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Cancer or malignant tumor

Cancer is a disease in which there uncontrolled multiplication and spread within the body of abnormal forms of the body owns cells. The terms cancer and malignant tumor are synonymous, and are distinguished from benign tumors by the properties of uncontrolled proliferation, dedifferentiation, invasiveness and the ability to metastasize (spread to other parts of body).

Properties of cancer cells: uncontrolled proliferation

The proliferation of cancer cells is not controlled by the processes that normally regulate cell division and

tissue growth. In cancer cells, the cell cycle control is

disrupted by (1) abnormal growth factor function and/or (2) abnormal cyclin/cdk function and/or (3)

abnormal DNA synthesis as a result of oncogene

activity and/or (4) abnormal decrease in negative regulatory forces owing to mutation of tumor suppressor genes.

Properties of cancer cells: dedifferentiation and loss of function

The multiplication of normal cells involves division of

the stem cells in a particular tissue to give rise to daughter cells, which eventually differentiate to

become the mature cells of the relevant tissue and

carry out their programmed functions.

Cancer cells loss of the capacity to differentiate. In general, poorly differentiated cancers multiply faster, and have a poorer prognosis than well-differentiated cancers.

Properties of cancer cells: invasiveness

Cancer cells secrete enzymes, e.g. metalloproteinases, that break down the extracellular matrix enabling the cancer cells to slip through. Expansion of the tumour requires the development of new blood vessels - angiogenesis, which occurs in response to vascular growth factors produced by the growing tumor. During angiogenesis, enzymes (e.g. metalloproteinases) break down surrounding tissue -

making space for new blood vessels.

Properties of cancer cells: metastases

These are secondary tumors formed by cells that have been released from the initial or primary tumor and have reached other sites through blood vessels or lymphatics. The aberrant migration of cells would lead to programmed cell death as a result of withdrawal of the necessary anti-apoptotic factors. Cancer cells which have the ability to metastasise, have undergone a series of genetic changes which alter their responses to the regulatory factors that control the tissue siting of normal cells.

The genesis of a cancer cell

A normal cell turns into a cancer cell because of a mutation in its DNA, which can be inherited or acquired. There are two main categories of genetic change which lead to cancer:

the inactivation of tumor suppressor genes the activation of proto-oncogenes to oncogenes

Oncogenes are genes which confer malignancy on a cell. Proto-oncogenes are genes that normally control cell
division and differentiation but which can be converted to oncogenes.

Inactivation of tumor suppressor genes

Normal cells contain genes that have the ability to suppress malignant change termed tumor suppressor genes (antioncogenes). If the DNA is damaged, the protein products of this gene accumulate and arrest DNA replication, allowing time for repair. If the repair fails, gene activity triggers cell suicide by apoptosis (apoptosis - the built-in self-destruct mechanism of the cell, consisting of a genetically programmed sequence of biochemical events leading to cell death). Cells in which suppressor genes are altered by mutation, or by binding to viral or altered host proteins, cannot stop the abnormal DNA replicating.

Activation of proto-oncogenes
The host's genes that control normal growth and differentiation - the 'proto-

oncogenes' - can promote malignancy

when converted into active oncogenes as a result of point mutations, gene amplification or chromosomal translocation, or the action of certain

viruses.
Oncogenes interfere not only with proliferation but also with differentiation - inducing defects in the execution of differentiation programmes. And it may well be that one of the fundamental effects of oncogene products is to interfere with the action of tumour suppressor genes.
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Approaches to treating cancer

Chemotherapy of tumors are necessarily aimed at producing as near a total cell kill as possible

The main approaches:

surgical excision irradiation chemotherapy

Chemotherapy is the main method of treatment for only a few cancers but it is increasingly used as an adjunct to surgery or irradiation for many types of tumor

Other approaches:

immunotherapy gene therapy use of biological response modifiers (e.g. interferons, haemopoietic growth factors, etc.)
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General principles of action of cytotoxic anticancer drugs

Most currently used anticancer drugs, in particular those which are 'cytotoxic', affect only the first of the characteristics of cancer cells outlined previously - the process of cell division, i.e. they are anti-proliferative; they have no specific inhibitory effect on invasiveness, the loss of differentiation or the tendency to metastasize. Because their main effect is on cell division, they will affect all rapidly dividing normal tissues and thus they are likely to produce the general toxic effects (bone marrow toxicity, impaired wound healing, loss of hair (alopecia), damage to gastrointestinal epithelium, depression of growth in children, sterility, teratogenicity, kidney damage, severe nausea and vomiting).

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Cell cycle and tumors

G2 and (mitosis).
G2 M

G0 G1

G1, S (DNA synthesis)

The cells of a solid tumor can be considered as belonging to three compartments: - compartment A - consists of dividing cells, possibly being continuously in cell cycle; - compartment consists of resting cells (in G0 phase) cells which, though not dividing, are potentially able to do so; - compartment consists of cells that are no longer able to divide but which contribute to the tumor volume.

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Actions of anticancer drugs on the cell cycle

Essentially only cells in compartment A, which may

form as little as 5% of some solid tumors, are

susceptible to the main currently available drugs.

The cells in compartment do not constitute a problem - it is the existence of cells in compartment that makes cancer chemotherapy difficult, because these cells are not very sensitive to cytotoxic drugs, but are liable to re-enter compartment A following a

course of chemotherapy.

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Classification of cytotoxic anticancer drugs in terms of actions on the cell cycle

Phase-specific agents - acting at a specific phase of the
cell cycle. The vinca alkaloids act in mitosis. Cytarabine, hydroxyurea, fluorouracil, methotrexate and mercaptopurine act in S phase. Some of these compounds have some action during G1 phase and thus may slow the entry of a cell into S phase, where it would be more susceptible to the drug.

Cycle-specific agents - acting at all stages of the cell cycle

and not having much effect on cells out of cycle: alkylating agents, dactinomycin, doxorubicin and cisplatin

Cycle non-specific agents - acting on cells whether in

cycle or not (phase G0): bleomycins and nitrosoureas

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Actions of anticancer drugs on the cell cycle

Tumors with a high growth fraction should respond to phasespecific and cyclespecific agents

For tumors with a small growth fraction the use of cycle non-specific agents (together with surgery or Xray) could be considered

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Resistance to anticancer drugs

The resistance can be primary (present when the drug is first given) or acquired (developing during treatment with the drug)

The mechanisms of resistance are:

Decreased accumulation of drugs in cells due to the increased expression of a cell surface, drug transport protein, termed Pglycoprotein (doxorubicin, vinblastine, etc.) Insufficient activation of the drug (mercaptopurine, fluorouracil, cytarabine) Increased concentration of target enzyme (methotrexate) Decreased requirement for substrate (L-asparaginase) Increased utilization of alternative metabolic pathways (antimetabolites) Rapid repair of drug-induced lesions (alkylating agents). Altered activity of target, for example modified topoisomerase II (doxorubicin)

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General classification of anticancer drugs

I. Alkylating agents:

Bis(chloroethyl)amines: Sarcolysine (Mephalan), Cyclophosphamide Ethylenimines: Thiotepa Nitrosoureas: Carmustine, Lomustine

Derivatives of alkylsulfonate: Busulfan (myelosanum)

Triazine derivatives: Procarbazine, Dacarbazine Platinum compounds: Cisplatin, Carboplatin

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General classification of anticancer drugs

II. Antimetabolites:

Folate antagonists: Methotrexate Purine analogues: 6-Mercaptopurine, Fludarabine Pyrimidine analogues: 5-Fluorouracil

III. Cytotoxic antibiotics:

Actinomycines: Dactinomycin Antracyclines: Rubomycin, Doxorubicin

Others: Bruneomycine, Mitomycin, Bleomycin

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General classification of anticancer drugs

IV. Plant derivatives: Vinca alkaloids: Vincristine, Vinblastine Taxanes: Paclitaxel, Docetaxel Podophyllotoxins: Teniposide, Etoposide Camptothecins: Topotecan, Irinotecan Alcaloids of Colchicine: Colchamine V. Enzymes: L-Asparaginase

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General classification of anticancer drugs

VI. Hormones and anti-hormones: Androgens: Testosterone, Drostanole Oestrogens: Estradiol, Ethinyloestradiol Progestogens: Progesterone, Medroxiprogesteron Anti-androgens: Flutamide, Cyproterone Anti-oestrogens: Tamoxifen, Toremifene Gonadotropin releasing hormone analogues: Leuprorelin, Goserelin Aromatase inhibitors: Aminoglutethimide, Letrozole Glucocorticoids: Prednisolone, Dexamethasone

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General classification of anticancer drugs

VII. Cytokines: Interferones: Alfa-interferon Interleukins: Aldesleukine VIII. Monoclonal antibodies: Trastuzumab (Herceptin), Rituximab IX. Tyrosin kinase inhibitors Imatinib Gefitinib

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Additional drugs for anticancer therapy

I. Bone marrow growth factors Filgrastim, Molgramostim, Epoetin alfa and beta II. Antiemetics (antivomiting drugs): Ondansetrone, Tropisetrone, Metoclopramide III. Immunomodulators: Interferons, Interleukins, Thymus derivatives, Levamisol IV. Drugs for osteoporosis preventing: Bisphosphonates Alendronate, Etidronate V. Chemoprotectors (cytoprotectors): Cardioprotectors: Dexrazoxane (Cardioxan) Cytoprotectors: Amifostine, Mesna
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New approaches for cancer chemotherapy

Inhibitors of metallo-proteinases These enzymes are involved in both the invasiveness and metastasis of cancer. Marimastat and others are the agents that inhibit these enzymes. Other angiogenesis inhibitors include an analogue of fumagillin (a fungal product), IL-2 and a calciumchannel blocker. Differentiation inductors Agents that can block the proliferation of cancer cells and induce their differentiation

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New approaches for cancer chemotherapy

Oligonucleotides (ONs) Small synthetic segments of single-stranded DNA that are complementary to a portion of the mRNA and which can bind to their corresponding sequence on the mRNA. This now double-stranded section - a hybrid of mRNA and ON DNA - prevents translation of the mRNA and thus blocks expression of the particular oncogene. Agents enhancing the chemo- and radio-sensitivity of tumor cells Anti-metastatics Decrease adhesion of cancer cells in the tissue and prevent metastases formation

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Alkylating agents and related compounds

Alkylating agents have alkyl groups which can form covalent bonds with cell substituents; a carbonium ion is the reactive intermediate. Most have two alkylating groups and can cross-link two nucleophilic sites such as the N7 of guanine in DNA. Cross-linking can cause defective replication due to pairing of alkylguanine with thymine leading to substitution of AT for GC, or excision of guanine and chain breakage. Their principal effect occurs during DNA synthesis; the resulting DNA damage triggers apoptosis. Unwanted effects include myelosuppression, sterility and risk of nonlymphocytic leukaemia. The main alkylating agents are:

Nitrogen mustards: e.g. cyclophosphamide, which is activated to give aldophosphamide, which is then converted to phosphoramide mustard (the cytotoxic molecule) and acrolein (which causes bladder damage that can be ameliorated by mesna). Cyclophosphamide myelosuppression affects particularly the lymphocytes. Nitrosoureas: e.g. lomustine may act on non-dividing cells; can cross the blood-brain barrier; causes delayed, cumulative myelotoxicity. Cisplatin causes intrastrand linking in DNA; it has low myelotoxicity but causes severe nausea and vomiting and can be nephrotoxic. It has revolutionised the treatment of germ cell tumours.

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Antimetabolites

These drugs block or subvert pathways in DNA synthesis. Folate antagonists

Methotrexate inhibits dihydrofolate reductase, preventing generation of tetrahydrofolate; the main result is interference with thymidylate synthesis. Methotrexate is taken up into cells by the folate carrier, and, like folate, converted to the polyglutamate form. Unwanted effects: myelosuppression, possible nephratoxicity.
Fluorouracil is converted to a fraudulent nucleotide and inhibits thymidylate synthesis. Cytarabine its triphosphate form inhibits DNA polymerase; potent myelosuppressive. Mercaptopurine is converted into a fraudulent nucleotide. Fludarabine its triphosphate form inhibits DNA polymerase; it is myelosuppressive.

Pyrimidine analogues

Purine analogues

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Cytotoxic antibiotics

Doxorubicin inhibits DNA and RNA synthesis; the DNA effect is mainly due to interference with topoisomerase II action. Unwanted effects: nausea and vomiting, myelosuppression, hair loss; it is cardiotoxic in high doses. Bleomycin causes fragmentation of DNA chains. It can act on non-dividing cells. Unwanted effects: fever, allergies, mucocutaneous reactions, pulmonary fibrosis. Virtually no myelosuppression. Dactinomycin intercalates in DNA, interfering with RNApolymerase and inhibiting transcription. It also interferes with the action of topoisomerase II. Unwanted effects: nausea and vomiting, myelosuppression. Mitomycin is activated to give an alkylating metabolite.

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Plant derivatives

Vinca alkaloids

Vincristine inhibits mitosis at metaphase by binding to tubulin. Relatively non-toxic, but can cause unwanted neuromuscular effects. Etoposide inhibits DNA synthesis by an action on topoisomerase II, and also inhibits mitochondrial function. Common unwanted effects include vomiting, myelosuppression and alopecia. Paclitaxel stabilises microtubules, inhibiting mitosis; relatively toxic, hypersensitivity reactions occur. Irinotecan binds to and inhibits topoisomerase 1; relatively few toxic effects.

Podophyllotoxins

Taxones

Campothecins

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Hormones and anti-hormones

Hormones or their antagonists are used in hormonesensitive tumours: Glucocorticoids for leukaemias and lymphomas Oestrogens for treatment androgen-dependent prostatic tumours and mammary cancer (during menopause) Progestogens for treatment endometrial neoplasms and renal tumours Gonadotropin releasing hormone analogues for prostate and breast tumours Analogue of somatostatin, octreotide for treatment various hormone-secreting tumours of the gastrointestinal tract Anti-oestrogens (tamoxifen) for breast tumours Antiandrogens (flutamide, cyproterone) for prostate cancers Aromatase inhibitors - inhibitors of sex hormone synthesis (aminoglutethimide) for postmenopausal breast cancer.

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