CHEMOTHERAPY OF NEOPLASTIC DISEASES

2005-04-09T08:00:00.000-07:00

This article has been published by the International Biopharmaceutical Association www.ibpassociation.org . Please note this article does not give any medical advice.

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CHEMOTHERAPY OF NEOPLASTIC DISEASES

Background
In modern medicine cytotoxic drugs are broadly and successfully in use not only in treatment of neoplastic diseases but also in many other clinical situations: as component of immunosuppressive regiments for rheumatoid arthritis (methotrexate and cyclophsphmide), organ transplantation (methotrexate and azathioprine), sickle cell anemia (hydroxyurea), anti-infective chemotherapy (trimetrexate and leucovorine), and psoriasis (methotrexate).
Many of cytotoxic drugs act at specific phases of the cell cycle and have activity only against the cells that are in process of division. These group of agents called cell-cycle specific (CCS). On other hand, there is the cytotoxic agent that affect cell without connection to phase of cell cycle, they called non-cell-cycle specific (NCCS).
Cell cycle divided on four phases – 1) G1-phase – presynthetic phase; 2) S-phase – DNA synthesis (this phase affect such agents as cytarabine, hydroxyurea, 6-mercaptopurine, methotrexate); 3) G2-phase – premitotic interval; 4) M-phase – mitotic phase (this phase affect such agents as vinctistine, vinblastine, paclitaxel).
Non-cell-cycle specific agents affect neoplastic cells in any phase. This group include alkylating drugs, nitrosurea, antitumor antibiotics, procarbazine, cis-platinum, dacarbasine.
A greatest problem of neoplastic diseases management is a tumor cell resistance to chemotherapy. Most commonly such cells appears after treatment with single cytotoxic agent. The resistance may be specific to the selected agent or more general to a broad range of cytotoxic drugs. To tumor cell resistance may lead a mutation or loss of p53 suppressive oncogen (a suppressor gene is essential for normal control of cell proliferation; its loss or mutation allows cell to undergo malignant transformation). Mutation of p53 or its loss inactivate the key pathway of programmed cell death and leads to continuous proliferation of tumor cells that have the capacity to survive DNA damage.
There are many types of tumor cells resistance, depend on type of activity of the cytotoxic agent.

I. ALKYLATING AGENTS
Mode of action – formation of covalent linkages by alkylation of various nucleonic structures (phosphates, amino, sulfhydryl, hydroxyl, carboxyl, imidazole groups), thus disturb fundamental mechanisms of cell proliferation. These compounds may alkylate nondividing cells, but cytotoxicity is markedly enhanced if DNA in cell is programmed to divide.
Mechanisms of tumor cells resistance – 1) decreased permeation of drug; 2) increased production of nucleophylic substances, that can compete with drugs for DNA; 3) increased activity of DNA repairing enzymes.

Nitrogen mustards
Mechlorethamide (Mustargen) – most reactive in this class
Absorption and administration – given intravenously, rapid absorption and distribution
Therapeutic use – mainly in treatment of Hodgkin’s disease
Clinical toxicity – major manifestations are nausea, vomiting, lacrimation, myelosuppression. Also seen reproductive system disturbances (menopause, oligospermia), teratogenic (not in use in first trimester of pregnancy); local manifestations – thrombophlebitis, in extravasation during infusion – severe in duration.

Cyclophosphamide (Cytoxan)
Absorption and administration – good oral absorption; activated by P-450; rapid distribution in oral and parenteral (intravenous) intake.
Therapeutic use – clinical spectrum of activity is very broad (non-Hodgkin’s lymphomas, breast cancer, multiple myeloma, carcinomas of lung, cervix, ovary, neuroblastoma, etc.)
Clinical toxicity - nausea, vomiting, mucosal ulcerations, hemorrhagic cystitis, increased skin pigmentation; less common – lung fibrosis; rare. No local manifestations in drug extravasation.

Ifosfamide (Ifex) – analog of cyclophosphamide
Therapeutic use – testicular cancer, sarcomas, lymphomas, lung and cervix carcinomas.
Clinical toxicity – as cyclophosphamide, severe urinary tract toxicity.

Melphalan (Alkeran)
Absorption and administration – given orally and intravenously; when given orally, the absorption is incomplete – 20-50% of drug excreted with stool.
Therapeutic use – orally – for treatment of multiple myeloma; intravenously – broad range of neoplastic diseases.
Clinical toxicity – similar to other alkylating agents.

Chlorambucil (Leukeran)
Absorption and administration - given orally and intravenously; good oral absorption and distribution.
Therapeutic use – treatment of chronic lymphocytic leukemia, primary macroglobulinemia.
Clinical toxicity – moderate myelosuppression, amenorrhea, lung fibrosis, seizures, dermatitis, hepatotoxicity, may cause secondary leukemia in long-term use.

Ethylenimines and Methylmelamines
Triethylenemelamine (TEM)
Thiotepa
Altretamine
Absorption and administration – given intravenously; almost fully metabolized (less than 10% appears in urine).
Therapeutic use – Thiotepa – in treatment of bladder cancer, others – ovarian cancer.
Clinical toxicity - similar to other alkylating agents.

Alkyl sulfonates
Busulfan (Myleran)
Absorption and administration – administrated orally, good absorption and distribution; almost fully excreted by urine as methanesulfonic acid.
Therapeutic use – treating of chronic leukemias
Clinical toxicity – myelosuppression, nausea, vomiting, impotence, amenorrhea, fetal malformations, may cause secondary leukemias. In high doses – lung fibrosis, CNS disturbances, seizures, cataract, Addison’s disease.

Nitrosoureas
Carmustine
Absorption and administration – unstable in aqueous solutions and body fluids (disappears from plasma in 15-90 min after infusion); administrated intravenously.
Therapeutic use – brain tumors, gastrointestinal cancer, Hodgkin’s disease.
Clinical toxicity - myelosuppression, nausea, vomiting, in high doses – lung fibrosis, renal and hepatic failure.

Lomustine, Semustine – analogs of Carmustine
Absorption and administration – given orally, high bioavailability
Therapeutic use – as Carmustine
Clinical toxicity – similar to Carmustine

Triazenes
Dacarbazine
Absorption and administration – administrated intravenously; activated in liver; rapidly disappears from plasma (20 min after infusion); almost ½ of the dose excreted intact with urine.
Therapeutic use – treatment of malignant melanoma, Hodgkin’s disease, sarcomas.
Clinical toxicity – major are nausea and vomiting, also seen myelosuppression, usually moderate, flulike syndrome, alopecia, neuro- and hepatotoxicity.

II. ANTIMETABOLITES

Folic acid analogs
Methotrexate
Mode of action – inhibition of dihydrofolatreductase and folat-depending enzymes, interfering with synthesis of DNA and RNA precursors.
Mechanism of tumor cells resistance to antifolates – 1) impaired transport of drug into the tumor cell; 2) production of altered forms of dihydrofolatreductase with decreased affinity to the inhibitor; 3) increased concentration of dihydrofolatreductase into the cell; 4) decreased activity of folat-depending enzymes.
Absorption and administration – administrated orally and intravenously; good oral absorption in doses less than 25mg\m2, in higher doses absorption is much poorer. Wide distributed in the body, approximately 50% of drug are connected to plasma proteins, and may be displaced by some other drugs, such as sulfonamides, salicylates, tetracyclines, chloramphenocol and phenytoin, which can thus to increase toxicity of methotrexate. About 90% of the drug is excreted with urine during 48 hours after intake.
Therapeutic use – psoriases, rheumatoid arthritis, acute lymphatic leukemia in children, chorioncarcinoma, osteosarcomas, non-Hodgkin’s lymphomas, various carcinomas.
Clinical toxicity – myelosuppression, nephrotoxicity (uses with leucovorine), alopecia, dermatitis, interstitial pneumonitis, teratogenesis.

Pyrimidine analogs
Mode of action – inhibits biosynthesis of pyrimidine nucleotides or change them to form that interfere with normal cellular functions, such as synthesis or function of nucleic acids.
Mechanisms of tumor cells resistance – 1) decreased activity of enzymes necessary for activation of the drugs; 2) production of altered enzymes, which are not inhibited by this group of agents.

Fluorouracil (5-FU)
Absorption and administration – administrated intravenously, since oral absorption is incomplete; dose do not have to be reduced in patients with hepatic diseases.
Therapeutic use – carcinomas of breast and GIT, ovary, cervix, bladder, prostate, pancreas, etc.
Higher response is seen then 5-FU is used in combination with other cytotoxic agents (such as cyclophsphamide, methotrexate, cis-platinum), because of synergetic effects.
Clinical toxicity – anorexia, nausea, stomatitis, diarrhea, GIT ulceration, myelosuppression, alopecia; dermatitis, neurological and cardiac toxicity also seen.

Cytarabine (Cytosar-U)
Absorption and administration – administrated orally, intravenously and subcutaneously; good absorption and distribution; only approximately 10% of the drug is excreted with urine, mostly metabolized in the body.
Therapeutic use – acute leukemias in children and adults, non-Hodgkin’s lymphomas.
Clinical toxicity – myelosuppression, GIT disturbances, stomatitis, pneumonitis; neurotoxicity seen in high doses.

Purine analogs
Mode of action – inhibits biosynthesis of purine nucleotides or change them to form that interfere with normal cellular functions, such as synthesis or function of nucleic acids.
Mechanism of tumor cells resistance – 1) decreased drug transport; 2) increased rate of degradation of the drug; 3) changes in production or activities of intracellular enzymatic systems.

6-Mercaptopurine (Purinetol)
Absorption and administration – given intravenously, sine oral absorption is incomplete (only 5%) and bioavailability is variable. Often given with allopurinol, which increase activity of the mercaptopurine and decrease possible hyperuricemia during treatment by inhibition of his inactivation by xantine-oxydase.
Therapeutic use – leukemias, lymphomas
Clinical toxicity – myelosuppression, nausea, vomiting, jaundice, rare – GIT disturbances.

Azathioprine – derivative of mercaptopurine. Effects and use are similar.

Thioguanine (6-TG)
Absorption and administration – available orally, though oral administration is incomplete. As mercaptopurine, may be given with allopurinol for the same purposes.
Therapeutic use – treatment of acute leukemia.
Clinical toxicity – myelosuppression, GIT disturbances.

Pentostatine (Nipent)
Absorption and administration – administrated intravenously; almost complete renal elimination (appropriate reduction of dose recommended for patients with renal disorders)
Therapeutic use – treatment of hairy-cell leukemia
Clinical toxicity - myelosuppression, GIT disturbances, impaired liver functions, skin rashes, in high doses neuro- and nephrotoxicity.

III. NATURAL PRODUCTS

Antimitotic drugs (Alkaloids)
Mode of action – cell-cycle specific agents that block cell mitosis. They are able to bind specifically to tubulin and thus inhibit normal activity of microtubuli in the mitotic apparatus of the cell.
Mechanisms of tumor cell resistance – 1) mutations in the tubulin, that prevent binding of the drug; 2) increased levels of P-130 glycoprotein, a membrane efflux pump that transport the drug out from cell (Ca-channels blockers, such as verapamil, inhibit this type of resistance).

Vincristine (Oncovin), Vinblastine (Velban), Vinorelbine (Navelbine) – alkaloids of Vinca rosea.
Absorption and administration - administrated intravenously, Vinorelbine also orally (oral bioavailability 30%); metabolized by liver, excreted with bile.
Therapeutic use – vinblastine – testicular cancer, Hodgkin’s disease, lymphomas, carcinoma of breast, chorioncarcinoma; vincristine – leukemias, Hodgkin’s disease, lymphomas, Wilms tumor, neuroblastoma, brain tumors, carcinomas of breast, bladder, reproductive system.
Clinical toxicity – myelosuppression, neurotoxicity, alopecia, GIT disorders, nausea, vomiting, rare – cardiac toxicity; local effects – phlebitis.

Paclitaxel (Taxol)
Absorption and administration – administrated intravenously; metabolized by P-450 in liver (patients with hepatic disorders need the dose reduction), only 10 % excreted with urine.
Therapeutic use – mostly - ovarian and breast cancer, also carcinomas of neck, head, bladder.
Clinical toxicity – myelosuppression, brady- or tachycardia, in high doses – neurotoxicity.

Epipodophyllotoxins
Mode of action – cell-cycle specific agents that block cell mitosis; binding to topoisomerase and DNA, that result in DNA breaks (cells most sensitive in phases S and G-2)
Mechanisms of tumor cell resistance – 1) mutations of topoisomerase; 2) increased levels of P-130 glycoprotein.

Etoposide (Vepeside)
Absorption and administration – administrated orally and intravenously, in oral intake absorption in about 50%, approximately 40% is excreted with urine (patients with renal disorders need dose reduction).
Therapeutic use – testicular cancer, carcinomas of lung and breast, lymphomas, leukemias.
Clinical toxicity – myelosuppression, alopecia, nausea, vomiting, stomatitis, diarrhea, allergy, in high doses – hepatotoxicity.

Teniposide (Vumon, VM-26) – analog of Etoposide
Absorption and administration – administrated intravenously, 45% excreted with urine. Anticonvulsants (dilantine) increase hepatic metabolism of teniposide. Dosage have to be reduced in patients with impaired renal function.
Therapeutic use – treatment of acute lymphoblastic leukemia
Clinical toxicity - myelosuppression, alopecia, nausea, vomiting.

Antitumor Antibiotics
Dactinomycine (Actinomycine D)
Mode of action – bind to DNA and cause blockage of transcription of DNA; in addition, the drug cause break of DNA by free radicals production.
Absorption and administration – give intravenously; metabolism is minimal, excreted with urine and bile, does not cross Blood Brain Barrier (BBB).
Therapeutic use – treatment of rhabdomyosarcoma, Wilms tumor in children, lymphomas, for immunological response inhibition, particularly in renal transplantation.
Clinical toxicity – nausea, vomiting, myelosuppression, diarrhea, glossitis, stomatitis, alopecia, erythema, local effects – in extravasation – severe inflammation in the site of infusion.

Daunorubicin, Doxorubicin, Idarubicin
Mode of action – affecting DNA and RNA synthesis, cause break of DNA strains by producing free radicals.
Absorption and administration – administrated intravenously; rapid distribution, do not cross BBB; metabolized in liver (need to reduce the dose in patients with impaired hepatic function).
Therapeutic use – Daunorubicin – treatment of acute leukemias; Doxorubicin – leukemias and lymphomas, breast cancer; Idarubicin – the same.
Clinical toxicity – myelosuppression, alopecia, GIT disorders, cardiac toxicity.

Bleomycin
Mode of action – causing fragmentation of DNA by producing of free radicals.
Absorption and administration – administrated intravenously; 2/3 of the given dose are excreted with urine (doses should be reduced in presence of impaired renal function).
Therapeutic use – testicular and ovarian cancers, lymphomas, carcinomas of neck and head.
Clinical toxicity – skin toxicity – hyperkeratosis, hyperpigmentation, erythema, ulceration; pulmonary toxicity – cough, rails, infiltrates, lung fibrosis; nausea, vomiting, headaches, hyperthermia.

Mitomycine
Mode of action – alkylation of DNA; in addition – cause breakage of DNA and chromosomes.
Absorption and administration - administrated intravenously; widely distributed in the body, inactivated by metabolism, only 10% is excreted with urine and bile, do not cross BBB.
Therapeutic use – carcinomas of cervix, colon, rectum, breast, lung head and neck.
Clinical toxicity – myelosuppression, nausea, vomiting, in high doses – neurotoxicity, pulmonary infiltration, hemolysis, nephrotoxicity.

Enzymes
L-Asparaginase
Mode of action – catalyses the big amounts of intracellular asparagine, causing deficit in this substance and cell death.
Mechanism of tumor cell resistance – increased capacity of tumor cell to produce asparagine.
Absorption and administration – given intravenously; volume of distribution is approximately the plasma volume.
Therapeutic use – treatment of acute lymphatic leukemia
Clinical toxicity – hypersensitivity and anaphylaxis, abnormalities of clotting factors, immunosuppression, pancreatitis, hyperammonemia.

IV. MISCELLANEOUS CYTOTOXIC AGENTS

Platinum coordination complexes
Cisplatin, Carboplatin
Mode of action – can react with DNA, forming cross-links, this inhibit DNA replication and transcription and cause DNA breaks.
Absorption and administration - given intravenously; more than 90% is covalently bound to plasma proteins, excreted mostly with urine.
Therapeutic use – ovarian and testicular cancer, carcinomas of head and neck, bladder, lung, etc.
Clinical toxicity – lower in Carboplatin; nephrotoxicity, alopecia, tinnitus, hearing loss, electrolyte disturbances, myelosuppression, anaphylaxis.

Hydroxyurea
Mode of action – inhibits biosynthesis of DNA; specific for S-phase of cells.
Absorption and administration – given orally; rapid oral absorption and distribution; cross BBB; 80% excreted with urine.
Therapeutic use – treatments of myeloproliferative diseases (lymphomas), melanoma, carcinomas of head and neck, cervix.
Clinical toxicity – myelosuppression, GIT disorders, dermatitis.

Procarbazine
Mode of action – methylating DNA; cause chromosomal damage; also products free radicals.
Absorption and administration – must undergo activation by P-450; given parenteral and orally, absorbed almost completely from GIT, metabolized in liver, induction of P-450 by other drugs increase metabolism of procarbazine; 70% excreted with urine.
Therapeutic use – treatment of Hodgkin’s disease, lymphomas, brain tumors.
Clinical toxicity – myelosuppression, nausea, vomiting, GIT disorders, CNS depression (use of sedative drugs should be avoided), hypertension, immunosuppression, may cause acute leukemia in long-term use.

Mitotane
Mode of action – not clear; affecting adrenocortical cells (normal and neoplastic).
Absorption and administration – given orally; 40% is absorbed from GIT; wide distribution, 60% excreted with stool.
Therapeutic use – adrenocortical carcinoma
Clinical toxicity – anorexia, nausea, dermatitis, adrenal insufficiency (corticosteroids should be given during the treatment).

V. BIOLOGICAL RESPONSE MODIFIERS

Interleukin-2 (IL-2)
Mode of action – induce T-cells response cytolytic to tumor cells
Absorption and administration – administrated by continuous infusion because of short half-life (13 min).
Therapeutic use – leukemias, melanoma, renal cancer.
Clinical toxicity – hypotension, arrhythmia, peripheral edema, elevated liver functions, nausea, vomiting, diarrhea, confusion, fever, anemia, thrombocytopenia.

Granulocyte Colony-Stimulating Factor (G-CSF, Filgrastim)
Mode of action – enhance the mobilization of stem cells from bone marrow to peripheral blood.
Absorption and administration – oral and parenteral administration.
Therapeutic use – prophylaxis of chemotherapy-induced neutropenia.
Clinical toxicity – bone pain (resulting from an expansion of cells and increased blood flow in the medullar space).

Granulocyte/Macrophage Colony-Stimulating Factor (GM-CSF, Sargramostim)
Mode of action – enhances antibody-dependent cellular cytotoxicity by stimulation of macrophages, neutrophils and eosinophils. More potent than G-CSF.
Absorption and administration – parenteral administration.
Therapeutic use - prophylaxis of chemotherapy-induced myelosuppression, bone marrow recovery after transplantation.
Clinical toxicity – bone pain, fever, myalgia; rare – tachycardia, hypotension, flushing, pericarditis.

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