Transcript 张纬萍_Caner chemotherapy

Antineoplastic drugs
－ Basic pharmacology
－ Typical antineoplastic drugs
－ Common toxicity and rational use
Weiping Zhang, Ph.D., MD
Email: [email protected]
Dept. Pharmacology, Medical School, Zhejiang University
Treatment of Cancer
 Chemotherapy (disseminated neoplams include
germ cell caner, non-Hodgkin’s lymphoma, Hodgkin’s
disease, choriocarcinoma, leukemia etc)
 Radiation therapy
 Surgery
 Adjuvant therapy, include temporary
improvement of the symptoms and
enhancement in the overall quality of life.
 Physical and psychological support
Treatment of Cancer
Hematologic malignancies
Solid tumor
 Low-differentiation
－induce
 Grow fast
－Inhibit proliferation
－kill
－inhibit angiogenesis
Palliative chemotherapy
姑息性化疗
Curative chemotherapy
治疗性化疗
Part I basis of antineoplatics
Classification
Cytotoxic agents - Most typical agents
 Alkylating agents (烷化剂 : 氮芥类等 )
 Antimetabolites (抗代谢物 : MTX, 5 5-FU 等)
 Antineoplastic antibiotics (抗肿瘤抗生素 )
 Antineoplastic plant drugs (抗肿瘤植物药 )
 Others：(其他 : 铂类配合物和门冬酰胺酶
Non-cytotoxic agents - Currently developed rapidly
 Hormones and their antagonists(激素及其拮抗剂 )
 Molecular targeted agents(分子靶向药物 )
Others
 Retinoic acid(维甲酸）
 Arsenious acid (三氧化二砷 , As As2 O3 )
Part I basis of antineoplatics
Classification
－According to the chemical structure and/or resources
 Antimetabolites
－Cytarabine (Ara-C，阿糖胞苷）
－Methotrexate (MTX, 氨甲蝶呤)
 Antitumor antibiotics
－Bleomycin （BLM，博莱霉素）
－Daunorubicin （柔红霉素）
 Alkylating agents
－Cyclophosphamide（CTX，环
磷酰胺）
－Nitrogen mustard（NH2，氮芥）
Plant alkaloids （microtule
inhibitor）
－Vinblastin (VLB，长春碱)
－Paclitaxel（taxol，紫杉醇）
 Hormones and antagonists
－Estrogens（雌激素类）
－Tamoxifen（TAM，他莫昔芬）
 Others
－Cisplatin（DDP，顺铂）
－Interferon（干扰素）
Part I basis of antineoplatics
Classification
－According to the biochemical mechanisms
(1) Drugs inhibiting biosynthesis of nucleic acid
(2) Drugs directly destroying DNA structure and
function
(3) Drugs interfering transcript process and
inhibiting RNA synthesis
(4) Drugs interfering protein synthesis and
function
Part I basis of antineoplatics
Classification
－According to the biochemical mechanisms
Part I basis of antineoplatics
Classification
－According to the biochemical mechanisms
1. Drugs inhibiting biosynthesis of nucleic acid





抑制二氢叶酸还原酶: MTX MTX（甲氨蝶呤 ）
抑制胸苷酸合成酶而阻止胸苷酸合成: 5-FU FU（氟尿嘧啶 ）
阻止嘌呤类核苷酸合成: 6-MP MP（巯嘌呤 ）
抑制核苷酸还原酶: HU HU（羟基脲 ）
抑制DNA 多聚酶 : Ara Ara-C（阿糖胞苷 ）
2. Directly destroying DNA structure and function




Alkylating agents ( 烷化剂 ): CTX ( 环磷酰胺 )
Platinum coordination complexes destroying DNA ( 破坏 DNA 的铂
类配合物 ):DDP ( 顺铂 ), CBP ( 卡铂 )
Antibiotics destroying DNA:MMC ( 丝裂霉素 C), ),BLM ( 博来霉素 )
Inhibitor of DNA-topoisomerase: )topoisomerase CPT ( 喜树碱 ),
VP16 ( 依托泊甙)
Part I basis of antineoplatics
Classification
－According to the biochemical mechanisms
3. Interfering transcript process and inhibiting RNA
synthesis

Antitumor antibiotics: DACT（放线菌素D）、ADM（多柔比星）、
DNR（柔红霉素）
4. Interfering protein synthesis and function

Affecting the formation of spindle fibers: Vinca alkaloids ( 长春碱
类 ）, VLB VLB（长春碱 ）, VCR , VCR（长春新碱 ）

Interfering the function of nucleoprotein: Harringtonine(三尖杉酯碱 )

Interfering the supply of amino acid: L-Asparaginase (L-门冬酰胺
酶)
Part I basis of antineoplatics
Classification
－According to the biochemical mechanisms
Non-cytotoxic antineoplastics
 Hormones (肾上腺皮质激素、雌激素、雄激素)
 Signal transduction inhibitors (various pathways)
 Anti-angiogenic agents
 Monoclonal antibodies
 Differentiation inducers
 Tumor radiosensitizing and normal tissue
radioprotecting drugs
 Cytoprotective agents
 Biologic response modifiers
Part I basis of antineoplatics
Classification
－According to the cell cycle
无增殖能力
有增殖的潜能
Relaps
e
Classes 3
Cancer chemotherapy drug classes
－According to the cell cycle
• Information to the mode of action, indication and
scheduling of cell cycle-specific (CCS) and cell
cycle-nonspecific (CCNS) drugs.
• CCS drugs are more sensitive to hematologic
malignancies and in solid tumors in which cells
proliferate very fast.
• CCNS drugs are very useful in both low and high
growth tumors
Classes 3
Cancer chemotherapy drug classes
－According to the cell cycle
Resistance
1. Resistance of cancer chemotherapeutic drugs
 Primary resistance (Natural resistance)
－The cancer cells in G0 phase
－Malignant melanoma
－Renal cell cancer
－Brain cancer.
Resistance
1. Resistance of cancer chemotherapeutic drugs
 Acquired resistance due to the mutation, decreasing or increasing
the expression of one or more specific genes. Reduce intracelluar
drug concentration or alter the target.
－Alkylating agents: DNA repair , drug influx , binding with GSH 
－Antitumor antibiotics, (1) actinomycin D and anthracyclines, P-gp
expression , topoisomerase II , P450 ; (2) Bleomycin and
mitomycin, e-flux , GSH-S-transferase .
－Antimetabolites, (1) methotrexate, DHFR , the affinity to DHFR ;
influx ; (2) 6-thiopurines, HGPRT , de-phosphate , metabolize ;
(3) 5-Fu, activation , ribonucleotide synthesis ，metabolize ; (4)
Cytarabine, transport , phosphorylase change, dCTP , metabolize .
－Micrtotubule inhibitors, P-gp 
－Hormones, the change of receptor numbers and affinity
Resistance
1. Resistance of cancer chemotherapeutic drugs
 Properties of acquired resistance
－High lipid soluble drugs
－Influx cell through passive transport
－The accumulation in resistant cells is fewer
than it in insensitive cells
－Most with P-gp expression.
Resistance
1. Resistance of cancer chemotherapeutic drugs
 Multidrug resistance protein 1 (MRP1)
－Belongs to the ATP-binding cassette transmembrane transporter superfamily.
Resistance
Some ATP-binding cassette trans-membrane transporter superfamily
Nomenclature
Traditional
name
Full name
ABCB1
P-gp/MDR1
Multidrug resistant gene/P-glycoprotein，
ABCB11
BSEP/SPGP
Bile salt export pump/sister P-glycoprotein，
ABCC1
MRP1
Multidrug resistance protein 1
ABCC2
MRP2/cMOAT
Multidrug resistance protein 2
ABCC3
MRP3
Multidrug resistance protein 3
ABCC4
MRP4
Multidrug resistance protein 4
ABCG2
BCRP
Breast cancer resistance protein
Resistance
Resistance
P-glycoprotein (MDR)
The strategy to enhance the effects of cancer
chemotherapy based on P-gp (MDR) inhibitors
Resistance
P-gp (MDR) inhibitors
2007
Resistance
P-gp (MDR) inhibitors
• 1st generation: some clinical using drugs with low
affinity to P-gp, verapamil, amiodarone, reserpine etc.
• 2st generation: can inhibit P450 and other
transporters. Low affinity and non-specific, PSC833 (valspodar)、 dexverapamil、Ro11-2933、
GF120918 (elacridar).
• 3rd generation: selective P-gp inhibitor,
XR9576（tariquidar）、VX-710 (biricodar)、
R101933（laniquidar）、LY335979、GF120918、
XR9051、OC144-093、VX-710、VX-853
Resistance
P-gp knockout and inhibitor can increase the intracaranal
concentration and therapeutic effect of cancer chemotherapy drugs
Typical antineoplastic drugs
Basic pharmacology of cancer
chemotherapeutic drugs
Alkylating agents
1. DNA damaging agents
1.1 Alkylating agents
1.2 Platinum complexes
1.3 Antitumor antibiotics
Alkylating agents
– CH3
Ifosfamide
异磷酰胺
Alkylating agents
－Mechanisms on DNA damage
 Sulfhydryl －SH
 Amino acid －N
 Hydroxyl －OH
 Carboxyl －COOH
 Phosphate －Pi
Guanine
鸟嘌呤
Adenine
Rang 50.4
Cytosine
Guanine
Nitrogen mustard, NH2
 The use of nitrogen mustard start from chemical warfare
－mustard gas (芥子气)
－blister gas （糜烂性毒气，起泡剂）
－Pure: colorless and smell less
－Chemical weapon: brown and smell
like mustard, garlic and horseradish
－1917
 Histopatholobical findings from the victims
－Low white blood cell count
－ Bone marrow aplasia (tissue growth failure).
A soldier with mustard
gas burns sustained
World War I
－1919
 Clinical property
－Hodgkin‘s disease 等恶性淋巴瘤（治疗头颈部肿瘤 , 用区域动脉内
给药 或者 半身化疗 压迫主 动脉阻断下半身循环 , 可以提高肿瘤局部
的药物浓度和减 少全身毒性
－High efficiency and fast effect
Cyclophosphamide, CTX
Metabolism
Cyclophosphamide, CTX
 Pharmacological property
－Metabolize to alkylating;
 Clinical property
－Broad spectrum;
－One of the most widely used alkylating agent;
－Oral route is common;
－Very sensitive to malignant lymphoma
－Cross-resistant with other alkylating agents
Cyclophosphamide, CTX
Ifosfamide （异磷酰胺）
－Closely related to CTX
－Higher response rate
Ifosfamide
异磷酰胺
Other alkylating agents
 Carmustine（卡莫司汀）
Lomustine （洛莫司汀）
－Inhibit DNA replication,
－Highly lipid soluble，esp. for brain cancer
－Carmustine only for iv injection
－lomustine can be orally taken
 Streptozocin （链脲霉素）
－A naturally sugar-containing nitrosourea
－Toxicity to pancreatic islet  cell
Streptozocin
Other alkylating agents
（略）
Procarbazine （丙卡巴肼）
• Inhibit DNA, RNA and protein biosynthesis
• Produces chromosome breaks
• Produces azoprocarbazine and H2O2
• Commnonly used in combination regimens for
Hodgkin’s disease, non-Hodgkin’s lymphoma
and brain tumors.
• Has leukemogenic, teratogenic and mutagenic
properties.
Other alkylating agents
（略）
Dacarbazine （达卡吧嗪）
• By oxidative N-demethylation dacarbazien can be
metabolized to monomethyl derivative and then
decomposes to 5-aminoimidazole-4-carboxamide
(excreted in the urine) and diazomethane.
• Diazomethane generates methyl carbonium ion
(cytotoxic species)
• Commnonly used in melanoma, Hodgkin’s disease
and soft tissue sarcomas
Other alkylating agents
（略）
Altretamine（六甲密胺）
• Structurally similar to triethylenemelanime.
• Insoluble and available only in oral form.
• Biotransformed into pentamethylmelamine and
tetramethylmelamine metabolites.
• Used in ovarian cancer patient
• Beside the usual toxicity, neurotoxicity in the from of
somnolence, mood changes and peripheral
neuropathy is also observed.
Platinum analogs
 Platinum analogs are inorganic metal
complex, which have the similar cytotoxicity
as alkylating agents.
Cisplatin，DDP，顺铂
 Primary biding site is the N7 position of
guanine, but covalent interaction with
adenine and cytosine.
 Can also bind to –SH of proteins
 Can synergize with certain other anticancer
drugs.
Carboplatin，CBP，卡铂
Platinum analogs
Cisplatin，DDP，顺铂
 Broad range of solid tumors, nonsmall cell and small cell lung cancer,
esophageal and gastric cancer, head
and neck cancer and genitourinary
cancer.
 The effect of CBP is stronger than
DDP.
 DDP is too toxic, thus developed CBP
Carboplatin，CBP，卡铂
Platinum analogs
 Oxaliplatin is relative new (proved by FDA in
2002, but has never been proved to be more
effective
Oxaliplatin, 奥沙利铂
Antitumor antibiotics damage DNA
Came from the screening of microbial
products
Products of various strains of the soil
microbe streptomyces.
Include mitomycin, bleomycin.
And Actinomycin D, Anthracyclines
Antitumor antibiotics damage DNA
Mitomycin (丝裂霉素，mitomycin C)
－MMC 结构中有 乙撑亚 胺基团和,氨甲酰酯基团有烷化作用 .
－A special use is in the intravesical treatment of superficial
bladder cancer.
－Hypoxic tumor stem cells of solid tumors are more sensitive.
－The best available drug for use in combination with radiation
therapy to hypoxic tumor cells.
Antitumor antibiotics damage DNA
Bleomycin (博莱霉素)
－A small glyco-peptide containing
DNA binding region and an
iron/copper-binding domain.
－Produce free radicals and breaks
DNA.
－A cell cycle-specific drug that causes G2/M arrest （someone
refers to a CCNS drug）.
－More sensitive to squamous cell carcinoma （磷状上皮癌）
－Can be used on malignant lymphoma
Clinical uses
主要治疗
鳞状细胞上皮癌
(squamous
epithelioma
epithelioma), 包括 头
部 , 颈部 , 口腔 ,食
管, 阴茎 , 外阴和宫颈的
鳞状细胞上皮癌。
Adverse reaction
主要是肺纤维化，与使
用的累积剂量有
密切关系，对骨髓和免
疫系统的抑制较
轻, 胃肠道反应也不严
重。
Basic pharm. 2
Basic pharmacology of cancer
chemotherapeutic drugs
Antimetabolites
2. Inhibitors of DNA/RNA
synthesis and integrity
2.1 Antitumor antibiotics
2.2 Antimetabolites/Folate
pathway inhibitors
2.3 Topoisomerase inhibitors
Antitumor antibiotics inhibit DNA/RNA synthesis
Actinomycin D (DACT, 放线菌素D)
－Actinomycin is redirected from
dactinomycin（更生霉素）
－Inhibit DNA-dependent RNA polymerase
－Stable topoisomerase II and DNA complex
－Narrow, highly toxic.
－主要治疗 恶性葡萄胎，绒毛膜上皮癌，淋巴
瘤和肾母细胞瘤，横纹肌肉瘤及神经母细胞
瘤等.
－CCNS, but more sensitive to G1
－Primarily used to inhibit transcription and DNA replication
Antitumor antibiotics inhibit DNA/RNA synthesis
 Anthracyclines (蒽环类，doxorubicin，多柔比星,
daunorubicin,柔红霉素,idarubicin，依达比星 and
epirubicin，表柔比星)
－
One of the most widely used cytotoxic anticancer
drugs.
－
Mechanism including (1) inhibition of topoisomerase
II; (2) high-affinity biding to DNA and block the
synthesis of DNA and RNA; (3) binding to cellular
membranes to alter fluidity and ion transport; (4)
generate semiquinone free radicals and oxygen free
radicals  cytotoxicity and cardiotoxicity.
－
Usually administered on every-3-week schedule or
longer.
Antimetabolites
 Antimetabolites are structurally
related to normal cellular
components.
 They generally interfere with the
availability of normal purine or
pyrimidine nucleotide precursors
by inhibiting their syntheisis or by
competing with them in DNA or
RNA synthesis.
 Their maximal cytotoxic effects
are S-phase (and therefore cellcycle) specific.
Synthesis of DNA, RNA and protein
Antimetabolites
 DHFR inhibitors
Methotrexate（氨甲喋呤）
Sulfonamides（磺胺类药物）
 Purine antagonists
6-thiopurines (6-MP, 6-TG，巯嘌呤)
 Pyrimidine antagonists
5-fluorouracil (5-FU，5-氟尿嘧啶)
 Ribonucleotide reductase
inhibitor
Hydroxycarbamide (HU，羟基脲）
 DNA polymerase inhibitor
Cytarabine（Ara-C，阿糖胞苷）
 Inhibit protein synthesis
Asparaginase (门冬酰胺酶)
Antimetabolites
Folic acid
DHFR
FH2
Methotrexate
DHFR
FH4
Methyl-FH4 (leucovorin)
N5N10-methene-FH4
Deoxyribonucleotides
Methotrexate
Clinical uses
 Acute leukemia in children (儿童急性白血病)
 Chorioepithelioma（绒毛膜上皮癌）
 目前主张先用大剂量MTX治疗，随后用甲酰四氢叶酸
作为“救援剂（rescue agents）”，可保护骨髓正
常细胞，拮抗其毒性
Fluorouracil（氟尿密度，5-Fu）
 5-FU 是尿嘧啶的衍生物 在尿嘧啶环第 位的 取代，转 变
为 氟尿嘧啶脱氧核苷酸（ 5F-dUMP ）
 5F-dUMP可抑制thymidylate synthase（脱氧胸苷酸合成酶）
 5F-dUMP可转化为5-FUR（5-氟尿嘧啶核苷），作为伪
产物掺入RNA中，感染蛋白质合成。
 用于多种实体瘤：esp消化道癌症和乳癌。
F
尿嘧啶
5-FU
Mercaptopurine（巯嘌呤，6-MP）
 6-MP  thioinosinic acid （硫代肌苷酸），
 硫代肌苷酸可抑制肌苷酸转变为胸苷酸（AMP）和鸟苷
酸（GMP），主要作用于S期细胞。
 用于儿童急性淋巴性白血病疗效显著，但起效较慢，大
剂量用于绒毛膜上皮癌。
NH2
巯嘌呤
6-MP
Hydroxyurea（羟基脲，HU）
 HU  抑制nucleotide reductase （核苷酸还原酶），阻止
胞苷酸（CMP）转变为退养胞苷酸（dCMP）。
 用于慢性粒细胞白血病，对转移性黑色素瘤有暂时缓解
作用。
 可用作同步化疗药，使细胞集中在G1期。
Cytarabine（阿糖胞苷，Ara-C）
 Ara-C与胞嘧啶核苷相似。主要作用于S期。
 经脱氧胸苷酸激酶催化二磷酸或三磷酸胞苷  抑制
DNA多聚酶。或者掺入DNA中干扰其复制。
 用于成人急性粒细胞白血病和单核细胞白血病。
Topoisomerase inhibitors
 Camptothecins (Topotecan, Irinotecan)
Hydroxycamptothecin (HCPT，羟喜树碱)
Topetecan（TPT，拓扑特肯）
Irinotecan（CPT-11，依林特）
－Derived from the camptotheca acuminata tree;
－Inhibit topoisomerase I (CCNS, but S>G1 and G2)
－Topotecan is usually a second-line drug for
advanced ovarian cancer
－Irinotecan is for metastatic clorectal cancer
Topoisomerase inhibitors
 Epipodophyllotoxins (etoposide, VP16, 依托泊苷and
teniposide, VM-26，替尼泊苷)
- Semisynthetic drivatives of podophyllotoxin（足叶草毒素，
鬼臼毒素）, which is extracted from the mayapple root
(podophyllum peltatum，盾叶鬼臼).
- CCNS, more sensitive to S and G2 phase. Inhibition of
microtubule, topoisomerase II and damage DNA
- Etoposide has been used for germ cell cancer, small cell
and non-small cell lung cancer, Hodgkin’s and nonHodgekin’s lymphomas and gastric cancer.
- Teniposide is limited mainly to acute lymphoblastic
leukemia.
Drugs inhibiting protein synthesis and functions
Plant alkaloids
- Vinca alkaloids （长春碱类）inhibit microtubule polymerization.
- Cochicine （秋水碱类） alters the 3D inter-microtubule instability.
- Taxanes （紫杉烷类） stabilize polymerized microtubules protofilaments.
Plant alkaloids
 Vinblastine （VLB，长春花碱）
- An alkaloid derived from the periwinkle plant vinca rosea.
- Disrupt assembly of microtubules.
- Used for Hodgkin’s disease, non Hodgkin’s lymphomas,
breast cancer and germ cell cancer.
M phase
 Vincristine（VCR，长春新碱）
- Effective when combined with prednisone
for acute lymphoblastic leukemia in
children and various hematologic
malignancies.
 Vinorelbine （NVB，长春瑞滨）
- New, effective for small cell lung cancer
Plant alkaloids
 Colchicine
（略）
- Derived from genus Colchicum
- Microtubules were identified as a cellular component
based on their ability to bind colchicine.
- Disrupting the 3D structure of tubublin interactions
- Originally used for rheumatic complaints and gout
disease (for cathartic and emetic).
- Its anti-cancer therapy is inhibited by its
toxicity.
Plant alkaloids
 Taxanes (Paclitaxel，紫杉醇)
- An alkaloid ester derived from the pacific yew, the European
yew and Chinese yew;
- Enhance and stable tubulin polymerization;
- Used on broad range of solid tumors, late phase ovary
cancer, metastatic breast cancer.
- Metabolize by liver P450 and
eliminate with feces
- Novel albumin-bound paclitaxel
formulation (Abraxane)
Less hypersensitivity
Hormonal agents
 Mechanisms of action
－Intracellular cascade of
events
• Apoptosis
• Paracrine vs autocrine
mechanisms
• HPA axon
－Activate/block the receptors
－palliative therapy （姑息性
治疗）
Hormonal agents
 Estrogen （雌激素） & androgen（雄激素）
inhibitors
- Tamoxifen (他莫昔芬，a partial agonist-inhibitor
of estrogen receptor), for early-stage and
metastatic breast cancer. Chemopreventive for
women at high risk for breast cancer.
- Flutamide（氟他米特） and bicalutamide（比卡
鲁胺）, nonsteroidal antiandrogen agents, for
early-stage prostate cancer and in the setting of
metastatic prostate cancer.
Hormonal agents
 Estrogen （雌激素） &
androgen（雄激素）
- Diethylstilbestrol (已烯雌酚),
inhibit HPA and thus
decrease the release of
testosterone. Directly
antagonize testosterone
- Methyltestosterone（二甲基
睾丸酮）, testosterone
propionate（丙酸睾丸酮）,
and fluoxymesterone（氟羟
甲酮）， inhibit HPA and
thus decrease the release of
estradrone. Directly
antagonize estradrone
Male hormones
Hormonal agents
 Gonadotropin-releasing hormone （GnRH）
agonists
- Leuprolide（醋酸亮丙瑞林） and goserelin（戈舍瑞林）
- Inhibition of the release of LH and FSH.
- Results in castration levels of testosterone in men.
- For advanced prostate cancer and for adjuvant
therapy of early-stage prostate cancer.
- Main adverse effects include hot flushes, impotence
and gynecomastia.
Hormonal agents
Cytochrome P450 superfamily
Aromatase inhibitors
×
Hormonal agents
 Aromatase inhibitors
Aminoglutethimide（氨鲁米特）, a nonsteroidal inhibitor of
corticosteroid synthesis
- Inhibit adrenal and extra-adrenal synthesis of estrone and
estradiol. Increase the metabolize of estrone.
- Inhibit P450 and block the conversion of cholesterol to
pregnenolon.
Anastrozole（阿那曲唑）, Letrozole（来曲唑）, Exemestane
（依西美坦）
- Inhibitors of aromatase
- Had no effects on adrenal glucocorticoid or mineralocorticoid
synthesis
- Anastrozole, Letrozole are among the first-line treatment of
postmenopausal women with metastatic breast cancer.
Hormonal agents
Corticosterioids
Prednisone（泼尼松） and prednisonlone
（泼尼松龙）
- Inducing apoptosis of T (low concentration) and
B lymphocytes (high concentration)
- Potently immunosuppressive
- Used in the regimen for lymphocytolytic
- Ineffective for the solid tumor
Interferon
 Include , , -interferon
 Kill cancer cells
 Probably through the stimulation of NK cell
 -INF can activate macrophage cell
 Effective in hairy-cell leukemia（毛细胞白
血病）， squamous cell carcinoma（磷状上
皮癌）, melanoma（黑色素瘤） and multiple
myeloma（多发性骨髓瘤）
Novel chemotherapies in oncology
http://clinicaltrials.gov/

Differentiation inducer

Proteasome inhibitor

TRAIL receptor signal pathway inducer

PI3K-AKT-mTOR signal pathway
inhibitor

MDM2–p53 inhibitor

Hypoxic selective agents

Tumor metastasis inhibitor

Reversal agents of chemoresistance

Vaccines

Adjuvant interferon
Novel chemotherapies in oncology
（略）
 Retinoic acid derivatives
- Induction of differentiation, induction of clinical remission
- All-trans-retinoic acid (tretinoin), effective for acute
promyelocytic leukemia, but result in a number of
serious adverse events.
 Arsenic trioxide
- Functions by inducing differentiation through
degratdation of the chimeric PML/RAR- protein. Also it
induce cell apoptosis.
Novel chemotherapies in oncology
（略）
 Imatinib
- Inhibitor of the tyrosine kinase domain of the Bcr-Abk oncoprotein
and prevents the phosphorylation of the kinase substrate by ATP.
- First-line for the treatment of chronic myelogenous leukemia, blast
crisis. Second-line for chronic phase CM that has progressed on
prior INF- therapy.
 Growth factor receptor inhibitors
- Cetuximab, a chimeric monoclonal antibody against the
extracellular domain of EGFR.
- Gefitinib & Erlotinib, small molecule inhibitor of the tyrosine
kinase domain associated with the EGFR.
- Bevacizumab, recombinant humanized monoclonal antibody that
targets all forms of VEGF-A.
Common toxicity and rational use
Long-term toxicity
 Secondly malignant tumor- alkylating agents
－Mutagenesis (致突变)
－Carcinogenicity (致癌)
 Sterility (不育) teratogenecity (致畸性)
－Man: azoospermia(无精), impotence（性无能）
－Woman: ovary dysfunction, amenorrhea（闭
经）, abortion（流产） or abnormity（畸胎）
Short-term toxicity
Common toxicity（共同毒性）
Target to the cells undergoing rapid
proliferation: buccal mucosa, bone marrow,
gastrointestinal (GI) mucosa, hair cells.
Myelosuppression（WBC, platelet, RBC）
GI responses: severe vomiting, stomatitis
Hair cells: alopecia
Dose-limiting
Short-term toxicity
--- Common
Comparison of
myelosuppression potential
Cancer treatment support
 Psychological support
 Physical support
Short-term toxicity --- Special
 Immunosuppression (infections)
 Skin (extravasation, photosensitivity)
 Liver (veno-occlusive disease, hepatocellular damage)
 Pancrease (pancreatitis)
 Lung (pulmonary fibrosis)
 Heart (congestive heart failure, arrhythmias)
 Genitourinary (cystitis, renal failure)
 Nervous system (peripheral neuropathy, autonomic neuropathy,
encephalopathy)
 Gonadal function (azoospermia, impotence, amenorrhea)
 Miscellaneous: electrolyte problems, diabetes, endocrine
failure, pathologic fractures, hemolytic anemia, growth
suppression, and others.
Short-term toxicity --- Alkylating agents
Mechlorethamine（氮芥）
 Severe vomiting (CNS) and myelosuppression
 Immunosuppression  virus infection
 Skin (extravasation)  can be treated with sodium thiosulfate (硫代硫
酸钠)
Cyclophosphamide （环磷酰胺）
Ifosfamide（异磷酰胺）
 Severe vomiting, alopecia and myelosuppression
 Cystitis（膀胱炎） MESNA (巯乙磺酸钠)
 Neurotoxicity  High dosage
Carmustine（卡莫司汀）Lomustine（洛莫司汀）
 Myelosuppression  骨髓再生性障碍
 Nephrotoxicity and lung fibrosis
Short-term toxicity --- Platinum complexes
Cisplatin （顺铂）
 Severe and lasting vomiting
 Nephrotoxicity and electrocyte disturbances rehydration and
diuresis
 Ototoxicity （耳毒性）
Carboplatin（卡铂）
 Severe and lasting vomiting
 Dose-dependent myelosuppression
Short-term toxicity --- Antibiotics
Mitomycin （丝裂霉素）
 Severe and lasting myelosuppression
 GI response and local injection site response
Bleomycin（博莱霉素）
 Skin toxicity and alopecia
 Lethal lung fibrosis
Actinomycin D（放线菌素D）
 Dose-dependent myelosuppression
 Immunodepression
 Skin (extravasation can induce necrosis, radiosensitivity induce local
inflammation)
Doxorubicin（多柔比星）Daunorubicin（柔红霉素）
 Irreversible cardiac toxicity
 Sever alopecia
Short-term toxicity --- Antimetabolites
Methotrexate （甲胺喋呤）
 Vomiting, stomatitis, alopecia and myelosuppression;
 Nephrotoxicity at high dosage
 Hepatic fibrosis
 Abnormal
 reversible lung toxicity
 All can be lightened by tetrahydrofolic acid
6-thiopurines（6-巯嘌呤）
 Myelosuppression
Short-term toxicity --- Antimetabolites
5-Fluorouracil （5-Fu, 5氟尿嘧啶）
 Vomiting, diarrhea and alopecia;
 Sever stomatitis (口腔炎) and myelosuppression (at high dose)
 Skin, hand-foot syndrome
Cytarabine（阿糖胞苷）
 Sever vomiting, diarrhea and myelosuppression
 CNS response at high dose or intra-vertebral cannal infusion
Short-term toxicity --- Topoisomerase inhibitor
Camptothecins （喜树碱）
 Vomiting, alopecia and myelosuppression;
Etoposide（依托泊苷）
 Myelosuppression
 Hypotension if the infusion is too fast
Short-term toxicity --- Plant alkaloids
Vinblastin （长春花碱）and Vincristin（长春新碱）
 Skin  extravasation and induce phlebitis （静脉炎）and cellulitis
（ 蜂窝组织炎）
 Vomiting, diarrhea and alopecia
 Vinblastin has severe myelosuppression
 Vincristin and induce peripheral neuronal toxicity, paraesthesia（感
觉异常）areflexia（反射消失）ataxia（共济失调）
Taxanes（紫杉醇）
 Severe allergy
 Granulocytopenia（粒细胞减少）
Short-term toxicity --- Hormonal agents
Tamoxifen （他莫昔芬）
 Can decrease LDL and protect cardiovascular system
 Induce hypercalcemia （高血钙）and endometrial cancer（子宫内膜
癌）
Estragen（雌激素）
 Azoospermia, impotence
Corticosteroids（糖皮质激素）
Minimizing the toxicity
 Decrease the dose;
 Local infusion;
 Follow-up;
 Prevention, e.g. tetrahydrofolic acid
 Physical and psychological support
 Targeting
Rational use of antineoplastic agents
(1) Goals for chemotherapy




Complete Remission
Partial Remission
Stable Disease
Progressive Disease
CURE ------ LONG-TERM, DISEASE-FREE SURVIVAL.
(2) Important of neoplastic cell burden
(3) Methods of treatment
Combination chemotherapy is more
effective than single-drug in most cancers
for which chemotherapy is effective
Advantages of Combination chemotherapy :
(1) Provide maximal cell kill within the range of
tolerated toxicity
(2) Effective against a broader range of cell lines
in the heterogeneous tumor population
(3) Slow or prevent the development of resistant
cell lines.
(3) Methods of treatment
Mechanisms under combination chemotherapy :
(1) Recruitment and synchronization
募集和同步化
(2) Synergistic mechanisms
协同机制
(3) Non-overlapping toxicities.
毒性反应无重叠
(3) Methods of treatment
Treatment protocols:
(1) Different treatment protocols have been
developed for various particular
neuoplastic state.
(2) Acronym: for example POMP is a
common regimen for the treatment of
acute lymphocytic leukemia(ALL)
consists of Prednisone, Oncovin
(vincristine), Methotrexate and Purinethol.