Introduction to Cancer Chemotherapy

most common treatments

surgery, radiation, chemotherapy

goal of anticancer drugs

to destroy cancer cells

how to achieve goal

single drug or combination of drug used alone or in addition to surgery/radiation

three mechanisms of actions of anticancer drufs

• Act on DNA

• Inhibit chromatin function 

• act on hormone/steroid/growth receptors

carcinomas

cancers of epithelial cells lining the surface of organs

sarcomas

cancers of muscle, bone, cartilage, fat, connective tissue

Leukemia

group of blood cancers, usually originate in bone marrow resulting in underdeveloped blood cells

lymphoma

group of cancers that develop from lymphocytes

blastoma

cancers that develop from precursor cells or embryonic tissue

what percent of cancers are carcinomas

80-90%

why are so many types of cancers carcinomas

because epithelial cells are sites of extensive cell proliferation and frequent exposure to chemical/physical danage

what classifies cancer

group of diseases

cells exhibit uncontrolled growth/proliferation

potential to invade surrounding tissue and sometimes colonize in other locations of the body (metastasis)

what do most cancers originate from

single aberrant cell

genetic

change in DNA

epigenetic

change in gene expression without change in DNA sequence

what is the normal mutation rate

10¹⁰/ gene / lifetime

is a single mutation enough to cause cancer

no

what is required to develop cancer

requires several independent changes in cell lineage

what does tumour progression depend on 

(1) mutation/epigenetic alteration rate

(2) selective advantage

(3) proliferation rate

(4) invasiveness

critical cancer genes

DNA proofreading/repair genes

Genes maintaining chromosomal integrity 

oncogenes

tumour suppressor genes

genetically unstable cells less fit, therefore,

additional mutations in genes regulating cell death, differentiation or division required

inherited mutations lead to

increased risk of developing cancer

oncogene

gain of function

what mutates in an oncogene

mutation in gene regulating cell growth→ increased mitosis

• hormones/growth factors

• receptors

• cell signaling molecules

• transcription factors

tumour suppressor

loss of function

what is mutated in a tumor suppressor

mutation in gene that normally suppresses mitosis and cell growth or induces apoptosis

• transcription factors/repressors

• regulate cell cycle, apoptosis or DNA repair

angiogensis

larger tumours require oxygen and nutrients

tumours secrete growth factors to induce blood vessel growth

metastasis (least understood and most feared aspect of cancer)

Detachment of cells from parent tumour

entry into lymph/blood vessel

exit circulation

survival and proliferation in new environment

treatment for a primary or localized tumour

surgery/radiation ± chemotherapy

treatment for a metastatic tumour

chemotherapy

what is chemotherapy used for

used with radiation/surgery

before: shrink tumor

after: to kill any remaining cancer cells

what are chemotherapeutic agents used for

to cure cancer or for palliative care

what do most anticancer drugs do

interfere with DNA, therefore, more effective at killing rapidly dividing cells

what is knowledge of cell cycle and tumour growth kinetics important for

• design of effective treatments

• understanding lack of drug response

which stage of the cell cycle are many drugs most cytotoxic during

many drugs most cytotoxic during S-phase

which stage arse some drugs effective during

M-phase

are drugs effective in G0 phase

No, most drugs ineffective in G0 phase

what is S phase

synthesis phase

what is M phase

metaphase checkpoint

check for:

• chromosome spindle attachment 

growth fraction

= % dividing cells sensitive to chemotherapy

majority of cells in young tumours are ____________. As the tumour grows, percentage-wise, not as many cells are _____________; it may be more ________, _________ or not _______________

majority of cells in young tumours are actively dividing. As the tumour grows, percentage wise, not as many cells are actively dividing; it may be more aggressive, metastasize, or not respond well to chemotherapy

debulking tumours does what

stimulates proliferation

early metastases have

high growth fraction

fast-growing cancers are

more responsive

several treatment cycles necessary to what

synchronize cells

chemotherapy kills cancer cells via

first-order kinetics (constant %)

at time of detection, how many cancer cells

>/= 1 billion cancer cells

if 99.99% of cells (10⁹) killed (9.999 × 10⁸), 0.01% of cells remain (10⁵ cells)

0.01% of cells remain (10⁵ cells)

10⁹ to 10⁵ =

4 log kill

can cancer growth occur between treatments

cancer growth can occur as tissues recover between treatments

chemotherapy principles

1. cure requires death of ALL tumour cells

2. drugs kill constant proportion of tumour cells

3. tumours detected later require prolonged treatment 

4. drugs have narrow therapeutic index

5. drug combinations can increase effectiveness and decrease adverse effects

6. intermittent high-dose therapy more effective 

7. adjuvant therapy may decrease metastases and/or adverse effects

factors influencing patient survival

nature of cancer

pharmacology

patient

failure of anticancer drugs

nature of cancer

• type

• stage at diagnosis

• cell-cycling phase

• growth rate 

• heterogeneity

pharmacology

• timing of initiation of treatment

• timing of treatments

• drug combination

patient

• general health

• tumour blood supply

• immune status

failure of anticancer drugs

• lack of specificity (side-effects, dosage limitations)

• cancer exhibits/develops resistance

major sites of toxicity

• bone marrow (myelosuppression)

• GI tract (vomiting, nausea, diarrhea)

• hair follicle (alopecia)

• Reproductive tract (decreased sperm, menopause, teratogenicity) 

• secondary carcinogenicity

resistance types

• natural (some neoplastic cells inherently resistant)

• Acquired (mutation leads to development of resistance)

• multidrug resistance (cells express resistance mechanisms that affects multiple drugs e.g. p-glycoprotein that pumps drugs out of the cell)