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Cancer Chemotherapy
Jillian H. Davis
Department of Pharmacology
Howard University
Cell Cycle
Cell Cycle Specific Agents
• Antimetabolites
• Bleomycin
• Podophyllin Alkaloids
• Plant Alkaloids
Cell Cycle Non-Specific Agents
• Alkylating Agents
• Antibiotics
•Cisplatin
• Nitrosoureas
Resistance to Cytotoxic Drugs
Increased expression of MDR-1 gene for a cell surface glycoprotein, P-glycoprotein
MDR-1 gene is involved with drug efflux Drugs that reverse multidrug resistance include
verapamil, quinidine, and cyclosporine MDR increases resistance to natural drug products
including the anthracyclines, vinca alkaloids, and epipodophyllotoxins
Schematic of P-glycoprotein
Alkylating Agents
Nitrogen Mustards Ethylenimines NitrosoureasAlkyl Sulfonates
Cyclophosphamide Thiotepa Busulfan Carmustine
Legend
Drug Class
Sub-class
Prototype Drug
Alkylating AgentsMechanism of Action
Alkylate within DNA at the N7 position of guanine
Resulting in miscoding through abnormal base-pairing with thymine or in depurination by excision of guanine residues, leading to strand breakage
Cross-linking of DNA and ring cleavage may also occur
Alkylating AgentsMechanism of Action
Nitrogen Mustards
Cyclophosphamide Ifosfamide Mechlorethamine Melphalan Chlorambucil
Cyclophosphamide Metabolism
Nitrosoureas
Carmustine Lomustine Semustine Streptozocin-naturally occuring sugar
containing
M.O.A.- cross-link through alkylation of DNA
All cross the blood brain barrier
Alkylating-Related Agents
Procarbazine Dacarbazine Altretamine Cisplatin Carboplatin
Platinum Coordination Complexes
These compounds alkylate N7 of guanine. They cause nephro- and ototoxicity. To counteract the effects of nephrotoxicity, give mannitol as an osmotic diuretic, or induce chloride diuresis with 0.1% NaCl.
Alkylating AgentsToxicity
Bone marrow depression, with leukopenia and thrombocytopenia
Cyclophosphamide/Ifosfamide - hemorrhagic cystitis Reduced by coadministration with MESNA
Cisplatin/Carboplatin - ototoxic and nephrotoxic Nephrotoxicity reduced by chloride diuresis and hydration
Alkylating AgentsTherapeutic Uses
Used to treat a wide variety of hematologic and solid tumors
Thiotepa – ovarian cancer Busulfan – chronic myeloid leukemia Nitrosoureas - brain tumors Streptozocin – insulin-secreting islet cell
carcinoma of the pancreas
Antimetabolites
Folic Acid Analogs Purine Analogs Pyrimidine Analogs
Methotrexate Mercaptoguanine Fluorouracil
LegendDrug ClassSub-classPrototype Drug
Folic Acid Analogs
Methotrexate Trimetrexate Pemetrexed
Folate
An essential dietary factor, from which THF cofactors are formed which provide single carbon groups for the synthesis of precursors of DNA and RNA
To function as a cofactor folate must be reduced by DHFR to THF
MethotrexateMechanism of Action
The enzyme DHFR is the 1º site of action MTX prevents the formation of THF, causing
an intracellular deficiency of folate coenzymes and accumulation of the toxic inhibitory substrate, DHF polyglutamate
The one carbon transfer reactions for purine and thymidylate synthesis cease, interrupting DNA and RNA synthesis
Major Enzymatic Reactions Requiring Folates as Substrates*
GARGAR transformylase
AICAR IMPAMP
GMP
AICAR transformylase
10-formylTHF
Formate+
THF
(3)
DHF b
e
5,10-CH2THF 5-CH3THFc
Methionine
Homocysteine
d
(2)
dUMP
dTMP
DNAa
(1)
a,thymidylate synthase; b, dihydrofolate reductase; c, methylenetetrahydrofolate reductase; d, methionine synthase; e, serine hydroxymethyl transferase
*from Bowen
Resistance
MethotrexateMechanism of Resistance
1. Decreased drug transport
2. Altered DHFR
3. Decreased polyglutamate formation
4. Increased levels of DHFR
Methotrexate Therapeutic Uses
Methotrexate- psoriasis, rheumatoid arthritis, acute lymphoblastic leukemia, meningeal leukemia, choriocarcinoma, osteosarcoma, mycosis fungoides, Burkitt’s and non-Hodgkin’s lymphomas, cancers of the breast, head and neck, ovary, and bladder
Trimetrexate Therapeutic Uses
Trimetrexate- Pneumocystis carinii pneumonia, metastatic colorectal carcinoma, head and neck carcinoma, pancreatic carcinoma, non-small cell carcinoma of the lung
Pemetrexed Therapeutic Uses
Pemetrexed- Mesothelioma
MethotrexateToxicity
Bone marrow suppressionRescue with leucovorin (folinic acid)
Nephrotoxic give sodium bicarbonate to alkalinize the
urine
Purine Antagonists
Mercaptopurine Thioguanine Fludarabine Phosphate Cladribine
Mercaptopurine/Thioguanine
Must metabolized by HGPRT to the nucleotide form
This form inhibits numerous enzymes of purine nucleotide interconversion
Fludarabine Phosphate
M.O.A.- phosphorylated intracellularly by deoxycytidine kinase to the triphosphate form
The metabolite inhibits DNA polymerase-α and ribonucleotide reductase
Induces apoptosis Tx- non-Hodgkin’s lymphoma and chronic
lymphocytic leukemia
Cladribine
M.O.A. -phosphorylated by deoxycytidine kinase and is incorporated into DNA
Causes DNA strand breaks Tx- hairy cell leukemia, chronic
lymphocytic leukemia, and non-Hodgkin’s lymphoma
Pyrimidine Antagonists
Fluorouracil - S-phase Cytarabine Gemcitabine Capecitabine
Figure 2. This figure illustrates the effects of MTX and 5-FU on the biochemical pathway for reduced folates.
X
X5-FU
MTX
Mechanism of Action 5-FU
5-FU inhibits thymidylate synthase therefore causing depletion of Thymidylate
5-FU is incorporated into DNA
5-FU inhibits RNA processing
Activation of 5-FU
Therapeutic Uses of 5-FU
Metastatic carcinomas of the breast and the GI tract
hepatoma carcinomas of the ovary, cervix, urinary
bladder, prostate, pancreas, and oropharyngeal areas
Combined with levamisole for Tx of colon cancer
Cytarabine It is activated to 5’ monophosphate (AraCMP) by
deoxycytidine kinase Through a series of reactions it forms the
diphosphate (AraCDP) and triphosphate (AraCTP) nucleotides
Accumulation of AraCTP potently inhibits DNA synthesis
Inhibition of DNA synthesis is due to competitive (-) of polymerases and interference of chain elongation
Cytarabine
It is a potent inducer of tumor cell differentiation
Fragmentation of DNA and evidence of apoptosis is noticed in treated cells
AraC is cell-cycle specific agent, it kills cells in the S-phase
Cytarabine Mechanisms of Resistance deficiency of deoxycytidine kinase increased CTP synthase activity increased cytidine deaminase activity decreased affinity of DNA polymerase for
AraCTP decrease ability of the cell to transport
AraC
Cytarabine Therapeutic Uses
Induction of remissions in acute leukemia Treats meningeal leukemia Treatment of acute nonlymphocytic
leukemia In combination with anthracyclines or
mitoxantrone it can treat non-Hodgkin’s lymphomas
Cytarabine Toxicities
Nausea acute myelosuppression stomatitis alopecia
Gemcitabine
Gemcitabine is S-phase specific it is a deoxycytidine antimetabolite it undergoes intracellular conversion to
gemcitabine monophosphate via the enzyme deoxycytidine kinase
it is subsequently phosphorylated to gemcitabine diphosphate and gemcitabine triphosphate
Gemcitabine
Gemcitabine triphosphate competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA strands
do to an addition of a base pair before DNA polymerase is stopped, Gemcitabine inhibits both DNA replication and repair
Gemcitabine-induced cell death has characteristics of apoptosis
GemcitabineTherapeutic Uses
Gemcitabine treats a variety of solid tumors
very effective in the treatment of pancreatic cancer
small cell lung cancer carcinoma of the bladder, breast, kidney,
ovary, and head and neck
Cancer Chemotherapy
Jillian H. Davis
Department of Pharmacology
Howard University
Plant Alkaloids
Vinca Alkaloids Podophyllotoxins Camptothecins Taxanes
Vinblastine Etoposide Topotecan Paclitaxel
Vinca Alkaloids
Vinblastine Vincristine Vinorelbine
Vinca Alkaloids
3
3
Inhibit microtubules (spindle), causing metaphase cell arrestin M phase.
Vinca AlkaloidsMechanism of Action
Binds to the microtubular protein tubulin in a dimeric form
The drug-tubulin complex adds to the forming end of the microtubules to terminate assembly
Depolymerization of the microtubules occurs Resulting in mitotic arrest at metaphase,
dissolution of the mitotic spindle, and interference with chromosome segregation
CCS agents- M phase
VinblastineToxicity
Nausea Vomiting Marrow depression Alopecia
VinblastineTherapeutic Uses
Systemic Hodgkin’s disease Lymphomas
VincristineToxicity
Muscle weakness Peripheral neuritis
VincristineTherapeutic Uses
With prednisone for remission of Acute Leukemia
VinorelbineToxicity
Granulocytopenia
Therapeutic Uses
non-small cell lung cancer
Podophyllotoxins
Etoposide (VP-16) Teniposide (VM-26)
Semi-synthetic derivatives of podophyllotoxin extracted from the root of the mayapple
PodophyllotoxinsMechanism of Action
Blocks cells in the late S-G2 phase of the cell cycle through inhibition of topoisomerase II
Resulting in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme
PodophyllotoxinsToxicity
Nausea Vomiting Alopecia Hematopoietic and lymphoid toxicity
PodophyllotoxinsTherapeutic Uses
Monocytic Leukemia Testicular cancer Oat cell carcinoma of the lung
Camptothecins
Topotecan Irinotecan
CamptothecinsMechanism of Action
Interfere with the activity of Topoisomerase I Resulting in DNA damage
Irinotecan- a prodrug that is metabolized to an active Top I inhibitor, SN-38
CamptothecinsToxicity
TopotecanNeutropenia, thrombocytopenia, anemia
IrinotecanSevere diarrhea, myelosuppression
CamptothecinsTherapeutic Uses
Topotecan- metastatic ovarian cancer (cisplatin-resistant)
Irinotecan- colon and rectal cancer
Taxanes
Paclitaxel (Taxol) Docetaxel
Alkaloid esters derived from the Western and European Yew
TaxanesMechanism of Action
Mitotic “spindle poison” through the enhancement of tubulin polymerization
TaxanesToxicity
PaclitaxelNeutropenia, thrombocytopeniaPeripheral neuropathy
DocetaxelBone marrow suppressionNeurotoxicityFluid retention
TaxanesTherapeutic Uses
Paclitaxel- ovarian and advanced breast cancer
Docetaxel- advanced breast cancer
Antibiotics
Anthracyclines- Doxorubicin & Daunorubicin Dactinomycin Plicamycin Mitomycin Bleomycin
Anthracyclines
Doxorubicin Daunorubicin
AnthracyclinesMechanism of Action
High-affinity binding to DNA through intercalation, resulting in blockade of DNA and RNA synthesis
DNA strand scission via effects on Top II Binding to membranes altering fluidity Generation of the semiquinone free radical
and oxygen radicals
AnthracyclinesToxicity
Bone marrow depression Total alopecia Cardiac toxicity
AnthracyclinesTherapeutic Uses
Doxorubicin- carcinomas of the breast, endometrium, ovary, testicle, thyroid, and lung, Ewing’s sarcoma, and osteosarcoma
Daunorubicin- acute leukemia
DactinomycinMechanism of Action
Binds to double stranded DNA through intercalation between adjacent guanine-cytosine base pairs
Inhibits all forms of DNA-dependent RNA synthesis
DactinomycinToxicity
Bone marrow depression Oral ulcers Skin eruptions Immunosuppression
DactinomycinTherapeutic Uses
Wilms’ tumors Gestational choriocarinoma with MTX
PlicamycinMechanism of Action
Binds to DNA through an antibiotic-Mg2+
complex This interaction interrupts DNA-directed
RNA synthesis
PlicamycinToxicity
Hypocalcemia Bleeding disorders Liver toxicity
PlicamycinTherapeutic Uses
Testicular cancer Hypercalcemia
Mitomycin Mechanism of Action
Bioreductive alkylating agent that undergoes metabolic reductive activation through an enzyme-mediated reduction to generate an alkylating agent that cross-links DNA
MitomycinToxicity
Severe myelosuppression Renal toxicity Interstitial pneumonitis
MitomycinTherapeutic Uses
Squamous cell carcinoma of the cervix Adenocarcinomas of the stomach,
pancreas, and lung 2nd line in metastatic colon cancer
Bleomycin
Acts through binding to DNA, which results in single and double strand breaks following free radical formation and inhibition of DNA synthesis
The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations
CCS drug that causes accumulation of cells in G2
BleomycinToxicity
Lethal anaphylactoid reactions Blistering Pulmonary fibrosis
BleomycinTherapeutic Uses
Testicular cancer Squamous cell carcinomas of the head
and neck, cervix, skin, penis, and rectum Lymphomas Intracavitary therapy in ovarian and breast
cancers
Hormonal Agents
Estrogen & Androgen Inhibitors
Gonadotropin-ReleasingHormone Agonists
Aromatase Inhibitors
Tamoxifen Leuprolide Aminogluthethimide
LegendDrug ClassSub-classPrototype Drug
Anti-Estrogens
Tamoxifen (SERMs) Raloxifene (SERMs) Faslodex
Tamoxifen Selective estrogen receptor modulator (SERM), have both
estrogenic and antiestrogenic effects on various tissues Binds to estrogen receptors (ER) and induces conformational
changes in the receptor Has antiestrogenic effects on breast tissue. The ability to produce both estrogenic and antiestrogenic
affects is most likely due to the interaction with other coactivators or corepressors in the tissue and the binding with different estrogen receptors, ER and ER
Subsequent to tamoxifen ER binding, the expression of estrogen dependent genes is blocked or altered
Resulting in decreased estrogen response. Most of tamoxifen’s affects occur in the G1 phase of the cell
cycle
TamoxifenToxicity
Hot flashes Fluid retention nausea
TamoxifenTherapeutic Uses
Tamoxifen can be used as primary therapy for metastatic breast cancer in both men and postmenopausal women
Patients with estrogen-receptor (ER) positive tumors are more likely to respond to tamoxifen therapy, while the use of tamoxifen in women with ER negative tumors is still investigational
When used prophylatically, tamoxifen has been shown to decrease the incidence of breast cancer in women who are at high risk for developing the disease
Anti-Androgen
FlutamideAntagonizes androgenic effectsapproved for the treatment of prostate cancer
Gonadotropoin-Releasing Hormone Agonists
Leuprolide Goserelin
Gonadotropoin-Releasing Hormone Agonist
Mechanism of Action Agents act as GnRH agonist, with
paradoxic effects on the pituitary Initially stimulating the release of FSH and
LH, followed by inhibition of the release of these hormones
Resulting in reduced testicular androgen synthesis
Gonadotropoin-Releasing Hormone Agonist
Toxicity
Gynecomastia Edema thromboembolism
Gonadotropoin-Releasing Hormone Agonist
Therapeutic Uses
Metastatic carcinoma of the prostate Hormone receptor-positive breast cancer
Aromatase Inhibitors
Aminogluthethimide Anastrozole
AminogluthethimideMechanism of Action
Inhibitor of adrenal steroid synthesis at the first step, conversion of cholesterol of pregnenolone
Inhibits the extra-adrenal synthesis of estrone and estradiol
Inhibits the enzyme aromatase that converts androstenedione to estrone
AminogluthethimideToxicity
Dizziness Lethargy Visual blurring Rash
Therapeutic Uses
ER- and PR-positive metastatic breast cancer
Anastrozole
A new selective nonsteroidal inhibitor of aromatase
Treats advanced estrogen and progesterone receptor positive breast cancer that is no longer responsive to tamoxifen
Miscellaneous AntiCancer Agents
Asparaginase Hydroxurea Mitoxantrone Mitotane Retinoic Acid Derivatives Amifostine
Asparaginase An enzyme isolated from bacteria Causes catabolic depletion of serum
asparagine to aspartic acid and ammonia Resulting in reduced blood glutamine levels
and inhibition of protein synthesis Neoplastic cells require external source of
asparagine Treats childhood acute leukemia Can cause anaphylactic shock
Hydroxyurea
An analog of urea Inhibits the enzyme ribonucleotide reductase Resulting in the depletion of deoxynucleoside
triphosphate pools Thereby inhibiting DNA synthesis S-phase specific agent Treats melanoma and chronic myelogenous
leukemia
Mitoxantrone
Structure resembles the anthracyclines Binds to DNA to produce strand breakage Inhibits DNA and RNA synthesis Treats pediatric and adult acute
myelogenous leukemia, non-Hodgkin’s lymphomas, and breast cancer
Causes cardiac toxicity
Mechanisms & Actions of Useful Chemotherapeutic Drugs in Neoplastic Disease