By:By:

Dr. Abdulaziz Bin SaeedanDr. Abdulaziz Bin SaeedanPh.D.Ph.D.Department of Pharmacology Department of Pharmacology E mail: E mail: a.binsaeedan@sau.edu.saa.binsaeedan@sau.edu.sa

PPharmacology – IVharmacology – IVPHL-425PHL-425

ChapterChapter 2: 2:

CANCER CHEMOTHERAPY: CANCER CHEMOTHERAPY: The basic Concepts The basic Concepts

Pathogenesis of Neoplasia

DNA is altered via mutagens including chemical carcinogens, DNA is altered via mutagens including chemical carcinogens, viruses, and radiation. This mutations is inherted by at least viruses, and radiation. This mutations is inherted by at least one cell division (initiation). one cell division (initiation).

This mutation mainly lead to activation of proto-oncogene This mutation mainly lead to activation of proto-oncogene into oncogenesinto oncogenes ( (leading to uncontrolled cell proliferation) leading to uncontrolled cell proliferation) and/or inactivation of tumor suppressor genes (leading to and/or inactivation of tumor suppressor genes (leading to resistance to apoptosis.) resistance to apoptosis.)

Once the cell reproduction process is altered, other factors Once the cell reproduction process is altered, other factors ((epigenetic factors ) epigenetic factors ) indirectly allow and promote these cells indirectly allow and promote these cells to proliferate unchecked to proliferate unchecked (promotion)(promotion)

These promoters can be (hormones, co- carcinogens, These promoters can be (hormones, co- carcinogens, immunosuppressant…which themselves are non immunosuppressant…which themselves are non carcinogenic).carcinogenic).

• Initiation - point at which an irreversible alteration, usually genetic, is introduced into a target cell.

Initiation:

(1) is essentially irreversible

(2) caused only by carcinogenic compounds

(3) occurs rapidly after carcinogen exposure

(4) alone does not result in tumor formation

• Promotion is the process whereby an initiated tissue or organ develop focal proliferations and it requires the presence of continuous stimulation.Promotion:

(1) reversible(2) acts only after exposure to an initiating agent(3) requires repeated administration of a promoter(4) is not carcinogenic in itself

50.2 Rang

EtiolopathologyEtiolopathology

ApoptosisApoptosis Programmed cell deathProgrammed cell death Cascade of Cascade of proteases proteases

initiate processinitiate process

Characteristics of Cancer CellsCharacteristics of Cancer Cells

The problem:The problem: Cancer cells divide rapidly (cell cycle is Cancer cells divide rapidly (cell cycle is

accelerated) accelerated) They are “immortal”They are “immortal” Cell-cell communication is alteredCell-cell communication is altered uncontrolled proliferationuncontrolled proliferation invasiveness invasiveness Ability to metastasise Ability to metastasise

The Goal of Cancer TreatmentsThe Goal of Cancer Treatments

CurativeCurative Total irradication of cancer cells Total irradication of cancer cells Curable cancers include testicular tumorsCurable cancers include testicular tumors

PalliativePalliative Alleviation of symptomsAlleviation of symptoms Avoidance of life-threatening toxicityAvoidance of life-threatening toxicity Increased survival and improved quality of lifeIncreased survival and improved quality of life

Adjuvant therapyAdjuvant therapy Attempt to eradicate microscopic cancer after surgeryAttempt to eradicate microscopic cancer after surgery e.g. breast cancer & colorectal cancere.g. breast cancer & colorectal cancer

Rx Modalities (Cancer Treatments)Rx Modalities (Cancer Treatments)1.1. SurgerySurgery

2.2. RadiotherapyRadiotherapy

3.3. ChemotherapyChemotherapy

4.4. Endocrine therapy (hormonal therapy)Endocrine therapy (hormonal therapy)

5.5. ImmunotherapyImmunotherapy

6.6. Targeted therapy or molecularly targeted therapy: Targeted therapy or molecularly targeted therapy: blocks the blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than interfering with all rapidly dividing cells and tumor growth, rather than interfering with all rapidly dividing cells

- Small molecule inhibitors: Tyrosine kinase inhibitors (e.g imatinib)- Small molecule inhibitors: Tyrosine kinase inhibitors (e.g imatinib)

- Genetic material (RNA or DNA)- Genetic material (RNA or DNA)

Major approaches to therapy of Major approaches to therapy of cancers cancers

Cell Cycle = Cell Cycle = Growth, DivisionGrowth, Division

Cancer ChemotherapyCancer Chemotherapy After completion of mitosis, the resulting daughter cells have After completion of mitosis, the resulting daughter cells have

two options: two options: (1) they can either enter G1 & repeat the cycle or (1) they can either enter G1 & repeat the cycle or (2) they can go into G0 and not participate in the cell (2) they can go into G0 and not participate in the cell

cycle.cycle. Growth fraction - at any particular time some cells are going Growth fraction - at any particular time some cells are going

through the cell cycle whereas other cells are resting. through the cell cycle whereas other cells are resting. The ratio of proliferating cells to cells in G0, is called the The ratio of proliferating cells to cells in G0, is called the growth fraction. growth fraction.

A tissue with a A tissue with a large percentage of proliferating cellslarge percentage of proliferating cells & few & few cells in cells in G0G0 has a has a high growth fraction. high growth fraction.

Conversely, a tissue composed of Conversely, a tissue composed of mostly of cells in G0mostly of cells in G0 has has a a low growth fraction.low growth fraction.

Cell Cycle Specific (CCS) & Cell Cycle Non-Cell Cycle Specific (CCS) & Cell Cycle Non-Specific Agents (CCNS)Specific Agents (CCNS)

Log kill hypothesisLog kill hypothesis According to the log-kill hypothesis, chemotherapeutic According to the log-kill hypothesis, chemotherapeutic

agents kill a constant fraction of cells agents kill a constant fraction of cells (first order (first order kinetics),kinetics), rather than a specific number of cells, after rather than a specific number of cells, after each dose.each dose.

In other words, at a given dose, in a given tumor the In other words, at a given dose, in a given tumor the drug will kill a constant % of cells, regardless the drug will kill a constant % of cells, regardless the tumor sizetumor size

1.1. Solid cancer tumorsSolid cancer tumors - generally have a low growth - generally have a low growth fraction thus respond poorly to chemotherapy & in fraction thus respond poorly to chemotherapy & in most cases need to be removed by surgerymost cases need to be removed by surgery

2. 2. Disseminated cancers-Disseminated cancers- generally have a high growth generally have a high growth fraction & generally respond well to chemotherapyfraction & generally respond well to chemotherapy

Log kill hypothesis:Log kill hypothesis:

LOG kill hypothesisLOG kill hypothesis

The example shows the The example shows the effects of tumor burden, effects of tumor burden, scheduling, initiation/duration scheduling, initiation/duration of treatment on patient of treatment on patient survival. survival.

The tumor burden in an The tumor burden in an untreated patient would untreated patient would progress along the path progress along the path described by the RED LINE described by the RED LINE – –

The tumor is detected (using The tumor is detected (using conventional techniques) conventional techniques) when the tumor burden when the tumor burden reaches 10reaches 1099 cells cells

The patient is symptomatic The patient is symptomatic at 10at 101010-10-101111 cells cells

Dies at 10Dies at 101212 cells. cells.

Cancer ChemotherapyCancer Chemotherapy Combinations of agents with differing toxicities & Combinations of agents with differing toxicities &

mechanisms of action are often employed to mechanisms of action are often employed to overcome the limited cell kill of individual anti cancer overcome the limited cell kill of individual anti cancer agents. Each drug selected should be effective aloneagents. Each drug selected should be effective alone

3 advantages of combination therapy:3 advantages of combination therapy: 1. Suppression of drug resistance - less chance of a cell 1. Suppression of drug resistance - less chance of a cell

developing resistance to 2 drugs than to 1 drug.developing resistance to 2 drugs than to 1 drug. 2. Increased cancer cell kill - administration of drugs with 2. Increased cancer cell kill - administration of drugs with

different mechanisms of action.different mechanisms of action. 3. Reduced injury to normal cells - by using a combination of 3. Reduced injury to normal cells - by using a combination of

drugs that do not have overlapping toxicities, we can achieve drugs that do not have overlapping toxicities, we can achieve a greater anticancer effect than we could by using any one a greater anticancer effect than we could by using any one agent alone.agent alone.

Resistance to Cytotoxic Drugs Increased expression of

MDR-1 gene for a cell

surface P-glycoprotein

MDR-1 gene is involved

with drug efflux

Drugs that reverse MDR :

verapamil, quinidine,

cyclosporine

MDR increases resistance

to natural drug products including the anthracyclines, vinca alkaloids, and epipodophyllotoxins

Modes of Resistance to Anticancer Modes of Resistance to Anticancer DrugsDrugs

MechanismMechanism Drugs or Drug GroupsDrugs or Drug Groups

Change in sensitivity or Change in sensitivity or ↓ ↓ binding binding affinity of target enzymes or affinity of target enzymes or receptorsreceptors

Etoposide, Etoposide, methotrexate, vinca methotrexate, vinca alkaloidsalkaloids, estrogen & androgen , estrogen & androgen receptorsreceptors

Decreased drug accumulation via Decreased drug accumulation via ↑ expression of glycoprotein ↑ expression of glycoprotein transporters, or ↓ permeabilitytransporters, or ↓ permeability

Methotrexate, alkylating agents, Methotrexate, alkylating agents, dactinomycindactinomycin

Formation of drug-inactivating Formation of drug-inactivating enzymesenzymes

Purine & pyrimidine antimetabolitesPurine & pyrimidine antimetabolites

Production of reactive chemicals Production of reactive chemicals that “trap” the anticancer drugthat “trap” the anticancer drug

Alkylators, bleomycin, cisplatin. Alkylators, bleomycin, cisplatin. doxorubicindoxorubicin

Increased nucleic acid repair Increased nucleic acid repair mechanismsmechanisms

Alkylating agents, cisplatinAlkylating agents, cisplatin

Reduced activation of pro-drugsReduced activation of pro-drugs Purine & pyrimidine antimetabolites Purine & pyrimidine antimetabolites

General problems with anticancer General problems with anticancer drugsdrugs

Most of them are antiproliferative, i.e. they Most of them are antiproliferative, i.e. they damage DNA and so initiate apoptosis.damage DNA and so initiate apoptosis.

They also affect rapidly dividing They also affect rapidly dividing normal normal cells.cells.

This leads to toxicity which are usually severe.This leads to toxicity which are usually severe.

To greater or lesser extent the following To greater or lesser extent the following toxicities are exhibits by all anticancer drugs.toxicities are exhibits by all anticancer drugs.

ADR of Antineoplastic Drugs in Humans ADR of Antineoplastic Drugs in Humans

Distinctive Toxicities of Some Anticancer DrugsDistinctive Toxicities of Some Anticancer Drugs

ToxicityToxicity Drug(s)Drug(s)

RenalRenal Cisplatin,* methotrexateCisplatin,* methotrexate

HepaticHepatic 6-MP, busulfan, cyclophosphamide6-MP, busulfan, cyclophosphamide

PulmonaryPulmonary Bleomycin,* busulfan, procarbazineBleomycin,* busulfan, procarbazine

CardiacCardiac Doxorubicin, daunorubicinDoxorubicin, daunorubicin

NeurologicNeurologic Vincristine,* cisplatin, paclitaxelVincristine,* cisplatin, paclitaxel

ImmunosuppressiveImmunosuppressive Cyclophosphamide, cytarabine, Cyclophosphamide, cytarabine, dactinomycin, methotrexatedactinomycin, methotrexate

OtherOther Cyclophosphamide (hemorrhagic cystitis);Cyclophosphamide (hemorrhagic cystitis); procarbazine (leukemia); procarbazine (leukemia); asparaginase* asparaginase* (pancreatitis)(pancreatitis)

Proliferating cellsProliferating cells are are especially sensitive to especially sensitive to chemotherapy because chemotherapy because cytotoxic drugscytotoxic drugs usually usually act by act by disrupting DNA disrupting DNA synthesis or mitosissynthesis or mitosis, , cellular activities that only cellular activities that only proliferating cells carry proliferating cells carry out. out.

Unfortunately, toxicity to Unfortunately, toxicity to the anticancer agents is the anticancer agents is to any rapidly dividing to any rapidly dividing cells. (e.g. cells. (e.g. bone marrow, bone marrow, hair follicles, sperm hair follicles, sperm forming cells).forming cells).

Chemotherapeutic agents are much more toxic to tissues that have a high growth fraction than to tissues that have a low growth fraction.

Prevention or Management of Drug Prevention or Management of Drug Induced toxicitiesInduced toxicities

The toxicities of some anticancer drugs can be The toxicities of some anticancer drugs can be well anticipated and hence be prevented by giving well anticipated and hence be prevented by giving proper medicationsproper medications

E.g. mesna is given to prevent hemorrhagic E.g. mesna is given to prevent hemorrhagic cystitis by cyclophosphamide (How? it reacts with cystitis by cyclophosphamide (How? it reacts with the drug metabolite)the drug metabolite)

Dexrazoxane, is used to reduce the risk of Dexrazoxane, is used to reduce the risk of anthracycline-induced cardiomyopathy anthracycline-induced cardiomyopathy

Anti-cancer drugsAnti-cancer drugs

Classification Classification Cell Cycle–Specific (CCS) Agents Cell Cycle–Nonspecific (CCNS)

Agents

Antimetabolites (S phase) Alkylating agents

Capecitabine Altretamine

Cladribine Bendamustine

Clofarabine Busulfan

Cytarabine (ara-C) Carmustine

Fludarabine Chlorambucil

5-Fluorouracil (5-FU) Cyclophosphamide

Gemcitabine Dacarbazine

6-Mercaptopurine (6-MP) Lomustine

Methotrexate (MTX) Mechlorethamine

6-Thioguanine (6-TG) Melphalan

Temozolomide Epipodophyllotoxin (topoisomerase II inhibitor) (G1–S phase)

Thiotepa

Etoposide Anthracyclines

Taxanes (M phase) Daunorubicin

Albumin-bound paclitaxel Doxorubicin

Docetaxel Epirubicin

Paclitaxel Idarubicin

Vinca alkaloids (M phase) Mitoxantrone

Vinblastine Antitumor antibiotics

Vincristine Dactinomycin

Vinorelbine Mitomycin

Antimicrotubule inhibitor (M phase) Camptothecins (topoisomerase I inhibitors)

Ixabepilone Irinotecan

Topotecan Antitumor antibiotics (G2–M phase) Platinum analogs

Bleomycin Carboplatin

Cisplatin

Targeted agentsTargeted agents

Monoclonal antibodies

bevacizumab humanized monoclonal antibody with a circulatory system target (VEGF-A)

cetuximab monoclonal antibody with a tumor target (EGFR)

ipilimumab fully human antibody with an immune system target (CTLA-4)

Small molecules

bortezomib small molecule proteasome inhibitor

imatinib small molecule tyrosine kinase inhibitor

seliciclib small molecule cyclin-dependent kinase inhibitor

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