Chapter 38 INTRODUCTION TO CHEMOTHERAPEUTIC DRUGS
1. Brief History of Chemotherapeutic Drugs
2. Several Terms related to Chemotherapy
Chemotherapy/Chemotherapeutic index(CI)/Antibacterial drugs/Antibiotics/Antibacterial spectrum/Bacteriostatic
drugs/Bactericidal drugs/Minimum inhibitory concentration(MIC)/Minimum bactericidal concentration(MBC)
/PAE
3．Mechanism of action of Antimicrobial Agents
（1）Inhibition of cell wall synthesis : β-lactam/ vancomycin
（2）Interfering with cell membrane permeability: Polymixins/Amphotericin B
（3）Inhibition of protein synthesis: Aminoglycosides/Tetracyclines/Chloramphenicol/Macrolides/Clindamycin
（4）Inhibition of nucleic acid synthesis: Rifampicin/Quinolones/Sulfonamides/ TMP
4. Bacterial resistance to antimicrobial agents
（1）Reasons : Antibiotics abuse
（2）Classification: Intrinsic resistance /Acquired resistance
（3）Mechanism of microbial resistance
①Production of enzyme that destroy the drugs： β-lactamase /Adenylase, phosphorylase, acetyltransferase
②Alteration of target for the drugs
③Alteration of membrane permeability
④Active efflux system
⑤Alteration of the metabolism route
（4）Brief introduction: ESBLs: extended spectrum β-Lactamases/ Pseudomonus aeruginosa
MRSA: Methicillin resistant Staphylococcus aureus/ VRE: Vancomycin resistant Enterococci
（5）Rational use of antimicrobial agents
①Basic principles: Diagnosis \Rational use: Newborn/Pregnancy/Elderly/Immune function
②Misuse: Virus infection/Unknown fever/Topical use
③Antimicrobial prophylaxis
Surgical prophylaxis: Infectious endocarditis/Trauma, burn/operation
Nonsurgical prophylaxis: Rheumatic fever/Epidemic meningitis/Malaria, Tuberculosis
④Antimicrobial agents combination
Synergism & antagonism
Drug categories: 1.β-Lactam antibiotics/2.Aminoglycosides
3.Tetracyclines, macrolide ,chloramphenicol/ 4.Sulfonamides
Rational use of antimicrobial agents
1+2: Synergism/ 1+3:antagonism/ 2+3:synergism or plus/ 3+4: plus
⑤Rationale for combination antimicrobial therapy
To Provide broad-spectrum empirical therapy in seriously ill patients/ Serious infection that can not be
controlled by one drug/ To decrease the emergence of resistant strains / To decrease dose-related
toxicity
1
Aminoglycosides
1. History
1944
Streptomycin/ 1957 kanamycin/ 1964 gentamicin/ 1967 tobramycin/ Amikacin & netilmicin
2. Physical and chemical properties
Structure/ Water-soluble, stable in solution/ More active at alkaline than at acid pH
3. Antibacterial spectrum
High activity against aerobic G- rods/ Effective on MRSA: netilmicin
Less active on gram-negative cocci/ P.aeruginosa: gentamicin,tobramycin, amikacin and netimicin
Resistant to enterococci and anaerobe/ Mycobacteria: streptomycin, kanamycin
4. Mechanism of Action: Inhibit protein synthesis irreversibly
（1）interfering with the initiation complex of peptide formation
（2）induce misreading of mRNA, resulting in nonfunctional protein
（3）inhibit the break of 70s initiation complex
5. Mechanism of resistance
（1）Produce enzyme that inactivate the aminoglycoside by adenylylation, acetylation and phosphorylation
（2）Impaired entry of aminoglycoside into the cell
（3）Alteration of target protein
6. Pharmacokinetics
（1）Absorption: po poorly, im, ivd（2）Distribution : low concentration in most tissue except renal cortex
（3）Excretion: in unchanged form by glomerular filtration
7. Adverse reactions
Dangerous factor：Using continuously more than 5 days/ High dose/ Eldly and children
Renal insufficiency/ Concurrent use with loop diuretics or other nephrotoxic drugs
（1）Ototoxicity
Auditory damage: tinnitus, hearing loss
Vestibular damage: vertigo, ataxia and loss of balance
（2）Nephrotoxicity
（3）Neuromuscular blockade
（4）Allergic reactions
8. Streptomycin
Clinical uses:
Second-line agent for tuberculosis/ Plage, tularmia and brucellosis: combination with tetracycline/
Enterococcal and viridans / Streptococcal endocarditis
9. Gentamicin
Clinical uses:
（1）Severe infections caused by gram-negative bacteria such as pseudomonas, enterobacter, serratia, proteus,
acinetobacter and klebsiella
（2）P.aeruginosa infections: combination with carbencillin
（3）Bowel preparation for elective surgery
10. Kanamycin
Topical administration/ Oral administration in preparation for elective bowel surgery
2
11. Amikacin
The most wide antibacterial spectrum/ Resistant to many enzyme that inactivate gentamicin and tobramycin
12. Tobramycin
Similar antibacterial spectrum with gentamicin/ More active against P.aeruginosa/
Treat infections caused by P.aeruginosa that are resistant to gentamicin
13. Netilmicin
（1）Resistant to many enzyme that inactivate gentamicin and tobramycin
（2）Lower toxicity than other aminoglycosides
Chapter 42 Tetracyclines and Chloramphenicol
1. Tetracyclines
（1）Natural: tetracycline, oxytetracycline
（2）Semi-synthesized: doxycycline and minocycline
2. Tetracycline
（1）Antimicrobial activity : Broad-spectrum bacteriostatic antibiotics
Many gram-positive and gram-negative bacteria including anaerobes
Rickettsiae, chlamydia and mycoplasm/ Some protozoa: ameba
（2）Mechanism of action
Tetracyclines bind reversibly to the 30s subunit of bacterial ribosome and block the binding of
aminoacyl-tRNA to the acceptor site, prevent the elongation of peptide.
（3）Mechanism of Resistance
 Production of an efflux pump
 Ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome
（4）Pharmacokinetics
 Absorption: affected by food ,divalent cations（Ca2+, Mg2+ , Fe2+ ）, dairy products and antiacid
 Distribution: distribute widely to tissues and body fluids, bind to and damage growing bone and teeth as a
result of chelation with calcium
 Cross placental barrier and excrete in milk
（5）Clinical uses

drug of choice in infections with mycoplasma pneumonia, chlamydia, rickettsia and some spirochetes

Relapsing fever: the most effective

Various gram-positive and negative infections

Gastric ulcer and duodenal ulcer caused by Helicobacter pylori in combination regimens
（6）Adverse reactions
 Gastrointestinal adverse effects
 Superinfection
Pseudomembranous enterocolitis caused by clostridium difficile
Candida albicans infection
3
 Effects on bony structure and teeth
Teeth: fluorescence, discoloration and enamel dysplasia
Bone: deformity or growth inhibition
 Liver and kidney toxicity, photosensitization
3. Synthesized tetracyclines
（1）Advantage:
Almost completely absorbed / Long-acting: t1/2 >14h/ Higher activity than tetracycline
/Effective against tetracycline-resistant bacteria/ Low toxicity
（2）Antimicrobial activity:
Broad-spectrum bacteriostatic antibiotics
 Both gram-positive and gram-negative aerobic and anaerobic organisms
 Rickettsia, spirochetes, mycoplasm
4. Chloramphenicol
（1）Mechanism of action
Chloramphenicol is a inhibitor of microbial protein synthesis. It binds reversibly to the 50s subunit of
the ribosome and inhibits the peptidyl transferase step of protein synthesis
（2）Clinical uses
 Typhoid and paratyphoid fever :first choice
 Serious rickettsial infections
 Topical use for treatment of eye infections
 Bacterial meningitis caused by penicillin-resistant bacteria or penicillin-allergic patients
（3）Adverse reactions
 Bone marrow disturbances
Reversible suppression of RBC production/ Irreversible aplastic anemia
 Gray baby syndrome
dose >50mg/kg/d
 Gastrointestinal reactions
Chapter 43 Synthetic organic antimicrobials
1. Quinolones
（1）Brief introduction of quinolones: Four generations
First generation :1962 nalidixic acid
Second generation: 1974 pipemidic acid
Third generation : 1980’s fluoroquinolones
Fourth generation: late 1990’s moxifloxacin and gatifloxacin
（2）Antibacterial activity of fluoroquinolones
 Excellent activity against gram-negative aerobic bacteria include enterobacteriacea, neisseria,
pseudomonas, haemophilus and campylobacter etc
 Good activity against gram-positive aerobic bacteria : eg pneumoniae and staphylococci
 Mycoplasmas, chlamydiae, mycobaterium tuberculosis and anaerobes
（3）Mechanism of action
4
A2B2/ To G+: Topo Ⅳ C2E2
To G-: DNA gyrase
（4）Resistance
Mutation of DNA gyrase/ Change in the permeability of membrane/ Active efflux pump
（5）Pharmacokinetics
Absorbed rapidly and completely/ Widely distributed/ Long T ½/ Low adverse reaction/
No cross-resistance with other drugs
（6）Clinical uses
 Urinary tract infections
 Bacterial diarrhea caused by shigella, salmonella or campylobacter
 Infections of soft-tissues, bones, joint and respiratory tract
(7) Adverse reactions
 The most common: nausea, vomiting and diarrhea
 CNS: headache, dizziness, insomnia and anxiety
 Allergic effect: skin rash, photosensitivity
 Damage growing cartilage and cause arthropathy
2. Drugs
（1）Nalidixic acid and pipemidic acid: Used only in urinary tract infection
（2）Norfloxin:
The least active in fluoroquinolones, F low
No effects on mycoplasma, chlamydiae, mycobacterium tuberculosis, legionella
Urinary tract and intestinal tract infections
（3）Ciprofloxacin: The most active agent in fluoroquinolones against gram-negatives, particularly P. aeruginosa
（4）Ofloxacin
Improved quality in pharmacokinetics
F 89%
Effective on mycobateria, chlamydiae and some anaerobes
Effective on resistant bacteria
Second line agent for tuberculosis
（5）levo-ofloxacin: F
100%
 Superior activity against gram-positive organisms
 Effective on mycoplasma, legionella, chlamydia and anaerobes
 Lowest toxicity among fluoroquinolones
（6）Lomefloxacin:
（7）Sparfloxacin:
Photosensitivity
Long-acting
C8-F
t ½>16h/ Improved activity against G+ bacteria, anaerobes, mycobateria,
mycoplasma, chlamydiae / Second line agent for tuberculosis
（8） Moxifloxacin : fourth generation
F
90%,t ½
12~15h / High activity on most G+ ,G-, anaerobes, mycobateria,
chlamydiae / Low toxicity
3. Sulfonamides
5
mycoplasma,
（1）Classification
①Used in systemic infections
Short-acting: SIZ/ Medium-acting: SD, SMZ/ Long-acting: SMD
②Used in intestinal infections: sulfasalazine
③Topical sulfonamides: SD-Ag, SA-Na, SML
（2）Antimicrobial activity: Broad-spectrum bacteriostatic agents
Both G+ and G- , nocardia, chlamydia, trachomatis and some protozoa
（3）Mechanism of action
Inhibit dihydropteroate synthesis and block bacteria folic acid synthesis
（4）Clinical uses
 Urinary tract infection: SIZ, SMZ
 Meningococcal meningitis: SD first choice
 Ulcerative colitis: sulfasalazine
 Topical use for trachoma and conjunctivitis
 Prevent infections of burn wounds
（5）Adverse effects
 Urinary tract disturbance: crystalluria, hematuria, obstruction
 Allergic reactions: fever, skin rashes, exfoliative dermatitis, photosensitivity
 Hematopoietic disturbances
Granulocytopenia, thrombocytopenia
Hemolytic reactions: lack of glucose-6-phosphate dehydrogenase
4. Trimethoprim （TMP）
（1）Inhibit bacterial dihydrofolic acid reductase
（2）Used in combination with sulfonamides: synergism
5. Metronidazole
（1）Clinical uses
Extraluminal amebiasis: drug of choice / Infections caused by anaerobes
Giardiasis/ Trichomoniasis
（2）Adverse reactions
 Gastrointestinal irritation: metallic taste in mouth, nausea, dry mouth and headache
 disulfiram-like effect
 CNS: vertigo, paranesthesia, ataxia and seizures
 Mutagenic and carcinogenic
6.Tinidazole
Chapter 44
antiviral and antifungal drugs
Anti-HIV agents
Nucleoside reverse transcriptase inhibitors(NRTIs, 核苷类逆转录酶抑制剂）
Non-nucleoside reverse transcriptase inhibitors (NNRTIs, 核苷类逆转录酶抑制剂）
6
Protease inhibitor(PI, 蛋白酶抑制剂）
1. Nucleoside reverse transcriptase inhibitors (NRTIs)
Zidovudine （齐多夫定，AZT, ZDV）/Lamivudine(拉米夫定,3TC)/Stavudine（司他夫定, d4T）, Zalcitabine (扎
西他宾, ddC）/Didanosine (去羟肌苷, ddI）/Abacavir (阿巴卡韦, ABC)
(1)
Zidovudine （齐多夫定，AZT, ZDV）
The first reverse transcriptase inhibitor for treatment of AIDS
Treatment of AIDS and HIV-associated dementia and thrombocytopenia
Mechanism:
Toxicity: myelosuppression
(2)
Non-nucleoside reverse transcriptase inhibitors
Delavirdine(地拉韦定）/Nevirapine（奈韦拉平）/Efavirenz （依法韦恩茨）
Mechanism: different with NRTIs
Used in combination with NRTIs and PI / Toxicity: rash
7
(3) Protease inhibitor
Drugs :saquinavir（沙奎那韦）, ritonavir(利托那韦）,indinavir（英地那韦）, nelfinavir（奈非地韦）
Mechanism: inhibit precursor molecules convert to mature virions during HIV replication
Clinical uses: in combination with other agents to treat AIDS
Toxicity: abnormality in metabolism include altered body fat distribution, insulin resistance and hyperlipidemia
Other Antiviral agents
1.
Acyclovir (ACV)
–Active against HSV-1 , HSV-2
–Convert to ACV triphosphate and inhibit viral DNA polymerase
–Treatment
of a variety of herpes infections include primary and recurrent genital herpes (one of the most
effective)
2. Valacyclovir (伐昔洛韦）
–Higher blood concentration
3.Ganciclovir
CMV
4.Vidarabine （Ara-A）
–Convert to Ara-A triphosphate and inhibit DNA polymerase
–Active against HSV, VZV, CMV, HBV etc/ Toxicity : neurotoxicity
5. Idoxuridine（IDU）
–Inhibit DNA synthesis by blocking thymidylic acid synthetase
–Topical use for treatment of HSV infections of the eyelid, cornea and skin
–High toxicity
•6. Ribavirin
（virazole）
–Inhibit replication of both DNA and RNA viruses
–Treatment of influenza A and B infections
–Teratogenesis
7. Lamivudine (3TC)
–NRTIs: HIV-1/ One of the most effective drugs on HBV infection
8. Amantadine and rimantadine
–Inhibit
penetration of virus to cells and the uncoating of certain virus
–Prevent diseases caused by influenza A
9. Foscarnet
10. Interferon
11. Polyinosinic polycytidylic acid
ANTIFUNGAL DRUGS
1. Fungal infection
Topical infection/ Systemic infection
8
2. Antifungal drugs
Antifungal antibiotics/ Azole: imidazole and triazole/ Others: terbinafine and flucytosine
3. Antifungal antibiotics
（1）Griseofulvin
①Antifungal activity
Inhibit the growth of dermatophytes include epidermophyton, microsporum and trichophyton
No effect on bacteria and systemic infections of fungi
②Mechanism of action: interfere with fungal nucleic acid synthesis
③Clinical use
only used in the systemic treatment of dermatophytosis include skin, hair and nails
④Adverse effects
Nausea, vomiting ,headache/ Allergic reaction: fever, skin rash and leukopenia
（2）Nystatin
 Has the same mechanism with amphotericin B
 Only used topically for suppression of local candidal infection
（3）Amphotericin B
①Antifungal activity: Has the broadest spectrum of antifungal action, Active against candida albicans,
cryptococcus neoformans, histoplasma capsulatum , bastomyces
②Mechanism of action
Bind to ergosterol on fungal cell membrane and alter the permeability of the cell by forming amphotericin
B-associated pores in the cell membrane, allow the leakage of intracellular ions and macromolecules leading to
cell death
③Clinical uses
Drug of choice for nearly all life-threatening mycotic infections include severe fungal pneumonia, crypotoccal
meningitis or sepsis syndrome
④Adverse reactions
 Infusion-related toxicity: fever, chills, muscle spasm, headache, hypotension
 Renal damage: azotemia, K+ ,Mg2+ wasting
 Others: Liver damage, arrhythmia, anemia
4. Azole
（1）Drugs :
Imidazole: Clotrimazole, miconazole, ketoconazole
Triazole : Fluconazole, itraconazole
（2）Mechanism of action
Reduction of ergosterol synthesis by inhibition of fungal cytochrome P450-dependent 14-α-demethylase
（3）Clinical uses
Broad spectrum: candida species, cryptococcus neoformans, dermatophytes
（4）Topical azoles: clotrimazole and miconazole
9
Poorly absorbed / Broad spectrum/ Too toxic for systemic uses/ Topical use in treatment of dermatophytosis
（5）Ketoconazole
 The first broad-spectrum oral azole introduced into clinical use
 Treatment of mucocutaneous candidiasis and dermatophytosis
 Major toxicity:
Endocrine disturbance: infertility, gynecomastia and menstrual irregularity
Hepatoxicity: hepatitis
（6）Fluconazole
 Can be administered orally and intravenously, high bioavalibility
 Least effect on hepatic microsomal enzyme
 Drug of choice in the treatment of cyrptococcal meningitis and other systemic fungal infections
（7）Itraconazole
 Can not penetrate BBB
 Choice in the treatment of dermatophytosis and onychomycosis
5. Other antifungal agents
（1）Terbinafine
 Inhibit fungal enzyme- squalene epoxidase and interfere with ergosterol biosynthesis
 Treatment of dermatophytosis especially onychomycosis
（2）Flucytosine
 Convert to 5-FU, inhibit DNA synthesis
 Synergism with Amphotericin B, Effective against cryptococcus and candida species
Chapter 45 Antituberculosis drugs
1. First-line drugs: Isoniazid, rifampin, pyrazinamide, ethambutol and streptomycin
Second-line drugs : Aminosalicylic acid（PAS）, kanamycin
2. Isoniazid : 1952, the most active drug for the treatment of tuberculosis
（1）Mechanism of action
Inhibit the synthesis of mycolic acid which is essential components of mycobacterial cell walls
（2）Antimicrobial activity
High activity against both extracellular and intracellular tubercle bacilli
（3）Pharmacokinetics
Diffuse readily into all body fluids and tissues/ Metabolized by acetylation
（4）Clinical uses: First choice for all types of tuberculosis
（5） Adverse reactions
 Peripheral neuropathy
 CNS toxicity: memory loss, psychosis, seizures
 Hepatoxicity: the most frequent, increase in aminotransferase, hepatitis
 Allergic reactions
10
3. Rifampicin
（1）Antimicrobial activity
Mycobacteria, some G+ and G- cocci, chlamydiae and some virus
（2）Mechanism of action
Bind to β-subunit of bacterial DNA-dependent RNA polymerase and inhibit RNA synthesis
（3）Clinical uses
 Tuberculosis and leprosy
 Infections caused by stapylococci and other rifampicin-susceptible bacteria
（4）Adverse reactions
 Gastrointestinal disturbance
 Liver toxicity: cholestatic jaundice, hepatitis
4. Ethambutol
（1）Mechanism: interfering with synthesis of RNA by combination with Mg2+
（2）Used in combination with INH or rifampicin
（3）Adverse effect: Loss of visual acuity, optical neuritis, red-green color blindness
5. Streptomycin
Penetrate into cell poorly, active mainly against extracellular tubercle bacilli
6. Pyrazinamide
 No cross-resistance with other antituberculosis drugs
 In conjunction with INH and rifampicin in short-course regimens to prevent relapse
7. Rationale for the use of antituberculosis drugs
 Use as early as possible
 Drug combination
 Appropriate doses
 Use regularly and enough time
8. Drugs used in leprosy
Rifampicin/ Sulfones: dapsone/ Thalidomide/ clofazimine
Chapter 47 Antineoplastic drugs
1. Classification according to structure
Alkylating agent/ Antimetabolites/ Antitumor antibiotics/ Plant alkaloids/ Hormonal agents/ Others
2. Classification according to mechanism of action
 Drugs affecting biosynthesis of nucleic acid
 Drugs destroying DNA structure and function
 Drugs interfering with transcription and blocking RNA synthesis
 Drugs affecting protein synthesis
 Hormonal agents
3. Effect on cell proliferation kinetics
11
 Cell cycle nonspecific drugs( CCNS)
 Cell cycle specific drugs(CCS)
 Tumor cell phase: G0 phase / Cell cycle: G1→ S → G2 → M
4. Drugs affecting nucleic acid synthesis(antimetabolites)
（1）Methothrexate (MTX)
 Mechanism: inhibit dihydrofolate reductase(DHFR), interfering synthesis of thymidylate, purine
nucleotides
 Clinical uses: childhood acute lymphoblastic leukemia and chorioepithelioma
 Toxicity: myelosuppression / Rescue method: calcium leucovorin
（2）Fluorouracil （5-Fu）: Pyrimidine antagonists
 Mechanism: convert to 5F-dUMP and inhibit thynidylate synthase,block the synthesis of dTMP
 Clinical uses: good effect on cancer of digestive tract, breast cancer
 Toxicity : myelosuppression and mucositis
（3）Mercaptopurine （6-MP）
 Mechanism: metabolized by HGPRT to 6-thioinsisnic acid and inhibit enzymes of purine nucleotide
interconversion
 Clinical uses: childhood acute leukemia
 Toxicity : myelosuppression and gastrointestinal symptoms
（4）Hydroxurea (Hu)
 Mechanism : Inhibit ribonucleotide reductase
 Clinical uses: chronic granulocytic leukemia
 Toxicity: bone marrow depression, nausea, vomiting
（5）Cytarabine （Ara-C ）
 Mechanism: Ara-C →Ara-CMP →→Ara-CTP, competitively inhibit DNA polymerase
 Clinical uses: acute granulocytic leukemia, mononuclear leukemia
 Toxicity: severe myelosuppression , nausea etc
5. Drugs dstroying DNA structure and function
（1）Alkylating agents
① Cyclophosphamide (CTX)

Mechanism: CTX →aldophosphamide → phosphoramide mustard

Clinical uses: malignant lymphoma, acute leukemia

Toxicity: cystitis, alopecia, nausea, vomiting, myelosuppression
② Thiotepa( TSPA)

Clinical uses: breast cancer, ovarian cancer, liver cancer etc

Toxicity: myelosuppression
③ Busulfan (myleran)

Good effect on chronic granulocytic leukemia

Toxicity: myelosuppression
12
④Nitrosoureas

Drugs : carmustine(BCNU), lomustine(CCNU)

Highly lipid-soluble, can cross BBB / Treatment of brain tumor
（2）Antitumor antibiotics
① Bleomycin （BLM）
 Clinical uses : treatment of squamous cell carcinoma of the neck, cervix, skin, penis ,rectum and in
combination therapy for lymphomas
 Toxicity:
Severe: pulmonary fibrosis
Common: anorexia, alopecia, blistering and hyperkeratosis of palms
②Mitomycin C

Clinical uses: adenocarcinomas of the stomach, pancreas,lung and breast

Toxicity
Severe: myelosuppression
Common: nausea, vomiting and anorexia
（3）Cisplatin & Carboplatin

Clinical uses: Genitourinary cancers, particular ovarian and bladder cancer
Testicular cancer / in combination with vinblastine and bleomycin

Toxicity
Acute toxicity: nausea, vomiting
Renal toxicity: hydration with saline infusion & diuretics
Myelosuppression
（4）Camptothecins

Drugs: topotecan(TPT), irinotecan(CPT-11)

Mechanism: interfere with the activity of topoisomerase Ⅰ

Clinical uses: cancer of lung, stomach, colon etc

No cross resistance with other anticancer drugs

Toxicity
Common: nausea, vomiting, alopecia
Dose-limiting side effect: neutropenia, thrombocytopenia
CPT-11: diarrhea
6. Drugs interfering with transcription
（1）Drugs: Dactinomycin/ Doxorubicin /Daunorubicin
（2）Mechanism: Bind tightly to double-stranded DNA through interaction between adjacent guanine-cytosine
base pair, and inhibit all forms of DNA-dependent RNA synthesis
（3）Clinical uses: narrow-spectrum
In combination with surgery and vincristine in the adjuvant treatment of Wilm’s tumor
（4）Toxicity : evident myelosuppression
13
（5）Doxorubicin (ADM) & Daunorubicin
 Mechanism : Bind with high affinity to DNA through intercalation and then block the synthesis of DNA and
RNA
 Clinical uses
 ADM: one of the most important anticancer drugs , treatment of carcinoma of the breast, endometrium,
ovary, testicle, thyroid, lung and many sarcoma, acute leukemia, Hodgkin’s disease
 Daunorubicin: acute leukemia
 Adverse reactions
 Cardiac toxicity: most severe and irreversibly
 Severe or total alopecia : at standard dosage
 Myleosuppression : short duration and rapid recovery
7. Drugs affecting protein synthesis
（1）Vinblastine（VLB）& vincristine（VCR ）
①Mechanism of action
bind specifically to the microtubular protein tubulin in dimeric form, terminate assembly of microtubules and
result in mitotic arrest at metaphase, cause dissolution of the mitotic spindle and finally interfere with
chromosome segregation
②Clinical uses
 VLB: systemic Hodgkin’s disease and other lymphoma
 VCR: acute leukemia in children ( combination with predinisone)
③Toxicity
 VLB: nausea, vomiting, alopecia, myelosuppression
 VCR: neurotoxicity , include muscle weakness, peripheral neuritis and areflexia
（2）Teniposide（VM-26）& Etoposide（VP-16）
① Mechanism
Inhibit topoisomerase Ⅱ,result in DNA damage through strand breakage
② Clinical uses
VP-16: lung and testicular cancer
VM-26: brain cancer and lymphoma
③ Toxicity
Nausea, vomiting, alopecia and myelosuppression
（3）Taxol & taxotere
① Mechanism
Enhance tubulin polymerization and promote microtubule assembly
② Clinical uses:
First choice for ovarian and advanced breast cancer
③ Toxicity
Hypersensitivity/ Peripheral neuropathy/ Neutropenia , thrombocytopenia
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（4）Harringtonine & Homoharringtonine
①Mechanism : Inhibit the start stage of protein synthesis, decompose the ribosome
②Clinical use: Acute granulocytic leukemia and acute mononuclear leukemia
③Toxicity : Nausea, vomiting, leukopenia and heart toxicity
（5）L-asparaginase
①Mechanism : Depletion of serum asparagine and inhibit protein synthesis in neoplastic cells
②Clinical uses: Childhood acute leukemia
8. Hormonal agents
（1）Adrenal corticosteroids : Predisone, prednisolone, dexamethasone
Actue leukemia, lymphoma and myeloma
（2）Sex hormones
Cancer of female and male breast, cancer of prostate, cancer of the endometrium of the uterus
（3）Tamoxifen
 Competitive partial agonist-inhibitor of estrogen
 Extremely useful in the treatment of breast cancer
9. Rationale for combination of antineoplastic drugs
 Cell proliferating kinetics
 The mechanism of the drugs
 Toxicity of the combinational drugs
 Anti-cancer spectrum
 Method of administering drugs
10. Toxicity of the anticancer drugs
（1）Acute toxicity
①Common toxicity: Myleosuppression /Gastrointestinal disturbance/ Alopecia
②Specific toxicity
 Cardiac toxicity: daunorubicin
 Liver toxicity: CTX, dactinomycin
 Bladder toxicity: CTX
 Neurotoxicity: VCR
 Hypersensitivity: taxol
（2）Chronic toxicity: Infertility, teratogenesis, carcinogenesis
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