Treatment options in oncology

Июль 25, 2022

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Treatment options in oncology

Содержание

2. Surgery Radiation therapy Drug therapy-anti-cancer drugs: - cytotoxic drugs - hormone therapy - cytokines, - targeted
3. Palliative Increased survival Symptom relief/Improved quality of life Curative Adjuvant/Neoadjuvant (induction chemotherapy) Disease free survival (DFS)
4. Adjuvant: -Breast cancer -Colon cancer (Dukes` C2; i.e. positive regional lymph nodes) Neoadjuvant: -Osteogenic sarcoma -
5. Groups of cytotoxic drugs and mechanism of action
6. Alkylating Agents & Platinum Analogs Antimetabolites Topoisomerase (I,II) interactive agents Antimicrotubule Agents Major Groups of Cytotoxic
7. The parent drug (prodrug) is activated to form an “active drug”, which has an alkylating group.
8. DNA alkylation produces a variety of defects - double-and single-stranded breaks Bifunctional alkylating agent form interstrand
9. Cyclophopsphamide (cytoxan) Ifosfamide The prodrug is activated by CYT-P-450 dependent metabolism in the liver. Chlorambucil (leukeran)
10. Nausea and vomiting are dose-related: > 90% for >1500 mg/m2, 60-90% for 750-1500 mg/m2, 30-60% for
11. Leukopenia Nausea and/or vomiting Alopecia Hemorrhagic cystitis (1-10%) Encephalopathy (10-50%) Side Effects of Ifosfamide
12. Cisplatin - Curative in testicular cancer and very active in ginecologic, GI, GU, Head and neck,
13. Activation of Cisplatin in Aqueous Soloution
15. This platinum-DNA adduct is repaired by the nucleotide excision repair (NER) pathway
16. ototoxicity (31%) myelosuppression nausea and vomiting (> 90%) neurotoxicity, usually peripheral neuropathies nephrotoxicity (28-36%) Side Effects
17. Carboplatin Myelosuppression Nausea and vomiting Oxaliplatin neuropathy, sensory Myelosuppression Side Effects
18. Antimetabolites Antimetabolites are antineoplastic agents that are structurally and chemically similar to naturally occurring compounds, required
19. Antimetabolites & analogs Methotrexate…………….. Folic acid 5-Fluorouracil…………… Uracil Cytosine arabinose……… Deoxycytosine Gemcitabine……………... Deoxycytosine Pemetrexed ……………… Pyrrolopyrimidine
20. Methotrexate - mechanism of action Methotrexate Dihydrofolate Reductase (DHFR) Binding & inhibition FH2 FH4 (reduced folates)
21. Reduced Folates and Thymidylate synthetase (TS)
22. 5 Fluorouracil (5FU) 5FU undergoes intracellular activation to the following active nucleotides: -fluorodeoxyuridine monophosphate (FdUMP): This
23. Cell cycle specific and non cell cycle specific drugs Alkylating agents and platinum analogs are non
24. Tubulin Binding Agents Vinca Alkaloids: Vincristine (Oncovin) Vinblastine Vinorelbine (Navelbine) Taxanes: Paclitaxel (Taxol) Docetaxel (Taxotere)
26. Vinca Alkaloids Mechanism of action: binding to specific site on tubulin with prevention of polymerization, inhibition
27. Mechanism of action of taxanes Bind to polymerized tubulin (beta subunit of microtubules) Binding is reversible
28. Hormone therapy
29. Hormone therapy in breast cancer: antiestrogens and aromatase inhibitors 2/3 of all post-menopausal breast cancers are
30. Target therapy
31. Rituximab (Mabthera) Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen.
32. Tyrosine kinase inhibitors
33. TKI The HER2 protein is a transmembrane thyrosine kinase that is a member of the epidermal
34. Trastuzumab (Herceptin) A recombinant humanized monoclonal antibody that binds with the extracellular domain of the HER2
35. Epidermal growth factor receptor (EGFR) as a target
36. EGFR EGFR is a 170-kd transmembrane receptor. It has a tyrosine kinase activity. It has an
37. EGFR inhibitors Monoclonal antibodies: bind to the extracellular domain of the receptor. Example: Cetuximab (Erbitux),Panitumumab (vectibix).
39. Inhibitors of angiogenesis
40. Avastin (Bevacizumab) VEGF (vascular endothelial growth factor) , a diffusible glycoprotein produced by normal and neoplastic
41. Sunitinib (Sutent) –bind to intracellular domain VEGFR
42. К наиболее распространенным побочным действиям циклофосфамида относятся все, кроме: 1. миелосупрессия 2. геморрагический цистит 3. кардиальная
43. Химиотерапевтическое лечение в онкологии применяется как: 1.паллиация (симптоматическое лечение) 2. куративное лечение (излечение) 3. предоперационное лечение
44. Основной препарат, используемый в лечении рака яичек (Testicular Cancer): 1. Паклитаксел (Таксол) 2. Метотрексат 3. Цисплатин
45. К ингибиторам ароматазы относятся все перечисленные препараты, кроме: 1.Тамоксифен 2.Летрозол 3.Фазлодекс 4.1,3 5.Экзаместен
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Слайд 2

Surgery
Radiation therapy
Drug therapy-anti-cancer drugs:
- cytotoxic drugs
- hormone therapy
-

cytokines,
- targeted therapy: monoclonal antibodies & “small molecules”
Drug that protect against side effects of chemotherapy

Anti-cancer treatment modalities

Слайд 3

Palliative
Increased survival
Symptom relief/Improved quality of life
Curative
Adjuvant/Neoadjuvant (induction chemotherapy)
Disease free survival (DFS)

as end point in adjuvant chemotherapy

Goals of cancer chemotherapy

Слайд 4

Adjuvant:
-Breast cancer
-Colon cancer (Dukes` C2; i.e.
positive

regional lymph nodes)
Neoadjuvant:
-Osteogenic sarcoma
- Gastric Adenocarcinoma

Adjuvant/neoadjuvant chemotherapy with proven efficacy

Слайд 5

Groups of cytotoxic drugs and
mechanism of action

Слайд 6

Alkylating Agents & Platinum Analogs
Antimetabolites
Topoisomerase (I,II) interactive agents
Antimicrotubule Agents
Major Groups of

Cytotoxic Drugs

Слайд 7

The parent drug (prodrug) is activated to form an “active drug”,

which has an alkylating group.
The “active drug”, which is positively charged, binds covalentely to various macromolecules at nucleophylic sites.
The biological effect results mainly from alkylation of DNA bases (particularly the electron-rich N-7 position of guanine) and formation of DNA adducts.

Alkylating agents

Слайд 8

DNA alkylation produces a variety of defects - double-and single-stranded

breaks
Bifunctional alkylating agent form interstrand DNA crosslinking, which disrupt DNA replication and transcription.

Alkylating agents

Слайд 9

Cyclophopsphamide (cytoxan)
Ifosfamide
The prodrug is activated by CYT-P-450
dependent metabolism in the

liver.
Chlorambucil (leukeran)

Commonly used alkylating agents

Слайд 10

Nausea and vomiting are dose-related:
> 90% for >1500 mg/m2,
60-90%

for 750-1500 mg/m2,
30-60% for < 750 mg/m2 or oral;
Myelosuppression
Hemorrhagic cystitis (up to 40%) with high-dose and/or long term therapy - severe, potentially fatal
Alopecia (40-60%);

Side Effects of Cyclophosphamide

Слайд 11

Leukopenia
Nausea and/or vomiting
Alopecia
Hemorrhagic cystitis (1-10%)
Encephalopathy (10-50%)
Side Effects of Ifosfamide

Слайд 12

Cisplatin -
Curative in testicular cancer and very active in

ginecologic, GI, GU, Head and neck, lung cancers
Carboplatin
Ovarian, lung cancer
the difference between the cisplatin and carboplatin molecules is in the leaving groups
Oxaliplatin
Colorectal cancer

Platinum analogs

Слайд 13

Activation of Cisplatin in Aqueous Soloution

Слайд 14

Слайд 15

This platinum-DNA adduct is repaired by the nucleotide excision repair (NER)

pathway

Слайд 16

ototoxicity (31%)
myelosuppression
nausea and vomiting (> 90%)
neurotoxicity, usually peripheral

neuropathies
nephrotoxicity (28-36%)

Side Effects of CDDP

Слайд 17

Carboplatin
Myelosuppression
Nausea and vomiting
Oxaliplatin
neuropathy, sensory
Myelosuppression
Side Effects

Слайд 18

Antimetabolites
Antimetabolites are antineoplastic agents that are structurally and chemically similar to

naturally occurring compounds, required for synthesis of purines, pyrimidines, and nucleic acids.
These drugs interfere with DNA synthesis by competitive inhibition of a key enzyme in the purine or pyrimidine synthesis pathway or by incorporation into the DNA or RNA molecules.

Слайд 19

Antimetabolites & analogs
Methotrexate…………….. Folic acid
5-Fluorouracil…………… Uracil
Cytosine arabinose……… Deoxycytosine
Gemcitabine……………... Deoxycytosine
Pemetrexed ……………… Pyrrolopyrimidine
6-Mercaptopurine……….

Hypoxantine
6-Thioguanine…………… Guanine

Слайд 20

Methotrexate - mechanism of action
Methotrexate
Dihydrofolate Reductase (DHFR)
Binding & inhibition
FH2
FH4 (reduced folates)

Слайд 21

Reduced Folates and Thymidylate synthetase (TS)

Слайд 22

5 Fluorouracil (5FU)
5FU undergoes intracellular activation to the following active

nucleotides:
-fluorodeoxyuridine monophosphate (FdUMP):
This nucleotide inhibits Thymidylate synthetase (TS) and, therefore, inhibits DNA synthesis (competitive inhibition of a key enzyme).
-5-fluorouridine triphosphate (FUTP):
This nucleotide undergoes incorporation into RNA and, therefore, causes RNA damage.

Слайд 23

Cell cycle specific and non cell cycle specific drugs
Alkylating agents and

platinum analogs are non cell cycle specific
Antimetabolites are S-phase specific.

Слайд 24

Tubulin Binding Agents
Vinca Alkaloids:
Vincristine (Oncovin)
Vinblastine
Vinorelbine (Navelbine)
Taxanes:
Paclitaxel (Taxol)
Docetaxel (Taxotere)

Слайд 25

Слайд 26

Vinca Alkaloids
Mechanism of action:
binding to specific site on tubulin with

prevention of polymerization, inhibition of microtubule assembly and mitotic spindle formation (leading to metaphase arrest)

Слайд 27

Mechanism of action of taxanes
Bind to polymerized tubulin (beta subunit of

microtubules)
Binding is reversible and stabilize the microtubules against depolymerization (induce tubular polymerization), thereby disrupting normal microtubule dynamics (halts mitosis) and lead to arrest at G2/M phase.

Слайд 28

Hormone therapy

Слайд 29

Hormone therapy in breast cancer: antiestrogens and aromatase inhibitors
2/3 of all

post-menopausal breast cancers are hormone-sensitive, expressing estrogen- and/or progesterone-receptors (ER/PgR)
Estrogens can stimulate cancer growth through binding to specific nuclear estrogen receptors (ER)
Cancer regression can be achieved by
Blocking estrogen receptors with an antiestrogen such as tamoxifen,faslodex
Effectively suppressing estrogen synthesis with aromatase inhibitors such as letrozole (femara) or anastrazole (arimidex) –through blocking conversion of androstenedione to estrone .
Non steroidal=Type II=reversible:
Anastrazole (Arimidex)
Letrozole (Femara)
Steroidal=Type I=irreversible:
Exemestane (Aromasin)

Слайд 30

Target therapy

Слайд 31

Rituximab (Mabthera)
Rituximab is a genetically engineered chimeric murine/human monoclonal antibody

directed against the CD20 antigen.
Active as single agent in CD-20 positive NHL and synergistic with chemotherapy in NHL.

Слайд 32

Tyrosine kinase inhibitors

Слайд 33

TKI
The HER2 protein is a transmembrane thyrosine kinase that is a

member of the epidermal growth factor.
HER2 is a growth factor receptor.
HER2 is overexpressed in 20-30% of human breast cancers (in the majority, HER2 overexpression is caused by amplification of the HER2 gene).
Overexpression of HER 2 is associated with worse prognosis in breast cancer.

Слайд 34

Trastuzumab (Herceptin)
A recombinant humanized monoclonal antibody that binds with the extracellular

domain of the HER2 cell-surface receptor, thereby inhibiting the growth of breast tumor cells that overexpress HER2.
It is active in breast cancer only in HER 2 positive pts, especially in combination with chemotherapy, both in metastatic disease and as adjuvant therapy in HER 2 positive tumors.

Слайд 35

Epidermal growth factor receptor (EGFR) as a target

Слайд 36

EGFR
EGFR is a 170-kd transmembrane receptor. It has a tyrosine kinase

activity.
It has an extracellular ligand-binding domain, a transmembrane segment and intracellular component.
When EGF (i.e. the ligand) binds to the extracellular domain, receptors dimers are formed with activation of the extracellular tyrosine kinase domain.
This results in autophosphorylation of downsream molecules with activation of multiple cellular functions including prpliferation and survival.
EGFR is often overexpressed (and is often mutated) in human tumors, thus there is a good rationale for trying to inhibit the EGFR.

Слайд 37

EGFR inhibitors
Monoclonal antibodies: bind to the extracellular domain of the receptor.

Example: Cetuximab (Erbitux),Panitumumab (vectibix).
Small molecules: bind to the intracellular domain of the receptor.
example: Erlotinib (Tarceva).

Слайд 38

Слайд 39

Inhibitors of angiogenesis

Слайд 40

Avastin (Bevacizumab)
VEGF (vascular endothelial growth factor) , a diffusible glycoprotein produced

by normal and neoplastic cells ,has been shown to have central role in the control of angiogenesis and to be essential for the development of tumor vasculature. VEGF (=ligand) binds to VEGF receptor.
Bevacizumab (Avastin) is a humanized anti- (VEGF) monoclonal antibody. It prevents VEGF to bond to its receptor, and therefore, has an antiangiogenic effect.

Слайд 41

Sunitinib (Sutent) –bind to intracellular domain VEGFR

Слайд 42

К наиболее распространенным побочным действиям циклофосфамида относятся все, кроме:
1. миелосупрессия
2. геморрагический

цистит
3. кардиальная токсичность
4. энцефалопатия

Вопросы:

Слайд 43

Химиотерапевтическое лечение в онкологии применяется как:
1.паллиация (симптоматическое лечение)
2. куративное лечение (излечение)
3.

предоперационное лечение
4. все верно

Слайд 44

Основной препарат, используемый в лечении рака яичек (Testicular Cancer):
1. Паклитаксел (Таксол)
2.

Метотрексат
3. Цисплатин
4. Флюроурацил (5FU)

Слайд 45

Treatment options in oncology

Содержание

SurgeryRadiation therapyDrug therapy-anti-cancer drugs: - cytotoxic drugs - hormone therapy -

PalliativeIncreased survivalSymptom relief/Improved quality of lifeCurativeAdjuvant/Neoadjuvant (induction chemotherapy)Disease free survival (DFS)

Adjuvant: -Breast cancer -Colon cancer (Dukes` C2; i.e. positive

Groups of cytotoxic drugs and mechanism of action

Alkylating Agents & Platinum AnalogsAntimetabolitesTopoisomerase (I,II) interactive agentsAntimicrotubule AgentsMajor Groups of

The parent drug (prodrug) is activated to form an “active drug”,

DNA alkylation produces a variety of defects - double-and single-stranded

Cyclophopsphamide (cytoxan)IfosfamideThe prodrug is activated by CYT-P-450 dependent metabolism in the

Nausea and vomiting are dose-related: > 90% for >1500 mg/m2, 60-90%

LeukopeniaNausea and/or vomitingAlopecia Hemorrhagic cystitis (1-10%)Encephalopathy (10-50%) Side Effects of Ifosfamide

Cisplatin - Curative in testicular cancer and very active in

Activation of Cisplatin in Aqueous Soloution

This platinum-DNA adduct is repaired by the nucleotide excision repair (NER)

ototoxicity (31%) myelosuppression nausea and vomiting (> 90%) neurotoxicity, usually peripheral

CarboplatinMyelosuppressionNausea and vomitingOxaliplatinneuropathy, sensory MyelosuppressionSide Effects

AntimetabolitesAntimetabolites are antineoplastic agents that are structurally and chemically similar to

Antimetabolites & analogsMethotrexate…………….. Folic acid5-Fluorouracil…………… UracilCytosine arabinose……… DeoxycytosineGemcitabine……………... DeoxycytosinePemetrexed ……………… Pyrrolopyrimidine6-Mercaptopurine……….

Methotrexate - mechanism of actionMethotrexateDihydrofolate Reductase (DHFR)Binding & inhibitionFH2FH4 (reduced folates)

Reduced Folates and Thymidylate synthetase (TS)

5 Fluorouracil (5FU) 5FU undergoes intracellular activation to the following active

Cell cycle specific and non cell cycle specific drugsAlkylating agents and

Tubulin Binding AgentsVinca Alkaloids:Vincristine (Oncovin)Vinblastine Vinorelbine (Navelbine)Taxanes:Paclitaxel (Taxol)Docetaxel (Taxotere)

Vinca AlkaloidsMechanism of action: binding to specific site on tubulin with

Mechanism of action of taxanesBind to polymerized tubulin (beta subunit of