Transcript ( I ) Chemotherapy

Cancer Signals and Drug
Development:
( 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
10
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
*每十萬人口
死亡人數 死亡率*
135,071
591.8
37,998
12,596
12,283
9,690
8,011
5,396
5,049
4,712
4,406
1,816
166.5
55.2
53.8
42.5
35.1
23.6
22.1
20.6
19.3
8.0
%
100.00
28.1
9.3
9.1
7.2
5.9
4.0
3.7
3.5
3.3
1.3
Loss of Normal Growth Control
NEOPLASIA

Fundamental to the origin of all
neoplasms is loss of
responsiveness to normal growth
control.
Mode of Growth
• Benign:
capsule
expansion with fibrous
• Malignant: invasion and infiltration
without capsule
Benign tumor
Malignant tumor
上皮癌症前期病灶變化
Betel nut-associated oral cancer
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
Mucosa
Muscularis
mucosae
Submucosa
Muscularis
propria
Subserosa
Serosa
Lymph node
Stage I Stage II Stage III
AJCC, 臨床分期 and Survival
Classification of cancers by origin
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
Viral and Microbial Carcinogenesis
•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 disease progression
HPV vaccination before 12 year of age
Helicobacter pylori-associated
mucosa-associated lymphoid tissue
(MALT) type-lymphoma
Extranodal
Postgerminal Trisomy 18,
Arises at
marginal
center
t(11;18),
extranodal
zone
memory
t(1;14); latter
sites in adults
lymphoma
B-cell
create MALT1with chronic
IAP2 and
inflammatory
BCL10-IgH
diseases; may
fusion genes,
remain
respectively
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 TGF-b 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
Treatment of cancers
•
•
•
•
Surgical removal (手術)
Radiotherapy (電療)
Chemotherapy (化療)
Targeted therapy (標靶治療)
Principle of cancer chemotherapy
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
Acute complication of cancer
chemotherapy
•
•
•
•
•
•
•
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