Cancer Chemotherapy

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