Anti-Neoplastic Drugs and Cancer Treatment Flashcards
Goals of cancer treatment
- Cure when possible
- Useful prolongation of life where cure is not possible
- Relief of symptoms whether cure or life prolongation is the goal
Methods of cancer treatment
- Surgery
- diagnostic –> biopsy to define the existence of tumor
- curative –> remove all the tumor
- palliative –> relieve symptoms - Radiation therapy
- Chemotherapy
- cytotoxic
- targeted - Immunotherapy
- cytokines
- antibodies
- immune cells/vaccines
What is radiation therapy?
Aim of radiotherapy?
What is radiation therapy?
- the treatment of disease, primarily malignant tumors, using ionizing radiation = high energy x-rays or particle radiation
Aim of radiotherapy?
- to deliver as uniform a dose as possible to an accurately localized target, with a goal to kill the tumor cells but avoiding as much normal tissue as possible in order to minimize physical, physiological and psychological consequences for the patient
What is radiation?
Propagation of energy over some distance from a central location
- difference between ionizing and non-ionizing radiation is the amount of energy delivered by the radiation
- primary property of ionizing radiation is to break bonds –> most important target is DNA
- ionizing radiation = x rays, gamma rays
How does radiotherapy work?
When ionizing radiation interact with living matter, energy is transferred from the beam
- biological effects may be direct or indirect (via the formation of free radicals)
- effects lead to…
- –> cell death (requires high doses)
- –> cell mitosis being delayed or cell may die in attempt
- –> permanent modifications to chromosomes - passed onto daughter cells
Radiobiology
Critical organelle in the cell is DNA –> when cells are irradiated the following may happen:
- no effect
- sublethal damage –> DNA may have breaks but can be repaired
- lethal damage –> critical targets in cell affected, leads to cell death
Cells are most vulnerable to damage during the mitosis phase of the cell cycle
- radiotherapy takes advantage of the fact that cancer cells do not behave normally –> due to rapid proliferation, more cells are undergoing proliferation at any given time than the normal cell population
- cancer cells are most likely to be damaged by radiation and die
- normal cells are more likely to be able to repair sub-lethal damage and repopulate
Radiation absorbed dose
Gray –> amount of energy imparted to matter from any type of radiation
- Gy = J/Kg
- Gy = 100 cGy
- 1 cGy = 100 ergs per gram = 1 rad
Radiobiology of cancer
DNA double strand breaks are most important lesions caused by radiation
- 2 DSBs may result in cell kill at the time of cell division, mutation, or carcinogenesis
- doses of radiation are ultimately tied to the elicitation of cell death
DNA damage is the result of direct and indirect effects of radiation
- DSB is the most important lesion
- indirect action = photon hits an electron –> results in formation of a free radical that then causes a break in the DNA
- direct action = electron itself acts as an ion –> directly damages DNA
Damage/Gy of X rays
- 40 DSB breaks –> most important
- 150 DNA crosslinks
- 1,000 SSB –> poorly correlates with lethality
- 2,500 base damages
Benefits of dose fractionation
- Allows repair of sublethal damage –> spares late responding normal tissue preferentially
- Reassortment/redistribution of cells in the cell cycle –> increases tumor damage, no effect on late responding normal tissue
- Reoxygenation –> increases tumor damage by production of free radicals; no effect in normal tissue
Normal tissue tolerance
There are intrinsic differences in normal tissues in respect to their tolerance of radiation
- High sensitivity –> cell turnover is high
- thyroid
- lungs
- breasts
- stomach
- colon
- bone marrow - Intermediate sensitivity
- brain
- esophagus
- liver
- small intestine
- ovaries
- pancreas
- lymph nodes - Low sensitivity
- skin
- dense bone
- spleen
- gall bladder
- kidneys
Factors that impact chances of long term toxicity from radiation therapy
- high dose
- high fraction size
- larger volume treated
- nature of cells treated
- overall organization of the tissue
- –> higher oxygen content (lung)
- –> proliferative component (GI tract, marrow)
Side effects of radiation
Acute and late sequelae –> if someone received radiation in a certain area in the past, you have to consider all of the potential side effects that could occur in the future due to the radiation
Effects on normal tissue are complex –> ie skin:
- acute erythema
- erythema, epilation, desquamation can occur after 2-3 weeks
- re-epitheliazation takes ~6-8 weeks
- late effects = atrophy, fibrosis, necrosis, stenosis, telangiectasia
X ray and electron beam dose profiles
Different energy radiation give different doses to different tissue depths
- X rays = have different degrees of penetration at different energies
- protons = tend to have a very different deposition pattern of dose
- –> will penetrate between 10-15 cm before delivering most of their dose
- –> most of their dose and the width of the deposition is much smaller than X rays = underlies the use of protons where you want to minimize the impact on adjacent structures
Gradually decrease the field of radiation over subsequent treatment
- want to make sure that the initial field is large enough to target outreaching portions of the tumor that may not be obvious by radiology
- final dose is an intense, targeted “boost” to get the last remaining difficult portions of the tumor
Radiation delivery methods
- External beam radiotherapy –> tele-therapy
- Brachytherapy –> insert radioactive source close to tumor
- Systemic radiotherapy –> administer isotope to circulation (e.g. isotopes of iodine for thyroid cancer)
- Radio-immunotherapy –> attach to antibody
Overview of cancer chemotherapy
Chemotherapy = use of drugs to treat cancers
- Cytotoxics –> more toxicity to tumor cells than host within a dose range
- chemicals
- natural products –> extracts of plants, bacteria, animals - Targeted agents –> modulate tumor cell biology to decrease viability
- hormonal/receptor agonists/antagonists
- oncogene products
- growth factor receptors
- immune modulators –> cytokines, antibodies
General principles of cytotoxics
- Log cell kill
- Combination chemotherapy
Log cell kill:
- each dose of drug kills a constant fraction of cells –> results in decrease by a number of “logs” of cell numbers
- successive cycles of chemotherapy necessary to get down to a low number of ideally poorly growing tumor cells
- time each round of therapy with recovery of host from toxicity
- better effect with smaller initial tumor volume + as high of a dose as possible
Combination chemotherapy:
- use of more than one drug –> each drug of regimen ideally have non-overlapping host toxicities
- each drug in a combination regimen has activity on its own
2 mechanisms of cell death in chemotherapy
- Induction of DNA damage that causes mitochondrial activation of apoptosis via caspase 3
- Elaboration of a cell death program via a death signal acting on a receptor
Alkylating agents
Act to cause covalent modification of cellular molecules with alkyl moieties
- different classes of agents differ in spectrum of cellular molecules affected –> all modify DNA structure
- intra/inter-strand crosslinks have greatest value as ant-cancer agents
Major toxicities of alkylating agents
- myelosuppression –> in general there is a return to normal levels of leukocytes and platelets between 18-22 days allowing for another round of treatment
- GI epithelial damage = mucositis
- alopecia
- impaired wound healing
- impaired growth in children
- reduced resistance to infection
- nausea and vomiting
- sterility
- teritogenic
- carcinogenic
Busulfan
Alkylating agent - an alkyl sulfonate
- causes acute and delayed myelosuppression
- lung damage with high doses
Cyclophosphamide
Alkylating agent
- bladder toxic in high or prolonged oral dosing
- high doses –> cardiotoxicity, SIADH, lung toxicity
- requires hepatic activation –> breakdown products are toxic to the bladder
- Use MESNA and hydration to protect bladder with high doses
Ifosfamide
Alkylating agent
- requires hepatic activation –> metabolites also bladder toxic and cause encephalopathy
- routine use of hydration and MESNA required
Procarbazine
Alkylating agent
- oral bioavailability
- CNS penetration –> CNS toxic effects = somnolence, mood swings
- part of curative regimens in hodgkin’s lymphoma
- current palliative use in gliomas (brain tumors)
DTIC/Temozolamide
Alkylating agents –> both activated to the same intermediate
- alkylate O6 of guanine
- distinct repair pathway
- alkylguanine alkyl transferase
- DTIC –> active in melanoma
- Temozolomide –> oral active in glioma
Nitrosureas
- Carmustine (BCNU)
- Lomustine (CCNU)
Bifunctional alkylating agents
- wide spectrum of use
- cross blood/brain barrier
- active agent against CNS metastases and brain tumors
Platinum derivatives
- Cisplatin
- Carboplatin
- Oxaliplatin
DNA damaging heavy metals –> act as alkylating agents
- bind N-7 of guanine on single strand
- cross links DNA
- binds proteins
- Cisplatin –> requires hydration = IMPORTANT
- Carboplatin –> dosed according to the patient’s renal function
Toxicities differ:
- cisplatin = renal > neuro/oto > heme
- carboplatin = heme»_space;» renal/neuron
- oxaliplatin = neuro»_space; heme»_space;» renal
Anti tumor antibiotics
Historically found to be produced by bacteria and have anti-bacterial and anti-tumor cell activities
- bind to DNA and cause damage to physical structure of DNA or alter DNA function
- important drugs = bleomycin + actinomycin
Bleomycin
- oxygen increases toxicity of bleomycin
- renal clearance
- tissues clear by a bleomycin hydrolase –> lungs + skin lack the hydrolase –> causes pulmonary and cutaneous toxicity, especially with decreased renal function
- increased toxicity with cumulative dose
- toxicity worse with underlying pulmonary disease
- persists in lung –> fatal activation of lung toxicity during surgery with high oxygen inspired
- cause Raynaud’s hypersensitivity
- part of curative regimens for germ cell and hodgkins disease
