Cancer Chemotherapy

Cancer Treatment Modalities

Surgery and Radiation _ % cancer patients will be cured by; the rest are cured by chemo

25

Chemotherapy

will result in a cure or prolonged remission in only 10% of patients in selective tumor types

Chemo allows for _ regression of disease systems

temporary

antineoplastic therapy

ant cancer

Cytotoxic drugs

any drugs that has a toxic effect on cells; also kills host cells

Cytostatic

stops proliferation

Therapeutic Index (TI)

tells us how safe a drug is: TI = TD50/ED50

TD50

the toxic dose of a drug for 50% of the population

ED50

he effective dose for 50% of the population

High TI means theres a big

gap between a helpful dose and a harmful

one — the drug is safer

A low TI means the effective and toxic doses

are close — the drug requires careful monitoring

Single agent drug therapy

in the earlier days of chemotherapy development

Combination chemotherapy:

long-term remissions, more effective prevention of resistance, and tolerable side effects with maximal doses

Rationale

use of multiple agents, each with cytotoxic

activity against the targeted tumor type but with different

mechanisms of action, allows maximum cell killing by each

agent

Cells resistant to one agent might still be sensitive to the

other drugs in the regimen: patterns of cross-resistance must

be taken into consideration in

formulating drug combination

High-dose chemotherapy with stem-cell rescue (autologous)

and bone marrow transplant from a compatible donor led to

cures for some patients with acute myelocytic leukemia and chronic myelocytic leukemia

Combined modality chemotherapy

drugs with other cancer treatments (e.g., radiation therapy)

Combination chemotherapy

combining agents with different mechanisms of action, different resistance mechanisms, and different dose limiting toxicities

Neoadjuvant chemotherapy

initial therapy- preoperative: Treatment given as a first step to shrink tumor before the main treatment is given

Reduces the bulk (size) of primary tumors prior to

surgical resection, to make resection possible or less difficult

Often used in patients with __ advanced tumor types

locally

may _ local recurrence

decrease

The initial clinical response of the tumor mass can serve as an

indication of tumor sensitivity to the drugs used; therefore an

indication to

continue/ not continue this chemotherapy after

surgery

Adjuvant chemotherapy

post-operative: Additional cancer treatment

given after the primary treatment to prevent the risk that cancer will

come back

based on

cell kinetic principles

Surgery shifts tumor cell growth from

“plateau phase” into “exponential phase”

Best time to use chemotherapy is early (right after the

surgery) when tumor burden is small and tumor cells that

are present are actively growing in the “exponential phase”

and therefore susceptible to chemotherapy

Palliative therapy

without curative intent, increase life expectancy &

life quality

Supportive therapy

to reduce toxicity, and side affects

Barriers to chemo

Toxicity to normal cells

• Tumor heterogeneity (intrinsic resistance)

• Drug resistance (acquired or endogenous)

• Not all cells in the tumor are replicating at the same time

complications of chemo

Anticancer drugs =

usually selectively toxic to dividing cells- including normal host cells

The epithelium of the gastrointestinal (GI) tract

nausea and vomiting, directly damage the proliferating mucosa of

the GI tract

Bone Marrow

caused by destruction of proliferating

hematopoietic stem cells or progenitor cells; results in a

decrease in all blood elements

GI

Nausea, vomiting, mucositis, GI infections- almost all drugs

hematological

Anemia, leukopenia, thrombocytopenia- almost all drugs

skin

Alopecia, darkening of the skin, nail changes

endocrine

Infertility, irregular periods, amenorrhea- almost all drugs

neurological complications

Peripheral neuropathy, fatigue, loss of interest, confusion-

common with the plant alkaloid vincristine

chemotherapeutic drugs

alkylating agents

drugs that work by directly modifying/damaging DNA. Cell-cycle nonspecific action

Antimetabolites

inhibit DNA synthesis - most effective during S-phase

Vinca alkaloids (inhibitors of mitosis)

prevent cell division by binding to tubulin & preventing formation of mitotic spindles –most effective during M-phase

Antitumor antibiotics

bind DNA to prevent replication or

RNA synthesis

Action sites of chemo drugs

cancer drugs and cell cycle

Alkylating Agents

General Indications

Broad spectrum activity against a range of solid and hematological

malignancies. Typically used in combination regimens

mechanisms of action

covalent DNA binding drugs

adding an _ group to DNA

alkyl

Transfers alkyl group to

nucleophilic sites on DNA, leading to DNA crosslinking or modification — disrupts DNA replication and transcription - Cell cycle non- specific

mechanisms of resistance

increase dna repair; decrease uptake

increase in GST attaches a

protective molecule glutathione. Prevents from damaging DNA.

ex of agents

Platinums

indications

Cancers of testes, ovary, bladder, head and neck, lung

MOA

Covalently binds to DNA bases and disrupts DNA function

• Crosslinks N7 guanine on DNA

MOR

DNA excision repair mechanisms

Platinums

Cisplatin

Broad range activity against solid tumors

• Toxicity– Nephrotoxicity, Ototoxicity

• Synergistic with other classes and used in combination

Carboplatin

Similar spectrum of activity as cisplatin, but with less nephrotoxicity

• Toxicity: Myelosuppression (bone marrow toxicity)

Oxaliplatin

Approved as a 2nd line treatment for metastatic colorectal cancer

• Tumors resistant to cisplatin or carboplatin are not cross-resistant to

oxaliplatin

• Dose limiting toxicity – Neurotoxicity

Antimetabolites

indications

Broad spectrum activity against a range of solid and

hematological malignancies. Typically used in combination

regimens.

dose limiting toxicity

Bone marrow suppression & GI toxicity

MOA

Inhibit nucleotide synthesis

Purine Analogs

Pyrimidine Analogs

Folic Acid Analogs

• Cells in S phase most susceptible

Purine Analogs

MOA

Inhibits synthesis of nucleotides

from purine bases (adenine, guanine)

• Incorporation into DNA and RNA

Inhibits DNA and RNA synthesis

toxicity

Bone marrow suppression

• GI & liver dysfunction

MOR

decreased activity of HGPRT

(hypoxanthine-guanine

phosphoribosyltransferase)

required for metabolic activation

Pyrimidine analogs

MOA

Inhibition of DNA synthesis by

interfering with enzymes involved in

pyrimidine synthesis

5-FU: blocks thymidylate synthase,

gemcitabine: ribonucleotide reductase

Toxicity

5-FU: myelosuppression, skin toxicity, GI

toxicity

MOR

Enzyme (e.g., thymidylate synthase or

ribonucleotide reductase) induction

Thymidylate synthase converts dUMP to dTMP in the process of ___

DNA synthesis

Folic Acid Analogs

MOA of MTX

Competitively inhibits dihydrofolate reductase (DHFR), a key

enzyme in intracellular folate homeostasis, to inhibit the synthesis

of tetrahydrofolate (THF) from folic acid (FA) [FA THF]

MOR

Induction of DHFR through gene amplification/other mechanisms

• Decreased drug transport

• Decreased formation of cytotoxic MTX polyglutamate (key metabolite)

Toxicities

Myelosuppression (bone marrow suppression): DLT

• GI effects (mucositis)

• Hepatic: acute and chronic liver toxicity

• Nephrotoxicity: MTX crystals in acidic urine (to prevent: aggressive

alkalized hydration)

• Dermatologic: skin reactions (dermatitis; photosensitivity)

Leucovorin rescue (antidote for MTX in cancer)

Leucovorin is given to decrease the damage done to normal cells by MTX.

• Usually begins 24 to 36 hrs following MTX infusion

MITOTIC SPINDLE INHIBITORS

AND

TOPOISOMERASE INHIBITORS

Vinca Alkaloids

indications

hematological malignancies, breast &

pediatric cancers

MOA

Binds to tubulin —> Inhibit polymerization

into microtubules, disruption of mitotic

spindle formation

M phase cell cycle arrest

toxicity

Vinblastine-bone marrow suppression

• Vincristine- neurotoxicity

MOR

increased efflux via MDR P-gylcoprotein

(Pgp)

Taxanes

indications

Paclitaxel –

broad spectrum activity

against solid tumors (primarily breast)

Docetaxel

similar activity as paclitaxel

MOA

Mitotic inhibitors

• Prevent microtubule disassembly into tubulin monomers: “frozen Mitosis”

• Stablizes GDP-bound tubulin, inhibition of mitosis and cell division (M phase block).

toxicity

Bone marrow suppression & GI toxicity, neutropenia, peripheral neuropathy

MOR

MDR P-glycoprotein mediated drug efflux

• Tubulin mutations

Targeted therapy for Cancer

cytotoxic chemo

Although these drugs can be effective, side effects limit

their use.

• Lack of selectivity – kill tumor cells, but cause toxicity in

normal (non-tumor) cells as well

Targeted EGFR

EGFR

a transmembrane receptor involved in a cell growth, survival, migration and invasion

EGFR activity and/or expression is

deregulated in human

epithelial tumors

– Gene amplification or

mutations: Head & neck,

lung, breast cancers