cc1.ppt cancer chemo-1
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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