Antineoplastics

Cancer – Definition and General Goal

Cancer presents a special therapeutic problem, since the tissues that must be pharmacologically targeted are self tissues

It is therefore necessary to determine how to:

(1) selectively kill the tumor tissue, and

(2) avoid normal cellular resistance to toxic substances

One significant difference between normal and cancerous tissue is rate of replication, so DNA synthesis is a good target

phase specific – attack DNA synthesis (e.g., mircotubule assembly) – kills replicating cells only

phase non-specific – kills replicating and non-replicating cells
a combination of both is usually used, to maximize killing and minimize potential development of resistance

Tumor Biology – Determinants of Response to Chemotherapy

Large Tumors are Harder To Destroy, for Three Reasons:

(1) Growth Fraction – More Cells Are Replicating in Smaller Tumors

since most anti-neoplastic agents preferentially kill replicating cells, larger tumors are harder to kill

phase specific drugs are not very useful against very large tumors

(2) Blood Supply – Larger Tumors are Not As Well Vascularized

poor blood supply leads to:

(a) diminished delivery of drug, since drugs are carried by the blood

(b) hypoxia, leading to less P-450 function (many drugs are activated by P-450)

(c) smaller growth fraction, so tumor is less sensitive to phase specific drugs

(3) Chemotherapy is a First Order Process – A Certain Fraction of Cancer Cells Are Killed

30 doublings produce clinically detectable cancer, 10 more doublings cause death

doubling time ranges from a few days (most lymphomas) to a few months (colon or lung cancer)
slower cancers are less virulent, but they are also harder to kill (less reaction to phase specific drugs)

because only a fraction is killed at one time, it is seldom possible to completely eradicate the cancer

a "good" chemotherapeutic response is 99% cancer cell death (2 log kill) – this produces remission

only seven doublings are required for the cancer to be as bad as before

Drug Therapy of Neoplasms

Chemotherapy drugs can be used alone (primary) or concurrently with surgery or radiation (adjuvant)

surgery is usually used to make the tumor smaller

radiation is a "specialized" chemotherapy drug that can be specifically targeted to a particular place

Chemotherapy Complications:

(1) Dose Limiting Toxicity – all drugs are dirty, so normal cells are always killed along with cancer cells

this reduces the maximum dose that can be used

phase-specific drugs kill replicating normal cells (bone marrow, GI tract, wound, hair, fetus)
many antineoplastics are mutagenic, and can produce secondary tumors
there are frequently dose-limiting side effects (fibrosis or organ toxicity)

(2) Drug Sanctuaries – some places are inaccessible to drugs due to physical barriers

e.g., CNS or bone marrow

(3) Tumor Size – if tumor is too big, waste products from tumor death can be very toxic

(4) Drug Resistance – can select for resistant cells (see Drug Resistance, next page)

Principles of Aggressive Drug Therapy – 5 Steps to Chemotherapy Success

(1) Use many drugs in combination to kill as much of the cancer as possible

(2) Use combinations of drugs that are synergistic due to biochemical interactions

(3) Use combinations of drugs that have different resistance patterns to minimize development of resistance

(4) Use combinations of drugs that do not overlap in major toxicity to prevent cumulative organ damage

(5) Use the highest dose and frequency possible to prevent resistance and maximize killing

Drug Regimens and Interactions – Two Examples

Hodgekins Lymphoma – Four Drugs (COPP) – different phase specificities and sites of action

(1) Cyclophosphamide (Nitrogen Mustard) – alkylating agent originally used as poison gas in World War I

phase non-specific – affects protein and disrupts transcription

nitrogen linked to b -halo compound Þ strained 3-membered ring – alkylate proteins, crosslinks DNA

requires P-450 activation so can produce toxic alternative metabolites

(2) Oncovin (Vincristine) – affects microtubule synthesis

phase specific

(3) Procarbazine – hydrazine compound – methylates DNA and breaks chromosomal strands

phase non-specific

body normally produces demethylases in response to methylation – resistance develops rapidly

(4) Prednisone – synthetic cortisol (normal hormone in body) – induces apoptosis of lymphocytes/macrophages

phase non-specific – relatively non-toxic, but high doses can cause immunosuppression
moderate doses cause CNS effects (feelings of euphoria and well-being) so often used in hospice care

Breast Cancer – Four Drugs

(1) Cyclophosphamide (see above)

(2) Methotrexate – inhibits dihydrofolate reductase, which is required to produce tetrahydrofolate (THF)

phase specific – THF is used for many one-carbon transfer reactions, principally thymine production

cells still can make RNA, which uses uracil instead of thymine
providing folic acid after lethal dose of methotrexate will rescue slower-replicating (noncancerous) cells

(3) 5-Fluorouracil – competitively inhibits thymidylate synthase

phase specific AND non-specific – disrupts DNA synthesis and RNA transcription
synergistic with methotrexate, since thymidylate synthase requires THF to be activated

(4) Tamoxifen – normal hormone that contacts estrogen receptors (high density in cancerous breast)

phase non-specific

Drug Resistance – Strategies Developed by the Tumor

Avoid the Drug – decreased uptake or increased efflux of drug

Overwhelm the Drug – increase quantity of substance targeted by the drug

Escape the Drug – alter the substance targeted by the drug to reduce affinity

Kill the Drug – increase drug inactivation or decrease its activation

Fool the Drug – produce an alternative drug target to divert it

Undo the Drug – repair cell damage (e.g., demethylation)

All of these are natural processes developed by the body to counteract xenobiotics (from bacteria, etc.)

Example of Multiple Drug Resistance: Methotrexate – tumors can develop methotrexate resistance by:

(1) impairing transport of methotrexate into cell
(2) impairing metabolism (formation of polyglutamate derivitives)
(3) increasing quantity of dihydrofolate reductase
(4) decreasing thymidylate synthase activity, reducing need for THF

New Therapies – The Future of Chemotherapy

(1) Immunostimulation – cytokines or colony stimulating factors to enhance presentation of tumor antigens

enhances T-cell killing of tumor

(2) Antisense Chemotherapy – short RNA oligonucleotide antisense to oncogenes – hard to get into cells

triple helix formation with DNA blocks transcription, duplex formation with RNA prevents translation

(3) Cancer Cell Targeted Toxins – send cell toxin or enzyme to activate prodrug directly to cancer cell

couple to monoclonal antibody directed against cancer cell-specific surface antigen

(4) Promotor-Targeted Drugs

decrease (increase) transcription from promoters of genes activated (repressed) in malignant cells