Toxicology

Antimitotics

Any substance that opposes mitosis and hinders cell proliferation. They can be
cytostatics or cytotoxic agents.

Classification
Spindle poisons: wine alkaloids and taxanes;
-Alkylating agents: nitrogen mustards, organo-platinum compounds, and nitrosoureas;
-Intercalating agents: anthracyclines and anthracenediones;
-Dividing agents: bleomycin;
Antienzymes: anti-topoisomerases and antimetabolites.

Mode of Action
Direct Action on DNA
Alkylating Agents and Related Compounds
Formation of covalent bonds with the nucleotides of the DNA strand, creating
intramolecular bonds that inhibit replication, create immediate alterations and
gene mutations, and block mitosis by agglutination of chromosomes.
They are non-specific to the cell cycle.
Intercalating Antibiotic Agents
Called so because they are extracted from microbial culture broths.
They form bonds with DNA, inhibiting replication and transcription.
The cytotoxic action is mainly related to their interaction with topoisomerase II.
the activity increases at the time of cell division: Doxorubicin intercalates
in the DNA and stabilizes the DNA-topoisomerase II complex, causing breaks in
the chain and an inhibition of replication.
They are non-specific to the cell cycle.
Scindants Agents
Glycopeptide metal chelators that degrade DNA.
Their action is related to the release of free radicals by chelation of ferrous iron then
oxidation, generating superoxide radicals.
They are active in the G2 phase (pre-mitotic period) and in the G0 phase (resting period).

Indirect Action on DNA

Antimetabolites
Inhibition of nucleic acid synthesis or DNA polymerase.
-Classes :
Anti-folates: Methotrexate;
Anti-pyramidal: Fludarabine;
Anti-purines: Fludarabine;
DNA polymerase inhibitors: Gemzar;
Thymidylate synthase inhibitors: Pemetrexed.
They are active in the S phase (synthesis period).
 Anti-Topoisomerases
-Anti-topoisomerase I: derivatives of epipodophyllotoxins;
Anti-topoisomerase II: Irinotecan, Topotecan, and Etoposide (VP-16).
Poisons of the Spindle
Alkaloid derivatives of periwinkle (vincarosea): inhibition of polymerization of the
tubulin.
Taxanes (derivatives of Taxus atlanticus): inhibition of tubulin depolymerization
after mitosis.
Their effects (blocking mitosis in metaphase) only manifest on the cells in
division.

Toxicokinetics
Absorption
- Modified by the decrease: of gastric acidity, of gastrointestinal secretions or of
intestinal absorption.

Distribution
Body fat increases by 15 to 30% of body weight;
Intracellular water decreases by 33 to 42%;
The volume of distribution of water-soluble drugs decreases and that of fat-soluble drugs
increases.
Anemia can influence the distribution of molecules strongly bound to red blood cells (anthracyclines,
taxanes and VP16.

Metabolism
Chemotherapies interacting with CYP 450: Cyclophosphamide, Paclitaxel, Etoposide,
Vincristine and Tamoxifen.

Elimination
Renal excretion (risk of nephrotoxicity with Methotrexate and Cisplatin).
Doxorubicin is excreted through the bile.

Kinetics of Some Antimitotics

Fluoro-Pyrimidines : 5-Fluorouracile et Capécitabine
Their metabolism depends on dihydropyrimidine dehydrogenase (DPD).
Intoxications with these molecules may occur in patients with a deficiency.
partial or total in DPD.

Methotrexate (MTX)
Small molecule strongly bound to albumin, capable of diffusing across the BBB at high doses.
Metabolized mainly into 7-OH-MTX inactive and active poly-γ-glutamyl derivatives.
- Eliminated mainly through urine in unchanged form, partially involving a
proximal tubular secretion.
It follows a triphasic kinetics (24, 48 and 72 hours).
It is a thermolabile and photosensitive molecule.

Bleomycin
Rapid distribution in all tissues of the body.
Rapid elimination through renal route.
 Cisplatin
The kinetics is biphasic:
The first phase is rapid, the half-life is 30 minutes, it corresponds to platinum.
ultrafiltrable (free platinum).
The second is long with a half-life of 02 to 08 days, it corresponds to the bound platinum.
to plasma proteins (the binding is strong and irreversible).
Platinum is found in several tissues including the kidney, liver, prostate, and bladder.
Platinum concentration in the CSF = 3% of the platinum concentration in the plasma.
It is not metabolized in the liver.
Its elimination is mainly urinary through glomerular filtration and tubular secretion.

Clinic
Circumstances of Intoxication
-Voluntary intoxications: suicide attempt, side effects during treatment or in a
but criminal.
Accidental intoxications: dosage, confusion or error.

Common Toxicity
Hematological: reversible myelosuppression, non-cumulative, dose-dependent.
-Alopecia: common, especially with taxanes and anthracyclines. Wearing a cap
Refrigeration can prevent it.
Gastrointestinal: nausea, vomiting, mucositis, and stomatitis.
Reprotoxicity: sterility that may be irreversible.
Related to extravasation: burns, tingling, pain, induration, edema and absence of
blood return.

Specific Toxicity
Class Molecules Toxicity
Methotrexate Hepatic, digestive, renal, and pulmonary
Antimetabolites Cardiac, hand-foot syndrome, mucositis,
5-FU
diarrhea, low emesis
Cyclophosphamide Vesical (hemorrhagic cystitis and cancer)
Alkylating agents Renal (CRF), auditory, neuropathy
Cisplatin
peripheral, very emetic
Intercalating agents Anthracyclines Dose dependent cardiac (IC)
Pulmonary
Cutting agents Bleomycin
No hematological toxicity or alopecia
Digestive (constipation and intestinal paralysis),
Vincristine
peripheral neuropathy, SIADH
Spindle poison
Anaphylactic shock and neuropathies
Taxol
devices

Treatment
Bleomycin
Symptomatic treatment of respiratory and hematological disorders.
In case of respiratory complications, the patient is treated with corticosteroids and antibiotics.
large spectrum (fibrosis is irreversible unless the diagnosis is made early).
Dialysis has no benefit.
 Methotrexate
High doses are administered with folinic acid which restores nucleotide synthesis.
(rescue by folinic acid) is accompanied by abundant alkaline diuresis.
Renal and hepatic function, albuminemia, complete blood count, and urinary pH must be
closely monitored.
Alkaline diuresis should be prolonged as long as a detectable serum level of MTX is present.
MTX treatment should not be started if the urinary pH is < 7.

Toxicological Analysis
Immuno-enzymatic or immuno-radiological dosage: MTX, Vinblastine, Vincristine and
Paclitaxel.
Dosage after chromatographic separation:
oHPLC/MS: Chlorambucil, Cyclophosphamide, Melphalan, Busulfan, Bleomycin, and 5-FU.
oGC/MS: Cyclophosphamide, Ifosfamide, Procarbazine and Mercaptopurine.
Platinum dosage: ICP/MS.

Therapeutic Monitoring
- Possible after 5 t½ (reaching the equilibrium state).
Residual rates are measured (dosage on a sample taken just before intake).
It is made for: MTX, Vincristine and its derivatives, organoplatins, and taxanes.

Targeted Therapy
Types
Anti-receptor antibodies;
Anti-receptor antibodies, cytotoxic by themselves (vaccines);
Antibodies against receptors coupled to a radioactive isotope or to an active cell poison (such as
the ricin)
Small molecules that can bind to the tyrosine kinases of target receptors.

Examples
EGFR inhibitors;
Tyrosine kinase inhibitors (STI-571);
Bevacizumab (anti-VEGF antibody);
Cetuximab (anti-EGF antibody = HER1);
Rituximab (anti-CD20 antibody);
Trastuzumab (anti-HER2 antibody).