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
Actinomycin D
Intercalate into DNA helix –> inhibit RNA/protein synthesis
- part of curative regiment for pediatric cancers
Toxicities
- myelosuppression
- nausea/vomitting
- mucositis
- diarrhea
- vesicant –> avoid extravasation
- radiation recall
Topoisomerase directed agents
Topoisomerases allow unwinding of coiled DNA molecules
- bind to DNA to make a break
- topo I = makes a single break –> forms an enzyme-DNA intermediate –> reseals the link after one strand rotates around the other
- topo II = makes a double strand break –> enzyme binds to broken ends –> passes another whole double helix between the strands
Topo-directed drugs form a ternary complex = drug + enzyme + DNA –> stabilizes the break + signals DNA repair and damage responses
Specific agents:
- Topo I = topotecan, irinotecan (derivatives of camptothecin)
- Topo II = doxorubicin, daunorubicin, idarubicin (anthracyclines), mitoxantrone, etoposide
Anthracyclines
Doxorubicin, daunorubicin, epirubicin, idarubicin
Toxicities:
- myelosuppression, mucositis, alopecia, cardiac toxicity –> dose related
- radiation sensitive
- extravasation damage to surrounding tissues - vesicant
- idarubicin = somewhat less cardiotoxic on a weight basis
- eliminated prominently by liver –> dose adjustment needed in hepatic failure
- generate free radicals –> not related to topo II –> causes cardiotoxicity
Mitoxantrone
Etoposide
Mitoxantrone –> similar structure to anthracyclines but less cardiotoxic and emetogenic
Etoposide (aka VP-16)
- toxicities = neutropenia, thrombocytopenia, alopecia
- reduce dose in proportion to creatinine clearance
Topotecan
Irinotecan
Topo I inhibitors
Topotecan
- toxicites = nausea, myelosuppression, fatigue, alopecia
Irinotecan
- toxcitiies
- –> early onset diarrhea = atropine sensitive
- –> late onset diarrhea = reflects enterohepatic clearance
- –> myelosuppression
- –> alopecia/nausea/fatigue
Anti-metabolites
- Folate antagonists
- Pyrimidine analogs
- Purine analogs
Folate antagonists
- methotrexate
- pemetrexed
Pyrimidine analogs
- fluorouracil
- cytarabine
- gemcitabine
- azacytidine/deazacytidine
Purine analogs
- thioguanine
- mercaptopurine
- pentostatin
- fludarabine
- cladribine
Common features of antimetabolite action
- cells must be in S phase to be maximally active –> must be growing cells
- mimic normal nucleic acid precursors and can be misincorporated into DNA or RNA –> results in altered function of DNA or RNA –> causes cell death
- interfere with production of DNA and RNA precursors –> inhibits normal nucleotide synthesis
- longer the exposure, the most toxic to the host –> more cells enter S phase and become effected
- may be able to rescue by replacing downstream metabolite
Antimetabolites
- Inhibitors of ribonucleotide synthesis from purines
- Inhibitors of deoxyribonucleotide synthesis from ribonucleotides
- Inhibitors of DNA synthesis from deoxyribonucleotides
Inhibitors of ribonucleotide synthesis from purines
- mercaptopurine
- thioguanine
- methotrexate (high dose)
Inhibitors of deoxyribonucleotide synthesis from ribonucleotides
- hydroxyurea
Inhibitors of DNA synthesis from deoxyribonucleotides
- methotrexate (low/high dose)
- cytarabine
- 5-flurouracil
- asparaginase (indirect)
Methotrexate
- mechanism
- major toxicity of standard dose MTX
Mechanism = inhibits dihydrofolate reductase, blocking DNA and RNA precursor formation
Major toxicity of standard dose MTX = myelosuppression
- other prominent = mucositis
- chronic exposure = hepatic fibrosis
High dose MTX
High dose MTX = give intentionally lethal dose
- use leucovorin = downstream metabolite –> already reduced folate does NOT require dihydrofolate reductase for action after exposure to high dose MTX
- leucovorin rescues normal cells while “loading” cancer cells with high concentrations of MTX
- cancer and normal cells have different folate receptors which accounts for differential uptake of leucovorin
5-fluorouracil
- mechanism
- major toxicities
- metabolism
Mechanism = inhibits thymidine synthesis by forming covalent complex with folate and thymidylate synthase
- orally available pro-drug = capecitabine
Major toxicities
- myelosuppression –> more continuous with infusion
- GI –> especially bolus 5FU
- cerebellar/neurocognitive
- coronary spasm –> rare
Metabolism
- metabolized in tissues by DHPD –> useful when there is hepatic/renal impairment
- deficiency of DHPD = severe toxicity
Enhance toxicity/activity of 5FU by coadministration with reduced folate –> usually leucovorin
Leucovorin uses
- Rescue/protect normal cells after high doses of MTX
- can treat MTX toxicity encountered even at lower doses - Enhance 5FU toxicity to cancer cells by increasing formation of ternary complex of thymidylate synthase + folate + 5FU
Cytosine analongs
- major toxicity
- metabolism
Cytarabine + gemcitabine
Major toxicity = myelosuppression, esp after continuous venous infusion
- cerebellar, eye irritation, hand foot
Metabolism
- metabolized by cytidine deaminase –> useful in hepatic/impairment
Bolus regimens of cytarabine (AraC)
- rationale = drive production of AraCTP
Continuous venous infusion regimens = prolong exposure –> maximize S phase exposure
Gemcitabine –> used in solid tumors, unique toxicity = hand food prominent
Purine analogs: Bases
- Mechanism
- Metabolism
- Toxcities
6-Mercaptopurine + 6-Thioguanine
Mechanism
- inhibition of de novo purine synthesis
- some incorporation into DNA (6MP) = dysfunction of DNA
- incorporation into RNA
- must be anabolized to nucleotide for incorporation
Metabolism of 6-mercaptopurine
- metabolized by xanthine oxidase –> use with allopurinol (drug to control uric acid synthesis) requires dose reduction
- thiopurine methyltransferase –> genetic deficiency results in excessive toxicity
Toxicities = myelosuppression, nausea, rare hepatotoxicity
Purine analogs: nucleosides
- Mechanisms
- Toxicities
Fludarabine = prototypic of adenine based analogs
- also cladribine
Mechanism
- incorporate into DNA as false nucleotide
- inhibit DNA synthetic activities
Toxcities
- myelosuppresion
- immunosuppression –> results in infections
- neurotoxicity at high doses
- rare interstitial pneumonitis and rare hemolytic anemia
Pentostatin unique –> not directly incorporated into DNA but inhibits adenosine deaminase –> therefore builds up levels of dATPs = signal to apoptosis in T cells
Asparaginase
- mechanism
- toxicities
Mechanism
- asparaginase = foreign protein that clears circulation of asparagine
- consequence –> decreased protein synthesis in susceptible cell types
- DNA synthesis requires concomitant protein synthesis –> therefore indirectly damages DNA
Toxicities
- hypersensitivity
- hyperglycemia
- pancreatitis
- altered clotting functions
Hydroxyurea
Mechanism
- reversible inhibition of ribonucleotide reductase by chelation of non-heme Fe at reactive center
- consequence –> decreased dNTP pools with consequent stalled replication forks –> perceived by the cells as damaged DNA and a signal for apoptosis
Toxicities
- myelosuppression
- mucosal damage
- enhanced effect in renal failure
Oral bioavailability
Microtubule directed agents
- mitotic inhibitors
- microtubule polymer stabilizers
- toxicities
Mitotic inhibitors
- vinca alkaloids = vincristine + vinblastine
- vincristine = neurotoxic > myelotoxic
- vinblastine = myelotoxic > neurotoxic
Microtubule polymer stabilizers –> promote microtubule formation, but microtubules formed are abnormal and shortened –> don’t function normally –> prevent cell cycle progression through M phase
- taxanes = paclitaxel, docitaxel
- epothilones
Common toxicities
- myelosuppression
- neuropaty
- fluid retention
Taxane specific side effects
- fluid retention/vascular leak
- hypersensitivity reactions
Arsenicals
Arsenic trioxide
- uniquely toxic to acute promyelocytic leukemia
- generates free radicals
Toxicities
- heavy metal toxicity = kidney + cardiac conduction (prolongs the QT interval)
Thalidomide derivatives
Unique cytotoxicity for developing endothelial cells = basis for teratogenic effects
- interact with cytokine production and elaboration
- useful in certain hematopoeitic neoplasms by mix of cytotoxic and immunoregulatory mechanisms
Toxicities
- teratogenic
- neuropathy
- cytopenias
- GI
Targeted therapy in cancer treatment
Drugs directed at the molecular or physiologic concomitants of malignancy
In contrast to cytotoxics…
- saturability of dose-response
- biological effective dose rather than maximal tolerate dose
- patient selection possible by presence of the drug target
Most targeted therapies target nuclear steroid hormone receptors –> all are transcription factors
Steroid hormone receptor agonists/antagonists –> Prostate cancer
Androgen receptor modulation
LHRH analogs –> decrease LH release by pituitary = decreased testosterone production
Antiandrogens = act at level of androgen receptor
- flutamide
- casodex
High dose estrogen –> feedback inhibition in hypothalamus to decrease LH elaboration
Steroid hormone receptor agonists/antagonists –> Breast cancer/endometrial cancer
Estrogen/progesterone receptor modulation
Antiestrogens –> tamoxifen
Aromatase (estrogen synthetase) inhibitors
- letrozole
- arimidex
- examestane
Progestational agents
Steroid hormone receptor agonists/antagonists –> Leukemia
Glucocorticoid receptor action induces apoptosis in lymphoid cells
Glucocorticoids –> high doses of prednisone, prednisolone and dexamethasone
Aromatase inhibitors
- mechanism of action
Type I = steroidal inhibitor –> target the substrate binding site
Type II = nonsteroidal inhibitor –> target the cyt P450 aromatase
All trans retinoic acid
- mechanism
- toxicities
Mechanism = binds to retinoic acid receptor
- induces differentiation of leukemic cells in acute promyelocytic leukemia that have a 15:17 translocation that alters the structure and function of the retinoic acid receptor
Toxicities
- teratogenic
- cutaneous = dry skin, ocular keratitis
- increased intracranial pressure
- differentiation syndrome
Tyrosine kinases
Oncogenes act through protein kinases
TKs = transfer phosphate from ATP to substrate tyrosines
Integral membrane TKs
- respond to external signals –> EGFR, PDGF, IGF
- respond to “matrix/contact” –> integrins
- dimerize to signal –> Her2/neu
Non-integral membrane TKs
- associate with primary signal recipients –> Ick, lyn, src
- may act independently –> abl
- may associate with membrane by post translational modification –> myristoylation
Common elements/repeated themes with TKs
- overexpressed or activated in cancer –> ex = EGFR (lung cancer) + Her2/neu (breast cancer)
- altered activity by mutation –> ex = c-kit
- altered activity by translocation –> ex = bcr-abl
- overexpression associated with advanced stage + inferior prognosis
Targeted cancer therapy - ATP site protein kinase antagonists
- common toxicity patterns
Since all protein kinases have structural similarities to ancestral kinases, ATP antagonists have varying degrees of shared capacity to inhibit many different families of kinases –> more specific the binding to one kinase, the more specific the inhibitor action
- results in common toxicity patterns
Bcr/abl
- cytopenias
- liver abnormalities
- fluid retention
- rare cardiomyopathy
VEGF receptor antagonists
- hypertension
- proteinuria
- perforated viscus
- clotting/bleeding
EGFR/ERBB2
- Diarrhea
- cutaneous
Targeted cancer therapy - MTOR protein kinase antagonists
- common toxicity patterns
- stomatitis
- thrombocytopenia
- hyperlipidemia
Targeted cancer therapy - post-translational modification of chromatin proteins/DNA methylation
Interact with epigenetic regulation of gene expression
- histone acetylation
- DNA methylation
- –> methylated cytosines cause transcriptional repression
- –> hypomethylation “wakes up” repressed genes and allows differentiation
Low doses of certain nucleosides inhibit cytosine methylation
Modulators of chromatin function
Histone deacetylase inhibitors
- vorinostat
- romidepsin
DNA hypomethylating agents –> low doses of certain nucleosides
- azacytidine
- decitabine
Proteasome inhibitors
Bortezomib
- clinically active in multiple myeloma and lymphomas
Major toxicites
- neuropathy
- thrombocytopenia
- altered GI tract function
Biological response modifiers
- IFNs
- IL-2
IFNs
- adjuvant for melanoma
- hairy cell leukemia
- kaposi’s sarcome
- side effects: fatigue, ctyopenias, fevers, chills
IL-2
- induces T cell response –> cytolytic for tumors
- renal, melanoma
- high dose IL-2 produces complete responses in small subset of metastatic renal tumors
- side effects: same as IFNs + hypotension, vascular leak, altered mental status, cardiopulmonary
Biological response modifiers
- Immune modulators = “imis”
Thalidomide + lenalidomide
- alter cytokine milieu that promotes angiogenesis + cell growth
- uniquely active in multiple myeloma and certain pre-leukemia syndromes
Side effects
- thromboses
- edema
- cytopenias
- fevers/chills
Cetuximab + Panitumumab
Anti-EGFR
- colon cancer with chemo in ras allele wild type
- squamous head and neck with radiation
Toxicities:
- infusion reaction –> fever, chills, rare hypotension, bronchospasm
- cutaneous
- diarrhea
Trastuzumab (herceptin)
Anti- Her2/Neu
- inhibits signaling and immune action
- hormone independent breast cancer
Toxicities
- infusion reaction
- cardiomyopathy
Rituximab
Anti CD20 on B cells
- non-Hodgkins lymphoma
- acts by inhibiting lymphocyte signaling and immune activation
Toxicities
- infusion reaction
Anti-angiogenic agents
Bevacizumab = anti-VEGF monoclonal antibody
- active in tumors that prominently express VEGF = renal + glioma
- potentiates actions of chemo in tumor by acting on microvasculature to decrease tumor interstitial pressure
Toxicities
- hypertension
- clotting
- bleeding
- perforation of viscus
- CNS dysfunction
Immune cell approaches to kill tumor cells
Ipilimumab = anti-CTLA4 antibody
- CTLA4 and PD1 are “negative” signals to T cell activation
- approved for treatment of melanoma
Side effects:
- autoimmune like side effects in gut
- hepatic
Resistance to cancer treatment
- excessive degradation of drug
- altered affinity of drug target
- changes in metabolic activation
- altered drug transport
- gene amplification of drug target
- DNA repair mechanisms
- increase thiol content (alkylators)
- altered apoptosis induction threshold
MDR gene family amplification
MDR = multidrug resistance protein = p-glycoprotin
- normal transport protein
- energy dependent efflux pump for lipophilic drugs
- overexpressed in drug resistant leukemia
- overexpressed in normal and cancer stem cells
Limitations of current cancer treatment approaches
- severe toxic effects of many agents
- lack of selectivity of the drugs against tumor ells
- lack of knowledge of target expression
- uncertainty of how target presence convey basis for activity
- total elimination of malignant cells is usually not possible with therapeutic doses
- host’s immune response is inadequate to deal with the remaining cells
