경희대학교 의과대학·의학전문대학원

Pharmacology of Cancer Chemotherapy

(

Types of cancer drugs

• Conventional chemotherapy agents

S

ll

l

l

– Small molecules

• Targeted agents

– Small molecules or Biologicals

• Hormonal therapies

• Biologic therapies

Cell death responses

Chemotherapeutic Agents

• Affecting DNA

– Direct DNA-Interactive agents

• Alkylators • Alkylators

– Formation of covalent DNA adducts

• Antitumor antibiotics & Topoisomerase poisons

– Bind to DNA directly – Affect topoisomerase I & II

– Indirect effectors of DNA function

• Antimetabolites

– Interfere with purine/pyrimidine synthesis

• Affecting microtubules

– Antimitotic agents

• Hormonal agents

• Molecularly targeted agents

Drugs disrupting DNA structure: Antitumor antibiotics, topoisomerase poisons, alkylating agents

Drugs disrupting DNA Synthesis:antimetabolites Haploid DNA Diploid DNA G1 checkpoint G2 checkpoint

S phase

M phase

Drugs disrupting chromosome

Segregation: antimitotic spindle poisons

M phase

Chromosome segregation

Pharmacodynamics

• Schedule

-dependent

– Prolonged g exposure time p results in increasing tumor cell killg

– Phase-specific agents – Antimetabolite

– Continuous intravenous infusion of 5-FU in GI malignancy

• Steep

dose

-response curves

– An increase in the drug concentration results in a proportional increase in tumor cell kill.

• Concept of Dose Intensity

– Alkylating agents

– High dose chemotherapy with Peripheral blood stem cell

transplantation(PBSCT)

Combination Chemotherapy

• Benefit

– Maximal cell kill

within range of toxicity

– Maximal cell kill

within range of toxicity

– Broader range

of interaction between drugs & tumor

cells

– Prevent development of cellular drug resistance

• Principles

I d

d

t

ti it

i

t th

ifi t

– Independent

activity

against the specific tumor

– Different mechanism

of action

Drug Resistance

• not being in appropriate phase of cell cycle • decreased uptake

• increased efflux & metabolism of drugincreased efflux & metabolism of drug

• alteration of the target

– Mutation or overexpression

Drug Resistance

• Multiple drug resistance (MDR)

– One drug show cross-resistance to other

compounds

– Anthracycline, vinca alkaloid,

epipodophyllotoxin, taxane

– P-glycoprotein

(170 kDa), multidrug

resistance protein (190 kDa)

• Energy-dependent efflux pump • Reverse drug resistance by verapamil,

New Drug Development

• It may take 10 years or longer for a compound to

proceed from initial screening to approval by the FDA

proceed from initial screening to approval by the FDA

for a specific indication.

• Phase I trial

– Determine drug toxicity in humans

• Phase II trial

– To determine if a drug has activity for a particular tumor

• Phase III trial

– To test an agent against the standard existing therapy for a

particular tumor

Criteria for response to therapy

• Complete response(remission)

– Disappearance of all

detectable disease

• Partial response

p

– Decrease by more than 50%

in the sum of the products

of the perpendicular diameters of all measurable lesions

– No increase in size of any lesion

– No appearance of new lesion

• Stable disease

– No change in measurable disease

• Progressive disease

– Increase by at least 25%

in the sum of the products of

the perpendicular diameters of the lesions

Response Evaluation Criteria in Solid Tumors

(RECIST)

• WHO criteria

• RECIST

– CR

– PR

: at least a 30% decrease in the sum of the

longest diameter of target lesion

– PD

PD

: at least a 20% increase in the sum of the

: at least a 20% increase in the sum of the

longest diameter of target lesions

Duration of Response

• Progression-free survival/Time to progression

– Palliative chemotherapy

• Disease-free survival

– Adjuvant chemotherapy

j

py

Performance Status

– Grade 0: fully active – Grade 1: restricted in

h i ll normal activity

– 80: normal activity with

effort

– 70: cares for self – 60: requires occasional assistance – 50: requires considerable assistance – 40: disabled 30 l di bl d physiccally strenuous activity – Grade 2: ambulatory, capable of all self-care but unable to carry out any work activities

– Grade 3: capable of only

limited self care

– 30: severely disabled – 20: very sick – 10: moribund – 0: dead limited self-care – Grade 4: completely disabled

Toxicity Grading Scale

• Grade II: Require symptomatic treatment

• Grade III: Potentially life-threatening if untreated

• Grade IV: Actually life-threatening

Alkylating Agents

• Mechanisms

– Cross-linkage of DNA strands, breaks in DNA

– Potent activator of cell cycle checkpoints

• Activate cell signaling pathway Æ apoptosis

• Common toxicities

– Myelosuppression, alopecia,

Myelosuppression, alopecia,

gonadal dysfunction

gonadal dysfunction

,

,

mucositis,

pulmonary fibrosis

,

2

_neoplasm

_(leukemia,

2%)

Alkylating Agents

• Classic

– Cyclophosphamide, ifosfamide

:

• hemorrhagic cystitis (mesna)

– Melphalan

:

– Busulfan

:

• prolonged myelosuppression, pulmonary toxicities

• Nitrosourea

– Carmustine(BCNU), lomustine(CCNU)

• Platinum compounds

Cisplatin

– Cisplatin

• nephrotoxicity, especially renal tubule • hypomagnesemia

• sensory neuropathy, severe nausea & vomiting

– Carboplatin

:

Antitumor Antibiotics

• Isolated from soil

microorganisms

g

• Bind to DNA directly, generate free radicals

• Anthracyclines

– Intercalate into DNA

• altering DNA structure, replication, topoisomerase

function

– Doxorubicin

• Severe vesicants, myelosuppression, alopecia • Cardiomyopathy(> 550 mg/m2_{, 10% incidence)}

– Daunorubicin, idarubicin

Antitumor Antibiotics

• Bleomycin

y

– Fever, facial flush, Raynaud’s syndrome

– Pulmonary fibrosis

(>300 cumulative unit)

• Mitomycin C

– Delayed myelosuppression at 4 to 6 weeks

– Hemolytic-uremic syndrome

y

y

(25-50% mortality)

(

y)

• Dactinomycin, Mithramycin

Topoisomerase Inhibitors

• Natural or semisynthetic product from

plant

• Mechanisms

– Inhibit topoisomerase I & II

• Enzymes regulating the capacity of DNA to unwind

– Arrest in S-phase or G2 phase

• Epipodophylotoxin

– Inhibit topoisomerase II, G2 arrest

– Etoposidetopos de

• Camptothecin

– Inhibit topoisomerase I, S phase arrest

– Topotecan: myelosuppression, mucositis

– Irinotecan: secretory diarrhea, myelosuppression

Antimetabolites (1)

• Structural similarity to precursors of purine or

pyrimidine

• Cause DNA damage through misincorporation into

DNA

• Toxicity to cells in

S phase

• 5-fluorouracil (5-FU)

– 5-FU metabolite(5’FdUMP) inhibit 5 U etabo te(5 dU ) b tthymidylate synthaset y dy ate sy t ase – Leucovorinaugments activity of 5-FU by promoting

formation of ternary covalent complex.

– Gastrointestinal tumor

Metabolic Map of Fluoropyrimidines

Uridylate kinaseFUTP

O F O H N NH 5-FU RNA damage Orotate phosphoribosyl-transferase (OPRT)

H2NCH2CH COOH TCA Cycle

F-β-Ala F Cataboic Pathway Dihydropyrimidine dehydrogenase (DPD) 80%

Thymidylate synthase inhibition by 5-FU

Antimetabolites (2)

• Methotrexate

Dih d

f l t

d

t

i hibit

– Dihydrofolate reductase inhibitor

– Leucovorin

(reduced folate) rescue

– High dose

regimen

• Osteosarcoma, Monitor serum levels

– Intrathecal

injection

• Cytosine arabinoside (ara-c)

Cytosine arabinoside (ara-c)

– Acute myeloid leukemia

– Mucositis

– intrathecal

injection

Antimetabolites (3)

• Gemcitabine: cytosine derivative

Pacreatic carcinoma NSCLC bladder cancer

– Pacreatic carcinoma, NSCLC, bladder cancer

• Pemetrexed: folate-directed antimetabolite

– Mesothelioma, NSCLC

• Fludarabine

– Chronic lymphocytic leukemia

• Pentostatin

H i ll l k i

– Hairy cell leukemia

• 6-mercaptopurine (6-MP), 6-thioguanine (6-TG) • Hydroxyurea

Mitotic spindle inhibitors

• Inhibit microtubule assembly • Plant alkaloid

– Microtubule disaggregation – Specific for M phase

– Vincristine, vinblastine, vinorelbine

• Neuropathy(glove-stocking form, paralytic ileus, urinay retention), vesicant

• Tubulin inhibitors

Microtubule stabilizaion

– Microtubule stabilizaion – Paclitaxel, docetaxel

– Hypersensitivity reaction, peripheral neuropathy, alopecia, fluid retension

Hormonal agents

– lymphoid malignancy

• Tamoxifen

– Partial estrogen receptor antagonist, breast cancer • Aromatase inhibitor

– Inhibit formation of estrogen • all-trans Retinoic Acid

– acute promyelocytic leukemia; t(15;17) • Flutamide

– prostate carcinomaprostate carcinoma

• block peripheral androgen binding • Leuprolide

– prostate carcinoma

Targeted therapies

• Hematopoietic neoplasm

– Imatinib, nilotinib, dasatinib;

at

b,

ot

b, dasat

b;

CML

C

– All-trans-retinoic acid(ATRA):

APL

– Bortezomib

: multiple myeloma

– Vorinostat:

cutaneous T cell lymphoma

• Solid tumor

– Gefitinib, erlotinib, lapatinib

– Sorafenib, sunitinib

– Imatinib

– Temsiroliums

Complication of Anticancer Drugs

Myelosuppression

Nausea & Vomiting

Mucositis

Alopecia

Myelosuppression

• Most common dose-limiting toxicity

• Leukopenia

• Leukopenia

– Nadir: 6-14 days, Recovery: day 21

– Febrile neutropenia

• ≥ 38.5°C, one time

• ≥ 38°C and ≤ 38.5°C, three times/24hr

– Neutropenia below 500/μL

Neutropenia, below 500/

μL

• Infectious complication

• Empirical broad spectrum antibiotics

Myelosuppression

• Thrombocytopenia

Hemorrhagic complication

– Hemorrhagic complication

• Anemia

– Packed RBCs transfusion

• compromised end-organ function, > 9 g/dL – E.g., coronary artery disease

– Erythropoietin

• Receive therapy for >2 months • Maintain hemoglobin 9-10 g/dL

Nausea & Vomiting

• Vomiting center, chemoreceptor trigger zone(CTZ)

• Cisplatin, doxorubicin, dacarbazine

• Combining & sequential use of different classes of agents

• Prevention

is a primary goal

– Start 24hr before – Use routine schedule

• Acute emesis

• Delayed emesis

– After 24 hrs

• Anticipatory emesis

Pathophysiology of Emesis

Emetogenic Potentials

• High emetic risk

– Cisplatin, cyclophosphamide(>1500mg/m

_{Cisplatin, cyclophosphamide(>1500mg/m )}

₎

– adriamycin+cyclophophamide

• Moderate emetic risk

– Carboplatin, ifosfamide, cyclophosphamide,

anthracycline

• Low emetic risk

T

t

id

fl

il

– Taxane, etoposide, fluorouracil

• Minimal emetic risk

Antiemetics(1)

• Serotonin antagonists

– Selectively block serotonin receptor 5-HTSelectively block serotonin receptor 5-HT₃3

– Acute emesis

– Ondansetron, granisetron, palonosetron

• NK1 receptor antagonist

– Aprepitant – Delayed emesis

• Dexamethasone

– Augmentation of other agents

– Delayed emesis

Antiemetics(2)

• Phenothiazine

• Lorazepam(ativan)

– Benzodiazepine

Anxyolytic effect

– Anxyolytic effect • Metoclopramide

– Antagonize dopamine activity – High doses (1-2mg/kg q 2-4h) – Extrapyramidal side effect

Principles of anti-emetic therapy

• High emetic risk

– 5HT3 antagoist+aprepitant+dexamethasone

• Moderate emetic risk

– 5HT3 antagonist+dexamethasone

• Low emetic risk

D

th

– Dexamethasone

– or with non-5HT3/NK1 receptor antagonist

Mucositis

Aopecia

• Erythema, edema, painful

ulceration

• Begin 1-2weeks after

chemotherapy

• Persist for 1 week • Secondary infection

• All chemotherapeutic agents

cause mucositis

• Antimetabolite: prolonged

• Return to pretreatment level

after stopping chemotherapy

• Cyclophosphamide,

dactinomycin, doxorubicin, paclitaxel, vincristine

exposure

• Oral hygiene

• Topical oral anesthetics

• Scalp-cooling devices

Late sequence of cancer treatment

• Cardiovascular dysfunction

– Anthracycline: congestive heart failure – Mediastinal radiation: constrictive pericarditis

• Pulmonary dysfunction

– Pulmonary fibrosis: bleomycin, radiation

• Renal/bladder dysfunction

– Reduced renal function: cisplatin

• Endocrine dysfunction

• Endocrine dysfunction

– Hypothyroidism: radiation in Hodgkin’s disease

• Nervous system dysfunction

– Peripheral neuropathy: vincristine, cisplatin

– Neurocognitive sequelae: intrathecal chemotherapy, radiation

Late sequence of cancer treatment

• Sexual, reproductive dysfunction

– Infertility: alkylating agent radiation – Infertility: alkylating agent, radiation

• Oral complication

– Dry mouth: radiation

• Second malignancy

– Second solid tumor

• Breast cancer, chest radiation in women • Endometrial cancer, tamoxifenEndometrial cancer, tamoxifen

– Acute myeloid leukemia

• Alkylating agent, deletion in chromosome 5 or 7