Antineoplastic drugs Antineoplastic drugs Weiping Zhang, Ph.D., MD Weiping Zhang, Ph.D., MD Email: [email protected]Email: [email protected]Dept. Pharmacology, Medical School, Zhejiang University Dept. Pharmacology, Medical School, Zhejiang University - - Basic pharmacology Basic pharmacology - - Typical antineoplastic drugs Typical antineoplastic drugs - - Common toxicity and rational us Common toxicity and rational us e e
91
Embed
Antineoplastic drugs Weiping Zhang, Ph.D., MD Email: [email protected] Dept. Pharmacology, Medical School, Zhejiang University - Basic pharmacology.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Antineoplastic drugsAntineoplastic drugs
Weiping Zhang, Ph.D., MDWeiping Zhang, Ph.D., MDEmail: [email protected]: [email protected]. Pharmacology, Medical School, Zhejiang UniversityDept. Pharmacology, Medical School, Zhejiang University
) Inhibitor of DNA-topoisomerase: )topoisomerase CPT ( 喜树碱 ),
VP16 ( 依托泊甙 )
-- According to the biochemical mechanismsAccording to the biochemical mechanisms
Classification
Part I basis of antineoplatics
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 )
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
-- According to the biochemical mechanismsAccording to the biochemical mechanisms
Classification
Part I basis of antineoplatics
Relapse
-- According to the cell cycleAccording to the cell cycle
Classification
Part I basis of antineoplatics
无增殖能力
有增殖的潜能
• 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
Cancer chemotherapy drug classes-- According to the cell cycleAccording to the cell cycle
Classes 3
Cancer chemotherapy drug classes-- According to the cell cycleAccording to the cell cycle
Classes 3
Primary resistance (Natural resistance)
- The cancer cells in G0 phase
- Malignant melanoma
- Renal cell cancer
- Brain cancer.
1. Resistance of cancer chemotherapeutic drugs
Resistance
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 .
The strategy to enhance the effects of cancer cheThe strategy to enhance the effects of cancer chemotherapy based on P-gp (MDR) inhibitorsmotherapy based on P-gp (MDR) inhibitors
Resistance
P-gp (MDR) inhibitors
Resistance
2007
P-gp (MDR) inhibitors• 1st generation: some clinical using drugs with low af
finity to P-gp, verapamil, amiodarone, reserpine etc.
• 2st generation: can inhibit P450 and other transporters. Low affinity and non-specific, PSC-833 (valspodar) 、 dexverapamil 、 Ro11-2933 、 GF120918 (elacridar).
P-gp knockout and inhibitor can increase the intracaranal concentr
ation and therapeutic effect of cancer chemotherapy drugs
Resistance
Basic pharmacology of cancer Basic pharmacology of cancer chemotherapeutic drugschemotherapeutic drugs
Alkylating agents
1. DNA damaging agents1.1 Alkylating agents1.2 Platinum complexes1.3 Antitumor antibiotics
Typical antineoplastic drugs
Ifosfamide异磷酰胺
Alkylating agentsAlkylating agents
– – CH3CH3
Sulfhydryl - SH Amino acid - N Hydroxyl - OH Carboxyl - COOH Phosphate - Pi
Alkylating agentsAlkylating agents- Mechanisms on DNA damage
Guanine鸟嘌呤
Rang 50.4
Adenine
Cytosine
Guanine
Nitrogen mustard, NHNitrogen mustard, NH22
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
A soldier with mustard gas burns sustained World War I
Histopatholobical findings from the victims - Low white blood cell count - Bone marrow aplasia (tissue growth failure). - 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
- 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.
Antitumor antibiotics inhibit DNA/RNA synthesis
Antimetabolites Antimetabolites are structurally r
elated 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 cell-cycle) specific.
- Cochicine (秋水碱类) alters the 3D inter-microtubule instability.
- Taxanes (紫杉烷类) stabilize polymerized microtubules protofilaments.
Drugs inhibiting protein synthesis and functions
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.
Vincristine ( VCR ,长春新碱) - Effective when combined with prednisone f
or acute lymphoblastic leukemia in children and various hematologic malignancies.
Vinorelbine ( NVB ,长春瑞滨) - New, effective for small cell lung cancer
M phase
Plant alkaloids
Colchicine
- 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.
(略)
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 hormonesMale 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
××Aromatase inhibitors
Cytochrome P450 superfamily
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.
- 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)
http://clinicaltrials.gov/
Novel chemotherapies in oncology 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
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 degratdatio
n of the chimeric PML/RAR- protein. Also it induce cell apoptosis.
Novel chemotherapies in oncology(略)(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.
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.