Cancer Cancer Chemotherapy-1Chemotherapy-1

Dr. R. Senthil KumarDr. R. Senthil Kumar

50.2 Rang

EtiolopathologyEtiolopathology

ApoptosisApoptosis Programmed cell Programmed cell

deathdeath Cascade of Cascade of proteases proteases

initiate processinitiate process

Characteristics of Cancer Characteristics of Cancer CellsCells

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 The Goal of Cancer TreatmentsTreatments

CurativeCurative– Total irradication of cancer cells Total irradication of cancer cells – Curable cancers include testicular tumors, Wills tumorCurable cancers include testicular tumors, Wills tumor

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 Attempt to eradicate microscopic cancer after

surgerysurgery– e.g. breast cancer & colorectal cancere.g. breast cancer & colorectal cancer

Six Established Rx Six Established Rx ModalitiesModalities

1.1. SurgerySurgery

2.2. RadiotherapyRadiotherapy

3.3. ChemotherapyChemotherapy

4.4. Endocrine therapyEndocrine therapy

5.5. ImmunotherapyImmunotherapy

6.6. Biological therapyBiological therapy

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 After completion of mitosis, the resulting

daughter cells have two options: daughter cells have two options: (1) they can either enter G1 & repeat the cycle (1) they can either enter G1 & repeat the cycle

or or (2) they can go into G0 and not participate in (2) they can go into G0 and not participate in

the cell cycle.the cell cycle. Growth fraction - at any particular time some Growth fraction - at any particular time some

cells are going through the cell cycle whereas cells are going through the cell cycle whereas other cells are resting. other cells are resting.

The ratio of proliferating cells to cells in G0, is The ratio of proliferating cells to cells in G0, is called the growth fraction. called the growth fraction.

A tissue with a A tissue with a large percentage of large percentage of proliferating cellsproliferating cells & few cells in & few 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 mostly of cells in G0cells in G0 has a has a low growth fraction.low growth fraction.

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

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

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

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

2.2. Disseminated cancers-Disseminated cancers- generally have generally have a a high growth fractionhigh growth fraction & generally & generally respond respond well to chemotherapywell 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, scheduling, initiation/duration of initiation/duration of treatment on patient 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 The tumor is detected (using conventional (using conventional techniques) when the techniques) when the tumor burden reaches 10tumor burden reaches 1099 cellscells

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 overcome the limited cell kill of individual anti cancer agents. Each drug selected should be cancer agents. Each drug selected should be effective aloneeffective alone

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

cell developing resistance to 2 drugs than to 1 cell developing resistance to 2 drugs than to 1 drug.drug.

2. Increased cancer cell kill - administration of 2. Increased cancer cell kill - administration of drugs with different mechanisms of action.drugs with different mechanisms of action.

3. Reduced injury to normal cells - by using a 3. Reduced injury to normal cells - by using a combination of drugs that do not have overlapping combination of drugs that do not have overlapping toxicities, we can achieve a greater anticancer toxicities, we can achieve a greater anticancer effect than we could by using any one agent alone.effect than we could by using any one 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 Modes of Resistance to Anticancer DrugsAnticancer Drugs

MechanismMechanism Drugs or Drug GroupsDrugs or Drug Groups

Change in sensitivity (or Change in sensitivity (or ↑↑ level) level) or or ↓ ↓ binding affinity of target binding affinity of target enzymes or receptorsenzymes or receptors

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 antimetabolitesPurine & pyrimidine antimetabolites

General problems with General problems with anticancer drugsanticancer drugs

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

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

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

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

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

Distinctive Toxicities of Some Anticancer Distinctive Toxicities of Some Anticancer DrugsDrugsToxicityToxicity 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

ImmunosuppressiImmunosuppressiveve

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

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

*Less Bone marrow suppression – “marrow sparing”*Less Bone marrow suppression – “marrow sparing”

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

Unfortunately, Unfortunately, toxicity to the toxicity to the anticancer agents is anticancer agents is to any rapidly to any rapidly dividing cells. (e.g. dividing cells. (e.g. bone marrow, hair bone marrow, hair follicles, sperm 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 Prevention or Management of Drug Induced toxicitiesDrug Induced toxicities

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

E.g. mesna is given to prevent E.g. mesna is given to prevent hemorrhagic cystitis by hemorrhagic cystitis by cyclophosphamidecyclophosphamide

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

Anti-cancer drugsAnti-cancer drugs