DRUGS USED IN THE CHEMOTHERAPY OF NEOPLASTIC DISEASES
Overview
- a neoplasm (“tumor”) is a mass of cells that originate from a single endogenous cell that is dividing independently from the physiological regulatory mechanisms that preserve cellular growth and division
- the independence from these physiological regulatory mechanisms is caused by mutations in genes belonging to 2 broad genetic groups
GENETIC GROUP DESCRIPTION
PROTOONCOGENES - genes that facilitate cellular growth and division
- induce neoplastic transformation upon gain-of- function mutations
TUMOR SUPPRESSOR GENES - genes that moderate cellular growth and division
- induce neoplastic transformation upon loss-of- function mutations
- mutations in multiple genes in both genetic groups are needed for the cell to undergo neoplastic transformation
- there are 2 types of neoplastic diseases
TYPE DESCRIPTION
BENIGN NEOPLASMS - consist of well differentiated cells that are sharply demarcated from the surrounding tissues by a fibrous capsule
MALIGNANT NEOPLASMS - consist of poorly differentiated cells that invade surrounding tissues
- benign neoplasms usually remain localized, thus are treated by surgical excision (or simply left untouched (!))
- on the other hand, malignant neoplasms may invade distant tissues by hematogenous spread
(“metastasis”), thus are treated by a combination of surgical excision, irradiation and drugs
(“chemotherapeutic agents”, see below)
ALKYLATING AGENTS
Overview
- alkylating agents are electron-poor (“electrophilic”) molecules that spontaneously form
covalent bonds with electron-rich (“nucleophilic”) molecules upon encounter
- the alkylating agents used in treatment of neoplastic diseases have 2 electrophilic domains
(“bifunctional alkylating agents”), thus have the ability to form covalent bonds with 2 nucleophilic molecules simultaneously
- upon encounter with DNA, the bifunctional alkylating agents form covalent bonds between the nucleophilic domains of guanine nucleotides, thus forming intrachain- and interchain
cross-linkages of the DNA
- this causes inhibition of replication as well as inhibition of transcription of the affected cells
- the nucleophilic domains of the guanine nucleotides are only exposed when the complement DNA strands are unwound during replication, thus alkylating agents are relatively specific for the highly mitotic cells of neoplasms
- though this renders most of the physiological tissues of the body refractory to the alkylating
agents, it also renders the less active cells of the neoplasms less susceptible
- , thus reoccurrence of the neoplasms are frequent upon increased mitotic activity of these
unaffected neoplastic cells
- also, due to the alkylating agents primarily affecting highly mitotic cells, the physiologic
tissues of the body with a high cell turnover are heavily affected, including
TISSUE SIDE EFFECT
HAIR - alopecia (“hair loss”)
GI TRACT - mucosal ulcerations
epigastric pain (due to mucosal ulceration)
- nausea and vomiting (due to mucosal ulceration) GONADS - sterility (primarily in males)
MUSCLE AND BONE - growth inhibition (in children and teenagers)
BONE MARROW - pancytopenia (anemia, leucopenia and thrombocytopenia)
- secondary microbial infections (due to leucopenia)
- impaired wound healing (due to leucopenia)
- hemorrhagic diathesis (due to thrombocytopenia)
- finally, due to the alkylating agents acting on DNA, the alkylating agents may also cause additional mutations in apparently healthy cells, and following secondary neoplasms (paradoxically (!))
Relevant Drugs
- 5 categories
- related to sulfur mustard (“mustard gas”, a chemical warfare agent)
- 2 types
DRUG NAME DESCRIPTION CYCLOPHOSPHAMIDE General information
- pro-drug
- activated in the liver by the cytochrome
P450 system
- administered orally, intramuscularly and/or
IV
- may not cross the blood-brain barrier
Side effects
- general side effects of alkylating agents
(see above)
- hemorrhagic cystitis
IFOSFAMIDE General information
- same as cyclophosphamide (see above)
2) NITROSUREAS
- 2 types
DRUG NAME DESCRIPTION CARMUSTINE General information
- may cross the blood-brain barrier (, thus is
primarily used against neoplasms of the
CNS)
Side effects
- general side effects of alkylating agents (see above)
LOMUSTINE General information
- same as carmustine (see above)
3) TRIAZENES
- 1 type
DRUG NAME DESCRIPTION DACARBAZINE General information
- pro-drug
- activated in the liver by the cytochrome
p450 system
- administered orally and/or IV
Side effects
- general side effects of alkylating agents (see above)
4) ALKYL SULFONATES
- 1 type
DRUG NAME DESCRIPTION BUSULFAN General information
- selectively affects the bone marrow (, thus
is primarily used against neoplasms of the bone marrow)
Side effects
- general side effects of alkylating agents (see above)
5) PLATINUM-CONTAINING COMPOUNDS
- 2 types
DRUG NAME DESCRIPTION CISPLATIN General information
- administered IV
Side effects
- general side effects of alkylating agents (see above)
- tinnitus and/or hearing loss (due to cochlear nerve damage)
- peripheral neuropathies (due to peripheral nerve damage)
- nephrotoxicity
- hypersensitivity reactions leading to fever and/or skin rashes
CARBOPLATIN General information
- same as cisplatin (see above)
ANTIMETABOLITES
Overview
- antimetabolites are structural analogues of substrates needed for the synthesis of the complementary DNA strands during replication
- they competitively inhibit the enzymes that act on these substrates, thus inhibiting the synthesis of the complementary DNA strands and following inhibition of replication
- since replication only occurs preceeding mitosis, antimetabolites are relatively specific for the highly mitotic cells of neoplasms
- due to the same reason, they have the same effect on physiological tissues and less active cells of neoplasms as the alkylating agents (see above)
Relevant Drugs
- 3 categories
1) DIHYDROFOLATE REDUCTASE INHIBITORS
- dihydrofolate reductase inhibitors used in the treatment of neoplastic diseases are structural analogues of folate
- like the dihydrofolate reductase inhibitors used in treatment of bacterial and protozoal infections, the dihydrofolate reductase inhibitors used in the
treatment of neoplastic diseases competitively inhibit dihydrofolate reductase, thus leading to inhibition of conversion of dihydrofolate (“FH2”) to
tetrahydrofolate (“FH4”)
- FH4 is a cofactor of thymidylate synthetase in the conversion of deoxyuridine
monophosphate (“dUMP”) to deoxythymidine monophosphate (“dTMP”, one of the two pyrimidine nucleotides needed for DNA synthesis)
- , thus dihydrofolate reductase inhibitors indirectly inhibit the synthesis of the complementary DNA strands during replication
- 1 type
DRUG NAME DESCRIPTION METHOTREXATE General information
- administered orally, intramuscularly, IV
and/or intrathecally
- may not cross the blood-brain barrier
Side effects
- general side effects of alkylating agents (see above)
- drug-induced pneumonitis
- nephrotoxicity
2) THYMIDYLATE SYNTHETASE INHIBITORS
- thymidylate synthetase inhibitors are structural analogues of deoxyuridine
monophosphate (“dUMP")
- they competitively inhibit thymidylate synthetase, thus inhibiting the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate (“dTMP”)
- , thus thymidylate synthetase inhibitors indirectly inhibit the synthesis of the
complementary DNA strands during replication
- 1 type
DRUG NAME DESCRIPTION FLUOROURACIL General information
- pro-drug
- converted to fluorodeoxyuridine monophosphate (“F-dUMP”) inside the cells
- administered IV
Side effects
- general side effects of alkylating agents (see above)
- motor disturbances (due to cerebellar damage)
3) DNA POLYMERASE INHIBITORS
- DNA polymerase inhibitors are structural analogues of the normal purine- and
pyrimidine nucleotides used by DNA polymerase during synthesis of the complementary DNA strands
- they competitively inhibit DNA polymerase, thus directly inhibiting the synthesis of the complementary DNA strands during replication
- 2 groups
A) PURINE ANALOGUES
- 2 types
DRUG NAME DESCRIPTION FLUDARABINE General information
- adenosine analogue
Side effects
- general side effects of alkylating agents (see above)
CLADRIBINE General information
- same as fludarabine ( see above)
B) PYRIMIDINE ANALOGUES
- 2 types
DRUG NAME DESCRIPTION CYTARABINE General information
- cytosine analogue
Side effects
- general side effects of alkylating agents (see above)
GEMCITABINE General information
- same as cytarabine (see above)
ALKALOIDS
Overview
- alkaloids are naturally occurring, cyclic, nitrogen-containing compounds isolated from plants
- alkaloids used in treatment of neoplastic diseases act on cellular events preceding mitosis, thus are relatively specific for the highly mitotic cells of neoplasms
- due to the same reason, they have the same effect on physiological tissues and less active cells of neoplasms as the alkylating agents (see above)
Relevant Drugs
- 2 categories
1) DNA TOPOISOMERASE INHIBITORS
- like the DNA topoisomerase inhibitors used in treatment of bacterial and
protozoal infections , the DNA topoisomerase inhibitors used in treatment of neoplastic diseases bind to DNA topoisomerase and prevent it from religating the DNA strands after cutting them
- , thus DNA topoisomerase inhibitors used in treatment of neoplastic diseases cause fragmentation of the DNA and following inhibition of mitosis
- 2 groups
A) CAMPOTHECINS
- campothecins are DNA topoisomerase I inhibitors
- they are naturally found in the campotheca tree (“happy tree”)
- 2 types
DRUG NAME DESCRIPTION IRINOTECAN Side effects
- general side effects of alkylating agents (see
above)
TOPOTECAN General information
- same as irinotecan (see above)
B) PODOPHYLLINS- podophyllins are DNA topoisomerase II inhibitors
- they are naturally found in the podophyllium flower (“mayapple flower”)
- 2 types
DRUG NAME DESCRIPTION ETOPOSIDE Side effects
- general side effects of alkylating agents (see
above)
TENIPOSIDE Side effects
- same as etoposide (see above)
2) MICROTUBULE INHIBITORS
- microtubule inhibitors inhibit the function of microtubules, thus inhibiting mitosis
- however, due to inhibition of microtubules, the microtubule inhibitors also inhibit the microtubule-mediated functions of leukocytes and neurons
- 2 groups
A) VINCA ALKALOIDS
- vinca alkaloids bind to depolymerized tubulin, thus inhibiting
polymerization of tubulin into microtubules
- this leads to inhibition of formation of the mitotic spindle during cell
division and following inhibition of mitosis
- they are normally found in the vinca flower (“periwinkle flower”)
- 2 types
DRUG NAME DESCRIPTION VINCRISTINE Side effects
- general side effects of alkylating agents (see
above)
- paresthesia (due to inhibition of axonal transport in neurons)
- asthenia (due to inhibition of axonal transport in neurons)
VINBLASTINE Side effects
- same as vincristine (see above)
B) TAXANES
- taxanes bind to polymerized tubulin (“microtubules”) thus inhibiting their ability to remodel
- this leads to inhibition of separation of the sister chromatides during cell division and following inhibition of mitosis
- they are normally found in the taxus tree (“pacific yew tree”)
- 2 types
DRUG NAME DESCRIPTION PACLITAXEL General information
- administered IV
Side effects
- general side effects of alkylating agents (see above)
- paresthesia (due to inhibition of axonal transport in neurons)
- asthenia (due to inhibition of axonal transport in neurons)
- leg edema (due to fluid retention)
- hypersensitivity reactions leading to fever and/or skin rashes
DOCELATEL General information
- administered orally
Side effects
- same as paclitaxel (see above)
ANTIBIOTICS
Overview
- antibiotics used in the treatment of neoplastic diseases act on cellular events preceeding mitosis, thus are relatively specific for the highly mitotic cells of neoplasms
- due to the same reason, they have the same effect on physiological tissues and less active cells of neoplasms as the alkylating agents (see above)
Relevant Drugs
- 2 categories
1) ANTHRACYCLINES
- anthracyclines are DNA topoisomerase II inhibitors (see 62 and above)
- , thus they cause fragmentation of DNA and following inhibition of mitosis
- 3 types
DRUG NAME DESCRIPTION
DOXYRUBICIN General information
- administered IV
Side effects
- general side effects of alkylating agents (see above)
- cardiac dysrhythmias
- heart failure
IDARUBICIN General information
- same as doxyrubicin (see above)
EPIRUBICIN General information
- same as doxyrubicin (see above)
2) STREPTOMYCES-DERIVED ANTIBIOTICS
- the streptomyces-derived antibiotics are an extremely diverse group of pharmacologically active compounds that have found their use in treatment of neoplastic diseases an well as in treatment of bacterial and fungal infections (aminoglycosides, chloramphenicol and macrolides )
- the streptomyces-derived antibiotics used in treatment of neoplastic diseases
have distinct mechanisms of action from the streptomyces-derived antibiotics used in treatment of bacterial and fungal infection
- the streptomyces-derived antibiotics used in treatment of neoplastic diseases also have distinct mechanisms of action from each other
- , thus these mechanisms will be discussed separately below
- they are naturally found in the streptomyces bacterium
- 3 types
DRUG NAME DESCRIPTION MITOMYCIN General information
- a bifunctional alkylating agent (see above)
- causes intrachain- and interchain cross-linkages
- , thus inhibits DNA replication and translation
- administered orally
Side effects
- general side effects of alkylating agents (see above)
- pulmonary fibrosis
- nephrotoxicity
BLEOMYCIN General information
- forms a pseudo-enzyme by chelation of iron
- the pseudoenzyme generates oxygen free radicals from intracellular oxygen
- the oxygen free radicals cause double-stranded breaks of the DNA and following DNA fragmentation
Side effects
- general side effects of alkylating agents (see above)
- pulmonary fibrosis
- hypersensitivity reactions leading to fever and/or skin rashes (primarily on the palms)
DACTINOMYCIN General information
- interposes between adjacent guanosine-cytosine pairs in the DNA
- the interposition causes an inability of RNA polymerase to move along the DNA during transcription
- , thus transcription and following protein translation is inhibited
Side effects
- general side effects of alkylating agents (see above)
HORMONAL AGENTS
Overview
- unlike the other chemotherapeutic drugs used in the treatment of neoplastic diseases (see
above), the hormonal agents used in the treatment of neoplastic diseases do not act by cytotoxic mechanims
- they are hormone agonists and/or -antagonists acting on normal hormone receptors found in physiological tissues as well as in some neoplasms
- , thus they are only effective against neoplasms that have retained their ability to express these hormone receptors (“hormone-sensitive neoplasms”)
- due to the same reason, they do not have the same general side effects as the other chemotherapeutic agents used in the treatment of neoplastic diseases (see above), but exhibit
the side effects commonly associated by the agonism and/or antagonism of the respective hormone receptors
Relevant Drugs
- 5 categories
1) GLUCOCORTICOIDS
- glucocorticoids act on glucocorticoid receptors found in vascular endothelial cells, mast cells, macrophages and T lymphocytes, thus decreasing the synthesis and secretion of GM-CSF (see 32) by these cells and following decreased proliferation of leucocytes in the bone marrow
- used in the treatment of bone marrow neoplasms
2) PROGESTOGENS
- progestogens act on progestogen receptors found in the uterus, thus
downregulating the oestrogen receptors of the endometrium and following inhibition of the proliferation of the endometrial tissues
- used in the treatment of endometrial neoplams
3) OESTROGEN RECEPTOR ANTAGONISTS
- oestrogen receptor antagonists inhibit the action of oestrogens on oestrogen
receptors found in the mamma, thus inhibiting the proliferation of the mammary tissues
- used in the treatment of mammary neoplasms
4) OESTROGEN SYNTHESIS INHIBITORS
- oestrogen synthesis inhibitors inhibit aromatase (see 55) found in the adrenal
cortex, thus inhibiting the synthesis of oestrogens
- this leads to decreased stimulation of oestrogen receptors found in the
mamma, and following decreased prolifereation of the mammary tissues
- used in the treatment of mammary neoplasms (primarily if postmenopausal)
5) ANDROGEN RECEPTOR ANTAGONISTS
- androgen receptor antagonists inhibit the action of dihydrotestosterone on androgen receptors found in the prostate, thus inhibiting the
proliferation of the prostatic tissues
- used in the treatment of prostatic neoplasms
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