cytotoxic cancer chemotherapy: antimetabolites, alkylating agents, Topoisomerase inhibitors, inhibitors of mitotic spindle (B32-34) Flashcards
Cancer therapy
Treatment depends on the type of cancer, the stage, age, health status and personal characteristics.
There is no single treatment for cancer. Patients often receive a combination therapies.
Surgery Radiation Chemo therapy Immuno therapy Hormone therapy Gene therapy Palliative therapy
EVIDENCE BASED MEDICINE!!!
Randomised, controlled, blinded clinical trials!!
ANTICANCER DRUGS
Cytotoxics
- poor efficacy, resistance, toxic side effects
1. antimetabolites,
2. DNA targeting drugs,
3. topoizomerase inhibitors,
4. mitotic inhibitors
Cytostatics
- hormone derivatives,
- cytokines,
- signal transduction modulators, enzymes
Characteristics of cytotoxic therapy
- Causes direct cellular damage leading frequently to cell death
- Tumor shrinkage is frequently observed if cell death is dominating
- has frequently poorly defined targets
- Host and tumor cells are equally damaged, toxicity is frequently severe
- Intermittent Therapy can be applied due to irreversible binding of the drug to the target and/or permanent cellular damage caused
- Continuous, prolonged administration causes lethal bone marrow damage, therefore intermittent administration is preferred to allow sufficient time for host tissue regeneration
Characteristics of cytostatic therapy
- Does not cause direct cellular damage, inhibits only cell
- Only tumor growth is inhibited, tutor shrinkage is only sometimes observed
- the molecular targets are well characterised
- Host toxicity compared to antitumor effect is usually mild
- Drug target binding is easily reversible, continuous therapy must be used
- Continuous, prolonged therapy can be maintained due to the mild toxicity to the host. Cumulative toxicity might be more severe
Chemotherapy
- acts on all rapidly dividing normal and cancerous cells
- compounds identified because they kill cells
- Cytotoxic- they kill tumor cells
used to:
- treat cancer: cure, lessen chance of return, stop or slow growth
- palliative care: shrink if it is causing pain or problem
- Neoadjuvant chemotherapy: make a tumor smaller before surgery or radiation
- adjuvant therapy: destroy cancer cells that may remain after surgery or radiation therapy
- Help other treatments, so they can work better
targeted therapy
- acts on specific molecular targets that are associated with cancer
- Compounds deliberately chosen or designed to interact with their target
- Cytostatic- they block tumor cell proliferation
Cytotoxic agenst
Antimetabolites: 1. 5-fluorouracil 2. Capecitabine 3. Cytarabine 4. 6-mercaptopurine (6-thioguanine) 5. Methotrexate 6. Pemetrexed (Hydroxyurea)
Alkylating agents: 1. Cyclophosphamide 2. Dacarbazine 3. Temozolomide 4. Cisplatin (Carboplatin) 5. Oxaliplatin
Intercalators:
- Dactinomycin
- Bleomycin
Topoisomerase inhibitors: 1. Irinotecan 2. Etoposide (Teniposide) 3. Doxorubicin (epirubicin)
Mitotic inhibitors: 1. Vincristine (Vinblastine) (Paclitaxel) 2. Docetaxel
https://www.youtube.com/watch?v=t7QDJOXeux4
Antimetabolites:
Pyrimidine antagonists:
- 5-fluorouracil
- Capecitabine
Dezoxycitidine analogs:
3. Cytarabine(Cytosine arabinoside)
Purinantagonist:
4. 6-mercaptopurine
(6-thioguanine)
Antifolate:
5. Methotrexate
6. Pemetrexed
(Hydroxyurea)
Alkylating agents:
- Cyclophosphamide
- Dacarbazine
- Temozolomide
- Cisplatin
(Carboplatin) - Oxaliplatin
An alkylating agent attaches alkyl groups to DNA bases – covalent bounds in DNA (mostly on guanine)
In the first mechanism an alkylating agent attaches alkyl groups to DNA bases. This alteration results in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases.
A second mechanism by which alkylating agents cause DNA damage is the formation of cross-bridges, bonds between atoms in the DNA. In this process, two bases are linked together by an alkylating agent that has two DNA binding sites. Cross-linking prevents DNA from being separated for synthesis or transcription.
The third mechanism of action of alkylating agents causes the mispairing of the nucleotides leading to mutations.
There are six groups of alkylating agents: nitrogen mustards; ethylenimes; alkylsulfonates; triazenes; piperazines; and nitrosureas.
Cyclosporamide is a classical example of the role of the host metabolism in the activation of an alkylating agent and is one or the most widely used agents of this class. It was hoped that the cancer cells might posses enzymes capable of accomplishing the cleavage, thus resulting in the selective production of an activated nitrogen mustard in the malignant cells. Compare the top and bottom structures in the graphic on the left.
Nitrogen Mustard and Cyclosporamide
Intercalators:
- Dactinomycin
2. Bleomycin
Topoisomerase inhibitors:
Topoisomerase I.:
1. Irinotecan
Topoisomerase 2.:
2. Etoposide
(Teniposide)
Anthtracyclins
3. Doxorubicin
(epirubicin)
Mitotic inhibitors:
Vinca alkaloids:
1.. Vincristine
(Vinblastine)
Inhibit polymerization of tubuline monomers
Taxanes:
(Paclitaxel)
2. Docetaxel
Microtubule-stabilizing, abnormal microtubules
Methotrexate
MOA:
- Antifolate
1. binds to the active catalytic site of dihydrofolate reductase
- inhibition of the synthesis of THF
- de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine (–) down
- > S phase specific effect
Pk.:
- adm.: intravenous, intrathecal, or oral
- oral bioavailability is saturable
- elim.: mainly renal route (renal dysfunction!)
- aspirin, NSAIDs, penicillin, cephalosporins!
Ind.: acute lymphoid leukemia, non-Hodgkin lymphoma, breast, ovary, stomach, colon, bronchial cc., osteosarcoma smaller dose: RA, psoriasis (immune suppression)!
SE, toxicity: mucositis, GI, liver, kidney tox. hair loss bone marrow toxicity -> leucovorine (iv.)
Resistance:
- reduced folate carrier or folate receptor protein (decreased transport)
- decreased formation of cytotoxic MTX polyglutamates
- increased levels of the target enzyme DHFR through gene amplification
- reduced affinity for MTX (altered DHFR) (dihydro-folate reductase)
- multidrug resistance transporter P170 glycoprotein activation (decreased accumulation)
Pemetrexed
- antifolate
- approved for use in combination with cisplatin or monotherapy
- second-line therapy of NSCLC and mesothelioma
SE: myelosuppression, skin rash, mucositis, diarrhea, fatigue, and hand-foot syndrome (folic acid and vitamin B12 suppl.)
5-Fluorouracil (5-FU):
Fluoropyrimidines
pyrimidine antagonist
MOA:
- requires activation via a complex series of enzymatic reactions
- inhibition of DNA synthesis (“thymineless death.”)
- 5-fluorouridine-5′-triphosphate (FUTP) is incorporated into RNA
- fluorodeoxyuridine-5′-triphosphate (FdUTP), is incorporated into cellular DNA -> function and synthesis is decreases
- combined effects on both DNA- and RNA-mediated events
Pk.:
- iv. administration
- clinical activity is highly schedule-dependent
- extremely short half-life (10-15 min) -> infusion
- 80–85% atabolized by the enzyme dihydropyrimidine dehydrogenase (DPD)
- partial or complete deficiency of DPD: 5% of cancer patients
- > myelosuppression, diarrhea, nausea, vomiting, and neurotoxicity
Indication:
colorectal cancer!!
wide variety of solid tumors, including cancers of the breast, stomach, pancreas, esophagus, liver, head and neck, and anus
SE:
mucositis / stomatitis, diarrhoea
hand-foot syndrome
myelo suppression
Capecitabine:
Pyrimidine antagonist
undergoes extensive metabolism in the liver,
70–80% oral bioavailability metabolised to 5-FU- requires thimydine phosphorylase, in most cancer cells
Ind.:
metastatic breast cancer (might be combinated with docetaxel, paclitaxel, lapatinib, ixabepilone, and trastuzumab)
stage III and high-risk stage II colon cancer
metastatic colorectal cancer
-> capecitabine/oxaliplatin (XELOX) regimen
Toxicity: diarrhea, hand-foot syndrome myelosuppression, nausea and vomiting, and mucositis is less frequent than with 5-FU
Cytarabine
Deoxycitidine analogs (Pyrimidine analogs) Cytarabine (ara-C):
MOA:
- converted by deoxycytidine kinase to the 5′-mononucleotide (ara-CMP) -> -> ara-CTP
- inhibition of DNA polymerase-α and DNA polymerase-β
- > blockade of DNA synthesis and DNA repair
- incorporated into RNA and DNA
- S phase-specific antimetabolite
Pk.:
- rapid degradation -> continuous infusion over a 5–7 day period
- highly schedule-dependent activity
Ind.:
- no activity in solid tumors!!
- activity is limited exclusively to hematologic malignancies
- > acute myelogenous leukemia and non-Hodgkin’s lymphoma
SE:
- myelosuppression,
- mucositis,
- nausea and vomiting
- high dose: neurotoxicity
6-Mercaptopurine
Purine antagonists
(azathioprine, 6-thioguanin)
MOA:
- metabolized by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) -> inhibits several enzymes of de novo purine nucleotide synthesis
- can be incorporated into both RNA and DNA
Ind.:
childhood acute leukemia
SE:
myelotoxicity,
GI,
anorexia
Cyclophosphamide
Alkylating agents
MOA:
- cytotoxic effects
- alkylations of DNA within the nucleus (major site of alkylation within DNA is the N7 position of guanine)
Resistance:
- increased capability to repair DNA lesions
- decreased transport of the alkylating drug into the cell
- increased expression or activity of glutathione and glutathione-associated proteins
Indication:
- solid tumors (breast cancer, ovarium, testicle, SCLC)
- lymphomas, leukemias
immune suppression
Toxicity:
- Bone marrow suppression
- vomiting
- alopecia
- neurotoxicity
- hemorrhagic cystitis (acrolein)
Adverse effects:
- generally dose-related and occur primarily in rapidly growing tissues (bone marrow, gastrointestinal tract, and reproductive system)
- nausea, vomiting!
they are potent vesicants; tissue damage at the site of administration
- secondary malignancies (acute myelogenous leukemia)
Dacarbazine
Nonclassic alkylating agents
MOA:
inhibition of DNA, RNA and protein biosynthesis (?)
- similar to cyclophosphamide?
- alkylating agent following metabolic activation in the liver
Indications:
- malignant melanoma,
- Hodgkin’s lymphoma,
- soft tissue sarcomas,
- and neuroblastoma
Toxicity:
- myelosuppression
- one of the metabolites is a MAO inhibitor ?? true for Procarbazine
- increased risk of secondary cancers
Temozolomide
Alkylating agents
MOA:
- cytotoxic effects
- alkylations of DNA within the nucleus (major site of alkylation within DNA is the N7 position of guanine)
Resistance:
- increased capability to repair DNA lesions
- decreased transport of the alkylating drug into the cell
- increased expression or activity of glutathione and glutathione-associated proteins
Toxicity:
- bone marrow
- vomiting
Indication:
- brain tumors
Adverse effects:
- generally dose-related and occur primarily in rapidly growing tissues
(bone marrow, gastrointestinal tract, and reproductive system)
- nausea, vomiting!
- they are potent vesicants; tissue damage at the site of administration
- secondary malignancies (acute myelogenous leukemia)
Cisplatin
Alkylating agents
Platinum analogs
MOA:
- alkylating agents (?)
- inhibition of DNA synthesis and function
Toxicity:
- very strong emetic effect!! (cisplatin)
- kidney damage, hearing damage – cisplatin
- neurotoxicity – cisplatin, oxaliplatin (paraesthesia, pain!)
- bone marrow – carboplatin
Indications:
- solid tumors
- colorectal c. – oxaliplatin
- FOLFOX regimen (leucovorin, 5-FU, oxaliplatin)
Oxaliplatin
Alkylating agents
Platinum analogs
MOA:
- alkylating agents (?)
- inhibition of DNA synthesis and function
Toxicity:
- very strong emetic effect!! (cisplatin)
- kidney damage, hearing damage – cisplatin
- neurotoxicity – cisplatin, oxaliplatin (paraesthesia, pain!)
- bone marrow – carboplatin
Indications:
- solid tumors
- colorectal c. – oxaliplatin
- FOLFOX regimen (leucovorin, 5-FU, oxaliplatin)
Dactinomycin
Intercalator
-intercalates with DNA
- Antitumor antibiotics ^
- CCNS - cell cycle non-specific
- Inhibits DNA-dependent RNA
polymerase, at high doses may inhibit DNA synthesis - Wilm’s tumor
- Ewing’s sarcoma
- Rhabdomyosarcoma
- Gestational choriocarcinoma
- Nausea, vomiting
- Myelosuppression
- Alopecia
Bleomycin
Intercalators
- Antitumor antibiotics ^
- CCS (G2 phase) - cell cycle specific
MOA:
- small peptide that contains a DNA-binding region and an iron-binding domain
- binds Fe2+ and then interclass
plates with DNA
- binding to DNA -> single- and double-strand breaks; free radical formation -> inhibition of DNA biosynthesis
- G2 specific effect
Pk.:
- excreted mainly via the kidney
- sc., iv., and also im. administration (inj.)
Ind:
- Hodgkin’s and non-Hodgkin’s lymphomas,
- germ cell tumor,
- head and neck cancer, and - squamous cell cancer of the skin, cervix, and vulva
SE, toxicity:
- pulmonary toxicity -
- pneumonitis with cough, dyspnea, dry inspiratory crackles on physical examination, and infiltrates on chest X-ray
- elderly! (70 years
- Pulmonary fibrosis, pneumonitis
- Hypersensitivity reaction
- Mucocutaneous reactions (alopecia, hyperpigmentation, blisters, hyperkeratosis)
- Complexes with Fe and O2 → free
radicals → DNA strand termination - Hodgkin lymphoma
- Testicular cancer
- Lymphoma
- Squamous cell carcinoma
Topoisomerases
- Topoisomerases catalyze and guide the unknotting or unlinking of DNA
- DNA repair
type I:
type II:
Irinotecan
Topoisomerase I inhibitors
(Topotecan)
MOA:
- activated by hydrolysis
- inhibition of topoisomerase I -> transcription and replication inhibition
- effect during the whole cell cycle
Ind.:
- colon cancer (+/- 5-FU)
- small cell lung cancer (cisplatin)
SE:
- bone marrow suppression
- diarrhea, vomiting (early and late GI symptoms)
Etoposid
Topoisomerase II inhibitor
Podophyllins (Teniposid)
MOA:
- Topo II inh. -> DNA double strand brakes
- apoptosis induction
- S/G2 specific effect
Ind.:
- Akute leukemia,
- Hodgkin, non-Hodgkin,
- SCLC
Resistance: MDR
Toxicity:
- bone marrow suppression
Doxorubicin
Topoisomerase II inhibitors
Antracyclines: (Daunorubicin, Epirubicin, Idarubicin, Mitoxantron)
MOA:
- Topo II inhibition -> DNA double strand brakes
- intercalation into DNA
Ind.:
- most widely used cytotoxic anti-cancer drugs
- doxorubicin:
1. lymphoma,
2. SCLC,
3. NSCLS,
4. Hodgkin,
5. non-Hodgkin,
6. prostate,
7. lung,
8. breast cc,
9. bone and
10. soft tissue sarcoma, stb.
(((- daunorubicin: leukemias mutagen/teratogen Danger on hospital personnel!) (epirubicin: =doxorubicin) (idarubicin: leukemia, cancercc) (mitoxantron: akute myeloid leukemia, non-Hodgkin, breast cancer, ovary,prostate, liver cc)))
Pk:
- elim. via biliary excretion
- metabolized extensively in the liver
- iv. admisitration
- usually administered on an every-3-week schedule (or low-dose weekly or 72- to 96-hour continuous infusions)
SE, toxicity:
- cardiotoxicity
- dexrazoxan inf.
- liposomes
- epirubicin, idrarubicin less side effects
- myelotoxicity,
- GI
Resistance: MDR transporter
Vincristine
Mitotic inhibitors VINCA ALKALOIDS (Vinblastine)
- Inhibit polymerization of tubuline monomers
- Vinca alkaloids prevent microtubule assembly
MOA:
- inhibition of tubulin polymerization -> disrupts assembly of microtubules -> cell division stops
Pk.:
- metabolized by the liver P450 system
- excreted via the hepatobiliary system
Ind.: vincristine: leukemias, Hodgkin, non-Hodgkin lymphoma, solid tumors
(((vinblastine: non-Hodgkin, Hodgkin, chronic lymphoid leukemia
vinorelbin: NSCLS, breast cc)))
SE:
- vomiting
- bone marrow suppression
- alopecia
- hyperurikemia
- neurotoxicty - vincristin
- potent vesicant!
docetaxel
Mitotic inhibitors
TAXANES (Paclitaxel)
- Microtubule-stabilizing, abnormal microtubules
- Taxanes prevent microtubule disassembly
MOA:
- high-affinity binding to microtubules -> tubulin polymerization up/increase++
- inhibition of mitosis and cell division
Resistance: MDR
(- Cabazitaxel in resistant cases!)
Pk:
- metabolized extensively by CYP
- nearly 80% of the drug is excreted via hepatobiliary route
Ind.:
- broad range of solid tumors 1. ovarian,
2. advanced breast,
3. NSCLC and
4. small cell lung cancer (SCLC),
5. head and neck,
6. esophageal,
7. prostate, and
8. bladder cancers and
9. AIDS-related Kaposi’s sarcoma)
SE:
((Paclitaxel:
- acute hypersensitivity reaction
- albumin-bound paclitaxel formulation))
- myelotoxicity,
- cardiotoxicity,
- neuropathy,
- liver toxicity
- docetaxel - neutropenia
renal toxicity
Cisplatin, Methotrexate
pulmonary toxicity
Bleomycin, (Busulfan, procarbazine)
Cardiac toxicity
Doxorubicin, (daunorubicin)
Immunosuppressive
Cyclophosphamide, MTX
other toxicities
hemorrhagic cystitis - Cyclophosphamide
leukemia - procarbazin
pancreatitis - (Asparaginase)
- rapidly proliferating cells like: BM, GI mucosa, hair follicles, gonads are the most sensitive to cytotoxic drugs
- most often BM suppression is dose-limiting
- Anticancer drugs dosage is usually carefully titrated to avoid excessive neutropenia and thrombocytopenia
- colony stimulating factors, EPO and Thrombopoetin can be supportive- reduce risk of infection and need for antibiotic
Log-Kill hypothesis
Cytotoxic drugs act with first-order kinetics → a given dose kills constant proportion (%) of cell population rather than a constant number of cells.
A key principle that stems from this finding and that is applicable to hematologic malignancies is an inverse relationship between tumor cell number and curability (tumor cell number ↑ —> curability ↓).
Growth fraction
Cytotoxic drugs are more effective against tumors that have a high growth fraction (large percentage of cells are actively dividing).
Normal tissues with high growth fraction (ex. bone marrow, hair, GI mucosa) are also more sensitive to anticancer drugs → side effects.
Cell cycle kinetic specificity
˃ Cell cycle-specific (CCS) drugs
Act specifically on phases of the cell cycle, more effective in tumors with high-growth fraction (leukemias, lymphomas)
˃ Cell cycle-nonspecific (CCNS) drugs
Act independently of the phase of cell cycle (including G0 cells), can be used in tumors with low-growth fraction, as well as tumors with high- growth fraction
Mechanisms of resistance to anticancer drugs
˃ Increased DNA repair in tumor cells ˃ Formation of trapping agents ˃ Changes in target enzymes ˃ Decreased activation of prodrugs ˃ Inactivation of anticancer drugs ˃ Decreased drug accumulation (P-glycoprotein ATP-dependent efflux pump)
Strategies in cancer chemotherapy
Administered in repeated cycles, separated by constant intervals.
Intervals permit the regeneration of organs whose function depends on rapid cell renewal (GI mucosa, bone marrow regeneration).
˃ Primary induction chemotherapy
Drug therapy as the primary treatment – hematological malignancies, or solid tumors with no alternative treatment options. Combination-drug chemotherapy regimens reduce the chance of drug resistance.
Each drug is chosen to have a different cellular site of action or different cell-cycle specificity, as well as different organ toxicity.
˃ Neoadjuvant chemotherapy
Administration of therapeutic agents before the main treatment;
goal is to render the local therapy (ex. resection, radiation) more effective.
˃ Adjuvant chemotherapy
Chemotherapy as adjuvant to local treatment procedures (resection, radiation); goal is to reduce the risk of local and/or systemic reoccurrence.
˃ Palliative chemotherapy
Initial remissions are transient, with symptoms recurring between treatments. Survival is extended, but the patient eventually dies of the disease.
Agents co-administered with cancer chemotherapy
Goal is to limit side effects, mainly myelosuppression, and prevent further complications – new infections, reactivation of latent infections.
Drugs enhancing bone marrow regeneration can also be given prophylactically (increasing cell counts prior to administration of the chemotherapeutic agent).
˃ EPO → enhances erythrocytes regeneration
˃ TPO → enhances platelets regeneration
˃ G-CSF, GM-CSF → enhances leukocytes regeneration
˃ Antibiotics, antivirals → infections treatment and/or prophylaxis
˃ Corticosteroids
˃ Antiemetic agents
cell cycle specific agents
alkylating agents: Bleomycin CCS (G2 phase)
antimetabolites Flourouracil (FU-5) CCS (S phase) Methotrexate CCS (S phase) 6-Mercaptopurine CCS (S phase) Cytarabine CCS (S phase) Capecitabine CCS (S phase) Pemetrexed CCS (S phase)
Microtubules inhibitors – Mitotic spindle inhibitors
Vincristine Vinblastine CCS (M-phase)
Docetaxel Paclitaxel CCS (M-phase)
Topoisomerase inhibitors
Etoposide Teniposide CCS (late S phase, early G2 phase)
Irinotecan CCS (S phase)
cell cycle non-specific agents
alkylating agents: Cyclophosphamide Cisplatin Oxaliplatin Dacarbazine Temozolomide Dactinomycin
Topoisomerase inhibitors Doxorubicin Daunorubicin (anthracyclines)
