoplasms do not metastasize
• Malignant neoplasms do metastasize (or have the capacity to metastasize)

大腸癌病理分期
Stage I Stage II Stage III
Mucosa
Muscularis mucosae
Submucosa
Muscularis propria
Subserosa
Serosa
Lymph node

AJCC, 臨床分期 and Survival

1. Epithelial carcinoma
2. Mesenchymal sarcoma
3. Hematopoietic (blood cancer) lymphoma, leukemia

Different Kinds of Cancer
Some common carcinomas:
Lung
Breast (women
)
Colon
Bladder
Prostate
(men)
Leukemias:
Bloodstream
Lymphomas:
Lymph nodes
Some common sarcomas:
Fat
Bone
Muscle

Liposarcoma

•Oncogenic RNA viruses ：
HTLV-1 (human T-lymphotropic virus type I) ： adult T cell leukemia/lymphoma Tax protein as Oncoprotein
HCV (hepatitis C virus) ： hepatoma, lymphoma
•Oncogenic DNA viruses ：
HPV (human papilloma virus) ： cervical cancer
HBV (hepatitis B virus) ： hepatoma
EBV (Epstein-Barr virus) ： lymphoma, nasopharyngeal carcinoma
•Helicobacter pyloric and gastric lymphoma
•Inflammation (virus and bacteria)–associated cancers ：
Cytokine and NFkB activation

HBV/HCV and hepatocellular carcinoma
(HCC, hepatoma): HCV-core, HBx, pre-S mutants, regeneration

HPV-associated papilloma and cancers: viral genotypes HPV 6/11 or 16/18

HPV vaccination before 12 year of age

Extranodal marginal zone lymphoma
Postgerminal center memory
B-cell
Trisomy 18, t(11;18), t(1;14); latter create MALT1-
IAP2 and
BCL10-IgH fusion genes, respectively
Arises at extranodal sites in adults with chronic inflammatory diseases; may remain localized; indolent

Helicobacter pylori -associated mucosa-associated lymphoid tissue
(MALT) type-lymphoma

Scanning EM and Warthin-Starry stain of Helicobacter pylori (HP)

Familial Adenomatous Polyposis (FAP)
家族性多發腸息肉症侯群
• 10-15 歲以前腸道（大腸為主）發生多數目的
腸息肉 .
• 50 歲以前這些腸息肉中會發生癌變 .
• 身體其它組織也可能有不正常的情形（例如視
網膜色素細胞先天性肥大 congenital hypertrophy of the retinal pigment epithelium 或
發生於胸、腹壁上的纖維瘤 desmoid ） .

Familial polyposis and colon cancer: cancer develops at 20 years of age

Genetic model for colorectal carcinogenesis

Kinetics of tumorigenesis: Tumor development usually takes a long period, a balance between tumor cells and environment factors

Oncogenes ( 致癌基因 ), Oncoproteins
• Growth factors: PDGF, FGF, TGF…
• Growth factor receptors: EGFR, PDGFR
• Signal-transducing proteins: RAS, RAF, βcatenin
• Transcription factors: MYC
• Cyclins and cyclin-dependent kinases

Growth factors and signal-transducing proteins

Insensitivity to Growth Inhibitory
Signals: Tumor Suppressor Genes
• Retinoblastoma as a Paradigm for the Two-Hit Hypothesis of Oncogenesis
• p53: Guardian of the Genome
• APC/ b
-Catenin Pathway
• Others:
– The INK4a/ARF locus, The TGFb pathway, NF-1 gene,
NF-2 gene, VHL, PTEN, WT-1, Cadherins, KLF6,
PTCH.

Guardian of the
Genome

DNA Repair Defects and Genomic
Instability in Cancer Cells
• Hereditary Nonpolyposis Cancer Syndrome
• Xeroderma Pigmentosum
• Inherited Diseases with Defects in DNA
Repair by Homologous Recombination
– BRCA1 and BRCA-2 Genes

XP is an autosomal recessive disease with sun sensitivity, photophobia, early onset of freckling, and subsequent neoplastic changes on sun-exposed surfaces

• Surgical removal (手術)
• Radiotherapy (電療)
• Chemotherapy (化療)
• Targeted therapy (標靶治療)

1. DNA replication: alkylating agents
2. Cell cycle ( proliferation ) inhibitors: tubulin inhibitor
3. Inhibition of protein synthesis and anti-metabolite

Chemotherapy (化療) and
Chemotherapeutic Agents
1. DNA alkylating agents cyclophosphamide, cisplatin
2. Indirect DNA interacting agents: azathioprine, bleomycin, gemcitabine
3. Anti-mitotic agents:
Vincristine, paclitaxel
4. Inhibitors of protein synthesis and antimetabolites
5. Disruption of cell cycle—tubulin inhibitor

• 1. Myelosuppression: transfusion,
•
G-CSF
• 2. Nausea and vomiting: GI tract
• mucosa damage
• 3. Alopecia: skin stem cells
• 4. Gonadal dysfunction: germ cell
• 5. Infection due to immunosuppression