Transcript Side effect

Cancer therapeutic drugs
Introduction of cancer therapy
1.
2.
3.
At present, about 50% of patients with cancer can be
cured, with chemotherapy contributing to cure in 10–
15% of patients.
Chemotherapy provides palliative rather than curative
therapy at present. Effective palliation results in
temporary improvement of the symptoms and signs of
cancer and enhancement in the overall quality of life.
Ideal anticancer drugs would eradicate cancer cells
without harming normal tissues. Unfortunately, no
currently available agents meet this criterion, and
clinical use of these drugs involves a weighing of
benefits against toxicity in a search for a favorable
therapeutic index.
Problem exiting in anticancer drug
1.Low efficacy to most of cancer
2.Severe toxicity
(1)Bone marrow suppresion
(2)GI
(3) alopecia
(4)Hepatic and renal toxicity
3.Resistance
(1) Absence the response to first exposure, e.g. MM
(2) Acquired resistance
Classification
1. According to the chemical structure and source
(1) Alkylating agents (Busulfan, Cyclophosphamide)
(2) Anti-metabolites (folic acid, pyrimidine, purine analogue)
(3) Antineoplastic antibiotics (bleomycin, actinomycin)
(4) Antineoplastic nature products (taxol, vinblastin)
(5) Hormone (GC, estrogen, androgen)
(6) Others (cisplatin, carboplatin)
Classification
2. According to the antineoplastic mechanism
(1) Disturbe the nucleic acid synthesis (Ara-C, 5-FU)
(2) Disrupt the DNA stucture and function (CTX, busulfan)
(3) Distrube the transcription and RNA synthesis (actinomycin D,
daunorubcin)
(4) Disturbe the protein synthesis (taxol, vinblastin)
(5) Affecting the balance of hormone (GC, estrogen, androgen)
Classification
3. According to cell cycle specificity
(1)
CCNSA
Alkylating agents:
Antineoplastic antibiotics:
(2) CCSA: vinblastin M stage
anti-metabolites S stage
Kinetics of cell proliferation
Two cell types
1.Proliferating cells: log formulation
Proliferating cell number
Growth fraction =
( GF)
total cell number
GF high：early.
Acute leukemia, Hodgkin's disease, and
choriocarcinoma，sensitive to antineoplastic agents
GF low：late. Chronic leukamia，solid tumor, low sensitivity↓
2.Non-proliferating cells
not sensitive to drug (G0 phase), recurrence
Resistance
1. Nature resistance
2. Acquired resistance
MDR (multidrug resistance)
PDR (pleiotropic drug resistance)
mutation
the larger cancer the more possibility of resistance
(times of division)
Antineoplastic agents
1. Disturbe the nucleic acid synthesis
MTX, 6-MP, 5-FU, Arac, HU
structure analogues of folic acid, purine, pyramidine, neucleic acid
(1)compititively binding to the enzymes
(2) structure analogues of metabolites
results in：inhibition of DNA, RNA and protein synthesis
Common properties
CCSA: S
1.Slow
2.Most of them are effective on leukemia
(except for 5-FU)
3.Resistance after long-term exposure
4.Low selection, and common side effects
5-fluorouracil; 5-FU
Pharmacological action：
•
5-Fluorouracil (5-FU) is a prodrug and undergoes a complex series of
biotransformation reactions to ribosyl and deoxyribosyl nucleotide
metabolites. One of these metabolites, 5-fluoro-2'-deoxyuridine-5'monophosphate (FdUMP), forms a covalently bound ternary complex with
the enzyme thymidylate synthase and the reduced folate N5,10methylenetetrahydrofolate, a reaction critical for the synthesis of thymidylate.
This results in inhibition of DNA synthesis through "thymineless death."
•
5-FU is converted to 5-fluorouridine-5'-triphosphate (FUTP), which is then
incorporated into RNA, where it interferes with RNA processing and mRNA
translation.
•
In addition, 5-FU is converted to 5-fluorodeoxyuridine-5'-triphosphate
(FdUTP), which can be incorporated into cellular DNA, resulting in inhibition
of DNA synthesis and function.
•
Thus, the cytotoxicity of fluorouracil is felt to be the result of effects on both
DNA- and RNA-mediated events.
5-fluorouracil; 5-FU
Indication：widely used
1.
2.
3.
choriocarcinoma ：first choice, ACTD
colorectal cancer, liver cancer (25%)
head and neck (30%), ovary cancer,bladder cancer,
thyroid cancer
Toxicity:
1.
2.
3.
Myelosuppression
GI
bleeding diarrhea
Methotrexate；MTX
mechanism：
structure analogue of folic acid, dihydrofolate reductase inhibitor
1. FH2
FH4
dTMP ↓
2. purine nucleotides↓
DNA ↓
RNA, protein ↓
Indication：Leukemia, choriocarcinoma
Side-effects：
• Mucositis,
• Diarrhea
• Bone marrow depression with leukopenia and thrombocytopenia
6-mercaptopurine;6-MP
Mechanism:
it must be metabolized by hypoxanthine-guanine
phosphoribosyl transferase (HGPRT) to the nucleotide
form (6-thioinosinic acid), which in turn inhibits a number
of the enzymes of purine nucleotide interconversion
Indication：
1.AL：child AL
2. choriocarcinoma ：less than 5-FU, ACTD, MTX
3.Immunosuppresive agent：a closely related analog, azathioprine
cytarabin; AraC
Mechanism：
1.Inhibitor of DNA polymerase
2.Incoporation into DNA，inhibition of DNA copy
Indication：
Acute Myeloid Leukemia , acute monocytic leukemia
Induction Chemotherapy ，28％ alone
hydroxyurea；HU
Mechanism：
↓ HU
ribonucleotide reductase inhibitor
cytidylate
deoxycytidylate DNA, S phase
Indication：
1. chronic myelogenous leukemia ：>50％
2. Melenoma (12％)
2. Disrupt the DNA stucture and function
2.1 alylating agents
CH2
Mechanism：alkyl groups
active group( CH2-CH2- or N-CH2) binds to NH2, SH, OH, COOH
or phpsphate, take place of H (alkylation)
Resulting in：
(1) The major site of alkylation within DNA is the N7 position of
guanine (covalent bond ).
(2) interactions can occur on a single strand or on both strands of
DNA through cross-linking, leading to the disruption of DNA
synthesis and cell death.
properties
1.CCNSA
2.Board spectrum
Defects：
Low selection, severe toxicity to bone marrow, GI,
reproductive system, liver and kidney.
nitrogen mustard
properties：
1.rapid：iv 3 min
2.short：several min but long-acting
Indication
1.Malignant lymphoma：lymphosarcoma 、
Hodgkin's Lymphoma
2. Hemi-body Irradiation ：nasopharyngeal
carcinoma 、Lung cancer.
65～71％effictive in 1180 cases，5 years
survival in 122 cases(10.33%)
Side effect：common and obvious(discussed
previous)
tissue necrosis due to leak during IV
Cyclosphosphamide；CTX
Pharmacological action ：
• CTX→phosphoramide→crosslinking with DNA
Characteristic：
1. Board spectrum
2. Chemotherapeutic index (CI) is bigger than
most alkylating agents
3.Short period of high-dose or intermittent middledose treatment are better than prolonged lowdose treatment
4. po is effective
Indication：
1. Malignant lymphoma：lymphosarcoma 、
Hodgkin‘s Lymphoma,
Hemangioblastomas ，50~90％ effective
2.Ovarian cancer (44％)、breast cancer (32
％)、Multiple Myeloma (29％)、seminoma
(40％)
3. Acute lympocytic leukemia
4. Autoimmune disease : Effective in almost
every type
Side effect
1. Myelosuppression
2. alopecia is common (30～60％)
3. hemorrhagic cystitis
Thio-TEPA
Characteristics：
1.High selection、 board spectrum
2. Low irritation：can be administrated iA、
iv、im and intra-thoracic,intraabdominal, intravesikale
3.Less and mild gastrointestinal reaction
Indication
Breast cancer (30％)、 Ovarian cancer (31％),
liver cancer、malignant melanoma 、lung
cancer、gastric carcinoma 、cervical cancer 、
nasopharyngeal carcinoma 、laryngocarcinoma
Busulfan (Myleran)
Chronic Myelogenous Leukemia :
effective in 80～90％cases，first
choice.
(二)Antibiotics
Mitomycin
Pharmalogical action：
Cross linking with double-stranded DNA，nonspecific interaction in cell cycle
Indication：
Breast cancer (34.7％)、 gastric carcinoma
(26.9％) 、cancer of pancreas (20.8％)
biliary Tract Carcinomas （16.9％）、CML、
malignant lymphoma
Side effect
1. Myelosuppression: obvious and longlasting
2. Cardiac toxicity：sudden occurrence of
heart failure
3. Tissue necrosis due to leak
4. Renal toxicity
Bleomycin，
Mechanism：break down DNA→interupt DNA duplication
indication：
1. squamous epithelial carcinoma 、cancer of the
esophagus (30~50％ effective，first choice)、
head and neck cancer (20～55％)、cervical cancer
2. Cancer of the Testes ：can be completely cured when
combined with DDPand VLB
Side effect：
pulmonary fibrosis : positive correlation with dose
(三) Drugs interrupted transcription
and blocked RNA synthesize
Dactinomycin
Mechanism:
Insert in guanin and cell pyrimidine of DNA
and inhibit RNA polymerase→interupt
mRNA synthesize
Indication
1. choriocarcinoma and ovarian malignant
mole ：50-70％ effective
2. nephroblastoma：cured in 80% cases by
combination use of this drug with surgery
and radiotherapy
3. malignant lymphoma 、neuroblastoma
Side effect：
Gastrointestinal reaction 、myelosuppression 、
alopecia 、foetal deformities
Doxorubicin，ADM
Characteristics：broad spectrum、high
efficiency
Indication：
Breast cancer(31～43％)、lung cancer
(12～36％), osteosarcoma (30％)、
Hodgkin's lymphoma、 gastric
carcinoma 、liver cancer
Side effect
Common: general toxicity
Rare: arrhythmia and heart failure
Total dose＜550 mg／m2
(四)、Drugs interupted protein
synthesize
Vinblastin (VLB) and Vincristin (VCR)
Mechanism：combine with tublin →
inhibit tublin assembling → block
spindle fiber formation→ terminate
mitosis
Indication：
VLB：acute leukemia、lymphoma、 ovarian
cancer
VCR：AML、 Lymphoma (20％), breast
cancer (20％)、lung cancer
Side effect：
VLB： obvious myelosuppression、 alopecia
VCR：light myelosuppression ，obvious
peripheral neuritis
Taxol
Mechanism：promote tublin assembling, inhibit
tublin depolymerization → block spindle fiber
formation→ terminate mitosis
Indication：Ovarian cancer (＞30％)、breast
cancer (50％), malignant melanoma 、
gastrointestinal cancer 、leukemia
Principles of combination use
Objective：
1.Increase efficiency
2.Decrease drug resistant
3.Decrease toxicity
Principles:
1．Based on proliferation dynamics of tumor:
Solid tumors(robust cells in G0)：use cell
cycle non-specific drugs first，then use
specific drugs
Acute Leukemia：Contrary to solid tumor
2. Based on mechanism of different drugs
(1) Sequential inhibition：inhibition at different
metabolic stage by combination of two or more
drugs
e.g：
Hydroxyurea
+
↓
inhibit ribonucleotide
reductase
AraC
↓
inhibit DNA polymerase
(2) Complementary inhibition
Inhibit nucleic acid synthesize
Directly interupt DNA repair
e.g.
Adriamycin
+
↓
Inhibit RNA synthesize
duplication
+
CTX
↓
interupt DNA
3. Based on toxicity
Avoid overlap of toxicity: ↑efficiency but
not↑toxicity
e.g. drugs with obvious
myelosuppression(most anti-cancer
drugs)+ drugs with no or mild
myelosuppression(prednisone、VCR、
BLM)
4. Based on distribution and metabolism
of drugs
e.g ：VCR can decrease intracellular distribution of
MTX, resulting in increased cellular concentration
of MTX，thus combination use can increase
efficiency
5. Based on anti-cancer spectrum：
gastrointestinal cancer ：5-FU、Thio-Tepa、
CTX、mitomycin etc.
squamous epithelial carcinoma ：BLM、MTX
sarcoma：CTX、ADM
6. Adminstrative strategy
Intermittent high-dose adminstration is priority.