ANTINEOPLASTIC AGENTS

BY:Israa Eltayib

Cancer pathogenesis and cancer chemotherapy: general principles• The term cancer refers to a malignant

neoplasm(new growth)• Cancer arises as a result of genetic changes, the

main genetic lesions being :1. Inactivation of tumor suppressor genes(e.g.

p53)2.The activation of oncogenes(mutation of the

normal genes controlling cell division and other processes).

Cancer pathogenesis and cancer chemotherapy: general principles• Cancer cell have four characterstics that

distinguish it from normal cells:1.Uncontrolled proliferation 2.Loss of function because of lack capacity to

differentiate 3.Invasiveness4.ability to metastasise

Cancer pathogenesis and cancer chemotherapy: general principles• Cancer cells have uncontrolled proliferation

because of changes in :1.Growth factor and there receptors 2.Intracellular signalling pathway, particularly

those controlling the cell cycle and apotosis 3.Telomerase expression 4.Tumor related angiogenesis

Cancer pathogenesis and cancer chemotherapy: general principles

• Most anticancer agents are antiproliferative; affecting cell division, most damage the DNA and thereby initiate apoptosis.

• But have no inhibitory effect on invasiveness, loss of differentiation or ability to metastasizes

Cancer cell cycle and anticancer agents

• Some anticancer agents exert their actions on cell undergoing cycling (cell cycle specific [CCS] drugs), and others (cell cycle non specific[CCNS]drugs) kill the tumor in both cycling and resting phase of the cell cycle (although cycling cell are more sensitive).

• CCS drugs are usually most effective when cells are in specific phase of the cell cycle

• Both types of drugs are more effective when a large prpotion of the tumor cells are proliferating

The log kill hypothesis

The log kill hypothesis

Cancers that are very difficult to treat with chemotherapy

• Solid tumors are very difficult to be treated with chemotherapy alone and need other modality of treatment like surgery and/or radiotherapy as opposed to hematological malignancies that shows good response to chemotherapy alone.

• Examples of solid tumors includes :1.Colon and stomach2.Lung3.Late stage breast cancer4.Uterus 5.Pancreatic cancer

Cancers that are very difficult to treat with chemotherapy

• Solid tumors are difficult to be treated with chemotherapy because the growth rate of this tumors falls as the neoplasm grows. This partly because the tumor partially necroses as it outgrows its ability to maintain its blood supply, and partly because not all the cells proliferate continuously.

Cancers that are very difficult to treat with chemotherapy

• Solid tumors cells can be divided in to three compartments

1.Compartment A consists of dividing cells 2.Compartment B consists of resting cells 3.Compartment C consists of cells that are no

longer able to divide but contribute to the volume • Essentially only the cells in compartment A, which

constitute around 5% of solid tumors, are susceptible to the main current cytotoxic drug.

Cancers that are very difficult to treat with chemotherapy

• Compartment C do not constitute any problem, but the existence of compartment B that make the chemotherapy difficult because those cells are not very sensitive to chemotherapy and are liable to re-entre compartment A following chemotherapy.

Toxicity and side Effects of Antineoplastic Agents

• They affect rapidly dividing normal cells and are thus likely to depress bone marrow, impair healing, damage to GI epithelium, and depress growth.

• Virtually all of them cause severe nausea and vomiting which has been affecting the patient compliance to completing a course of chemotherapy.

• Most can cause sterility, hair loss and teratogenicity

Toxicity and side Effects of Antineoplastic Agents

• They can be carcinogenic by themselves in certain circumstances

• Rapid cell destruction also entails extensive purine catabolism, and urate can precipitate in the renal tubules and cause kidney damage.

• some compounds have particular toxic effect that are specific for them.

Resistance to chemotherapyResistance to chemotherapy may develop by several

mechanisms: 1. Decrease in the amount of drug uptake by cancer cell

e.g. Methotrexate2. Increase in the amount of drug removed by cancer

cells. (Transporters=P-glycoprotein).e.g. Vinblastine ,doxorubicin, bleomycin

3. Decrease or alteration in target molecule sensitivity – this is caused by mutation in the molecule targeted by the drug e.g.Methotrexate,Mercaptopurine.

4. Increase in DNA repair ability of the cell via an increased expression of DNA repairing enzymes.e.g. Alkylating agent

Anticancer Drugs

There are two Major Groups of Anticancer Drugs:

1) Cytotoxic Drugs (largest group)• Alkylating agents • Antimetabolites• Antitumor antibiotics• Plant alkaloids• Miscellaneous cytotoxic drugs

Anticancer Drugs

2) Hormones and hormone antagonists These are among the best-tolerated

chemotherapeutics because they target specific receptors, and thus only specific cell types e.g. Tamoxifen

Cell cycle Scientists have determined that cell

cycle can be divided into:. Gap 0 (G0): There are times when a

cell will leave the cycle and quit dividing. This may be a temporary resting period or more permanent. An example of the latter is a cell that has reached an end stage of development and will no longer divide (e.g. neuron).

Gap 1 (G1): Cells increase in size in Gap 1, produce enzymes needed for DNA synthesis

S Phase: To produce two similar daughter cells, the complete DNA instructions in the cell must be duplicated. DNA replication occurs during this S (synthesis) phase.

Gap 2 (G2): It is the gap between DNA synthesis and mitosis, the cell will continue to grow and produce new proteins & RNA.

Mitosis or M Phase: Cell growth and protein production stop at this stage

in the cell cycle. All of the cell's energy is focused on the complex

and orderly division into two similar daughter cells .

CYTOTOXIC DRUGS

I-Alkylating Agents• used in cancer treatment that attaches an alkyl group

(CnH2n+1) to DNA.• The alkyl group is attached to the guanine base of DNA,

at the number 7 nitrogen atom of the purine ring.• Since cancer cells, in general, proliferate faster and with

less error-correcting than healthy cells, cancer cells are more sensitive to DNA damage — such as being alkylated.

• Alkylating agents are used to treat several cancers.

I-Alkylating Agents

• However, they are also toxic to normal cells (cytotoxic), leading to damage, in particular in cells that divide frequently, as those in the gastrointestinal tract, bone marrow, testicles and ovaries, which can cause loss of fertility. Most of the alkylating agents are also carcinogenic.

• Hyperthermia is especially effective at enhancing the effects of alkylating agents

Mechanism of action

• Dialkylating agents can react with two different 7-N-guanine residues, and, if these are in different strands of DNA, the result is cross-linkage of the DNA strands, which prevents uncoiling of the DNA double helix.

• If the two guanine residues are in the same strand, the result is called limpet attachment of the drug molecule to the DNA.

• Busulfan is an example of a dialkylating agen

Mechanism of action

• Monoalkylating agents can react only with one 7-N of guanine.

• Limpet attachment and monoalkylation do not prevent the separation of the two DNA strands of the double helix but do prevent vital DNA-processing enzymes from accessing the DNA. The final result is inhibition of cell growth or stimulation of apoptosis, cell suicide.

I-Alkylating Agents

Subgroups of Alkylating Agents1. Nitrogen mustards2. Nitrosoureas3. Alkyl sulfonates 4. Platinum Coordination Compounds

1-Nitrogen Mustardsa- Cyclophosphomide

• The most commonly used alkylating agent.• It is inactive until metabolized in the liver to give

aldophophamide, which is then converted to phosphormide mustard and acrolein (which cause bladder damage that can be ameliorated by Mensa or N-acetylcystiene).

• It has a profound effect on lymphocytes ,so it can be used as immune -suppressant

• Imporatant toxic effect include nausea, bone marrow suppression and hemorrhagic cystitis

Cyclophosphomide

1-Nitrogen Mustards b- Estramustine

• Is combination of chlormethine (mustine) with an estrogen

• It has both cytotoxic effect and hormonal action, and generally used for treatment of prostatic cancer

• other nitrogen mustard include Melphalan and chlorambucil.

2-Nitrosoureas

• Example of this group include carmustine and lomustine

• They can cross the blood brain barrier ,so they can be used for brain and meningeal tumors

• Most nitrosoureas have a severe cumulative depressive effect on the bone marrow that start 3-6 weeks after initiation of treatment

3-Busulfan

• It has selective action on the bone marrow, depressing the formation of granulocyte and platelets in low dosage and RBCs in higher dosage.

• It has little effect on lymphoid tissues or the gastrointestinal tract.

• It is used in chronic granulocytic leukemia.

4-Platinum compoundsCisplatin

• Forms crosslinks within DNA strands. • Cis-platin is not really an “alkylating” agent, but

since it operates via the same mechanism as the alkylating agents, it is placed within that group.

• It has revolutionized the treatment of germ cells tumors

• It has low myelotoxicity but causes severe nausea and vomiting (which can be prevented by Ondansetron), and can be nephrotoxic.

• Other adverse effect include tinnitus and hearing loss ,peripheral neuropathy and anaphylactic reaction.

II-Antimetabolites (CCS)• An antimetabolite is a chemical with a similar

structure to a metabolite required for normal biochemical reactions, yet different enough to interfere with the normal functions of cells, including cell division.

• Antimetabolites are used in cancer treatment, as they interfere with DNA production and therefore cell division and the growth of tumors (mainly in S-phase specific).

• They are classified into: 1- Folate antagonists. 2- Purine analogues. 3- Pyrimidine analogues .

1 -Folate antagonists• Methotrexate: inhibits dihydrofolate

reductase, preventing generation of tetrahydrofolate interfering with thymidylate synthesis.

• Methotrexate is taken up in to the folate carrier and, like folate, is converted to the polyglutamate form.

• Normal cells affected by high doses can be “rescued by folinic acids.₺

• Unwanted effects are mylosupression and possible nephrotoxicity.

1 -Folate antagonists

2- Purine analogues Mercaptopurine

• It is a purine analogue and once enter the cell, it is converted to 6-MP-ribosephophate and can be incorporated into RNA&DNA resulting in non functioning RNA & DNA &finally inducing cell cycle arrest and apoptosis.

2- Purine analogues • Azathioprine: non-enzymatically cleaved to 6 -

M P that acts as a purine analogue and inhibits DNA synthesis

• Fludarabine: in its triphosphate form inhibits DNA polymerase and is myelosuppressive.

• Penostatin: inhibits adenosin deaminase- a critical pathway in purine metabolism

3 -Pyrimidine analogues

• 5-flurouracil (5-FU):It act as a uracil analogue, it is transformed inside the cell into 5-FU deoxynucleotide which compete with deoxyuridine DUMP for thymidylate synthase leading to inhibition of dthymidine monophosphate DTMP synthesis inhibition of DNA synthesis

• Cytarabine: In its triphosphate form inhibits DNA polymerase.

• They are potent myelosupressive.

5-flurouracil (5-FU)

Cytarabine

III-Antitumor antibiotics (CCNS)

• This is a widely used group of drugs that mainly produce their effects through direct action on DNA.

• As a rule, they should not be given together with radiotherapy, as the cumulative burden of toxicity is very high.

III-Antitumor antibiotics• 1-Doxorubicin: Inhibits DNA and RNA synthesis;

the DNA effect is mainly through interference with topoisomerase II action. Unwanted effects include nausea, vomiting, myelosuppression and hair loss.It is cardiotoxic in high doses.

• 2-Dactinomycin: It inhibits transcription by binding to DNA at the transcription initiation complex and preventing elongation by RNA polymerase,it can also interfere with DNA replication.

III-Antitumor antibiotics• 3-Bleomycin: Causes fragmentation of DNA

chains. It acts on non-dividing cells. Unwanted effects include fever, allergies, mucocutanous reactions and pulmonary fibrosis,there is virtually no myelosuppression .

• 4-Mitomycin: Is activated to give an alkylating metabolite ,it can cause Lung fibrosis may occur. If these lung problems do occur, corticosteroids may provide effective therapy.

IV-Plant alkaloids (Phase specific) 1-The vinca alkaloids

• Vincristine & vinblastine (M-phase): Vincristine binds to tubulin inhibiting polymerization of microtubule structures. Disruption of the microtubules arrests mitosis in metaphase. The vinca alkaloids therefore affect all rapidly dividing cell types including cancer cells, but also intestinal epithelium and bone marrow.

IV-Plant alkaloids (Phase specific) 1-The vinca alkaloids

• Vincristine & vinblastine (M-phase): The Vinca alkaloids are relatively non-toxic. Vincristine has very mild myelosupressive activity but cause (sensory changes), abdominal pain and muscle weakness fairly frequently.

• Vinblastine is less neurotoxic but causes leucopenia, while Vindesine has both moderate myelotoxicity and neurotoxicity

• All members of the group can cause reversible

IV-Plant alkaloids (Phase specific) 2-Taxanes

• Paclitaxel & docetaxel: paclitaxel hyper-stabilizes microtubule structure (freez them). Paclitaxel binds to the β subunit of tubulin ,the resulting microtubule/paclitaxel complex does not have the ability to disassemble.

• This adversely affects cell function because the shortening and lengthening of microtubules is necessary for their function

IV-Plant alkaloids (Phase specific) 3-Etoposide

• Chemically it is deriven from podophyllotoxin, a toxin found in the mandrake root.

• An inhibitor of the enzyme topoisomerase II, cause breaks in the DNA inside the cancer cells and prevent them from further dividing and multiplying.

• It also inhibit mitochondrial function .

IV-Plant alkaloids (Phase specific) 4-Campothecins

• Irinotecan: it works by inhibition of topoisomerase II

• It has relatively very few adverse effects.

V-Miscellaneous cytotoxic drugs1-Crisantaspase

• It is a preparation of asparaginase which kills cancer cells by breaking down (L−asparagine) that is necessary for survival and growth of certain tumors e.g. acute lymphoblastic leukemia ALL.

• Fortunately, normal cells are able to synthesize Asparagine .

• The drug has fairly selective action, with very little suppressive effect in bone marrow, GI mucosa and hair follicle.

• It may cause nausea and vomiting and anaphylactic reaction.

V-Miscellaneous cytotoxic drugs2-Mitotan

• Effective in the treatment of adrenocortical carcinoma.

• As a chemical, mitotane resembles the insecticides DDD and DDT, although mitotane does not harm people as these do. Scientists do not understand why, but the drug causes damage to the adrenocortex in such a way as to be helpful for some patients with adrenocortical tumors.

• In addition, mitotane restricts the ability of the gland to produce steroids.

• Rituximab and Alemtuzumab lyse B-lymphocyte and is used for B-cell lymphomas. unwanted adverse effect include fever, chills, hypotension and hypersensitivity reaction.

• Trastuzumab: (Herceptin) targets epidermal growth factor receptor (HER2)and is used for breast cancer

V-Miscellaneous cytotoxic drugs3-Monoclonal antibodies

V-Miscellaneous cytotoxic drugs4-Biological response modifier

• Those are agents that are used to inhance host immune response against cancer cells

• Examples include interferone-α and it is pegylated derivative ) are used in the treatment of solid tumor and lymphoma, and Aldeslukin(recombinant interleukin-2) is used in some cases of renal tumors.tretinoin (a form of vitamin A) is a powerful inducer of differentiation in leukaemic cells and is used as an adjunct to chemotherapy to induce remission

V-Miscellaneous cytotoxic drugs

2 -Hormones and hormone antagonists

I-Glucocorticoids

• Glucocorticoids such as prednisolone and dexamathasone have marked inhibitory effects on lymphocyte proliferation and are used in the treatment of leukaemias and lymphomas.

• Their ability to lower ICP, and to mitigate some of the side effects of anticancer drugs, makes them useful as supportive therapy when treating other cancers, as well as in palliative care.

II-Gonadal hormone antagonistTamoxifen

• Tamoxifen selectively inhibits the effects of estrogen on breast tissue, while selectively mimicking the effects of estrogen on bone (by increasing bone mineral density) and uterine tissues

• Unwanted effects are similar to menopause, potentially more serious are hyperplastic events in the endometrium, which may progress to malginant changes, and the risk of thromboembolism.

III-gonadotrophin-releasing hormome(GnRH)analogs

• Leuprolide, Goserelin, and Nafarelin are GnRH agonist, effective in prostatic carcinoma and premenopausal breast cancer.

• When administered in constant doses so as to maintain stable blood levels, they inhibit release of pituitary luteinizing hormone(LH) and follicle stimulating hormone(FSH).

• Leuprolide can cause bone pain, gynecomastia, impotence and testicular atrophy

IV-Aromatase inhibitors

• Anastrozole and Letrozole inhibit the conversion of androstenedione (androgenic precursor) to estrone (estrogenic precursor).

• both drugs are used in advanced breast cancer.

General approaches to cancer therapy

• Kill or remove malignant cells: cytotoxic drugs, surgery, irradiation, and radioactive agent

• Inactivate components of oncogene signaling pathway: inhibitors of growth factors receptors (e.g. receptors tyrosine kinase)

• Restore function of tumor suppressor : gene therapy

General approaches to cancer therapy

• Employ tissue-specific proliferation inhibitors: estrogen, antiestrogen, androgen, antiandrogen, glucocorticoids and GnRH

• Inhibit tumor growth, invasion, metastasis: inhibitors of angiogenesis.

• Enhance host immune response: cytokine-based therapies ,gene therapy-based approach, cell-based approach

• Reverse drug resistance: inhibitors of multidrug resistance transport.

Good luck