Chemotherapy:

Resistance to anticancer drugs:

Mechanisms of resistance:

1. Increased DNA repair: thus the rate of DNA damage of the tumor is slower than the rate of DNA repair. Against alkylating
agents and cisplatin.
2. Formation of trapping agents: by increasing the production of trapping agent like glutathione with can interact with anti-
cancer drugs that form reactive electrophilic species. Against alkylating agent bleomycin, cisplatin, and the anthracyclines.
3. Changes in target enzymes: changes some aspect of a critical enzyme like dihydrofolate reductase, with affecting their
functionality. Thus, is ineffective against “new” enzyme. Against methotrexate.
4. Decreased activation of prodrugs: Resistance to the purine antimetabolites (mercaptopurine, thioguanine) and the
pyrimidine antimetabolites (cytarabine, fluorouracil) can result from a decrease in the activity of the tumor cell enzymes
needed to convert these prodrugs to their cytotoxic metabolites.
5. Inactivation of anticancer drugs: increased activity of enzymes that are against the drug
6. Decreased drug accumulation: increased expression of normal gene MDR1, which makes a transmembrane protein, a
transporter that is involved in kicking out the antidrugs out of cell.

Antimetabolites:

•Chemotherapy drugs used to treat malignancy

•Block formation of components of DNA

•Cell cycle specific (CCS) – which means it acts on the tumor stem cells when
they are in the cell cycle, this is unlike cell cycle-nonspecific (CCNS) which acts on
the tumor stem cells when they are in the resting phase.

•Toxic effects in S phase of cell cycle

Common side effects:

since these drugs target rapidly dividing cells (DNA synthesis), in addition to targeting tumor stem cells, it will also target bone
marrow precursors cells  myelosuppression {megablastic anemia, thrombocytopenia, leukopenia}; absolute neutrophil count
(ANC) will be less than 500 cells/μL  neutropenia  high risk of infections

Megaloblastic anemia:

 Anemia (hematocrite ↓)
 Larger RBCs (↑MCV) mean corpuscular volume – which the measure of the average size of RBCs. It helps in diagnosing
different types of anemia.
 Hypersegmented neutrophils – when the neutrophils have 6 or more lobes instead of 2 to 5 lobes. Identified by complete
blood count test (CBC).
 Associated with defective DNA production – B12/folate deficiency or the use of chemotherapy drugs (MTX, 5-FU,
hydroxyurea)
 Adverse effects:
Myelosuppression
Pyramidine analog Nausea/vomiting
Cytarabine: Mimics cytidine High doses: neurtoxiticity
Inhibits DNA polymerase Peripheral neuropathy (presented as
Effective in leukemia and lymphomas numbness, tingling, muscle weakness or
paralysis, loss of coordination or balance,
etc.), confusion, and cerebellar ataxia
List of antimetabolites:

Purine analog Highly toxic to lymphocytes

Cladribine: Mimics adenosine Main adverse effect in myelosuppression
Drug of choice in hairy cell leukemia

Mimics of folate Clinical use: Side effects:

Inhibits dihydrofolate Many malignancies: myelosuppression:
reductase Solid tumors More common with high doses
Blocks synthesis of Leukemia/lymphomas Reversible by the use of leucovorin (folinic acid) – it can be
tetrahydrofolate, Autoimmune diseases converted into tetrahydrofolate (THF) without the
which is required for Immunosuppression functionality of dihydrofolate reductase “Leucovorin
DNA, RNA and some “steroid sparing” agents rescue”
proteins Used to eliminate need Mucositis (mouth soreness)
Blocks synthesis of for long-term steroid use Occurs with many chemo agents, common with
thymidine (dTMP) Pregnancy abortion methotrexate.
which is a building Ectopic/tubal GI epithelial cell damage  GI upset
Methotrexate block of DNA pregnancies Loss of mucosial integrity  pain, bacterial growth  if
oral or intervenous ignored then it can lead to septic shock cuz of the escaping
of normal flora of the mouth to the blood circulation
Abnormal LFTs  liver function test – blood test that
checks for the levels of AST& ALT in the blood

Rarely – methotrexate-induced lung injury:

After week/moths of low-dose therapy
It is hypersensivity reaction. There will be lymphocytes,
eosinophils
It can progress to pulmonary fibrosis.
 Resolved by discontinuing the drug

Mimics uracil (pyramidine) Adverse effects:

Converted to 5-FdUMP (abnormal
dUMP)
Inhibition thymidylate synthase, thus
blocks dTMP synthesis (thymineless
death)
5-fluorouracil Effects enhanced by leucovorin
Used in colorectal cancer + soldi tumors
of breast and pancreas
Topical therapy for basal cell skin cancer
Myelosuppression
Nausea/vomiting/diarrhea
Mucositis
Cerebellar ataxia and encephalopathy
(rare)
Coronary vasospasm
Hand-foot syndrome (palmar-planter
erythrodysesthesia) – characterized by
redness, swelling nad pain in palms of
hands and soles of foot. In extreme
conditions, blisters and peeling skin can
develop.

Mimics hypoxanthine/guanine (purines)

Added to PRPP (Phosphoribosyl Pyrophosphate) by HGPRT (Hypoxanthine-Guanine
6-mercaptopurine Phosphoribosyltransferase)  thioinosinic acid.
Inhibits multiple steps in purine salvage
↓IMP/AMP/GMP
It is a prodrug, which gets Adverse effects:
converted by the body to 6-MP Myelosuppression
Clinical uses: Abnormal LFTs (liver function test)
Immunosuppression Anorexia/nausea/vomiting
Steroid sparing agents NOTE: 6-MP gets metabolized by xanthine
Azathioprine Inflammatory disease oxidase into inactive metabolites. So when this
Solid organ transplant enzyme is blocked by allopurinol/fabuxostat,
Autoimmune disease there will be accumulation of 6MP bone-
marrow suppression.
6-Thioguanine Also mimics hypoxanthine/guanine Similar mechanism to 6 MP ↓IMP/AMP/GMP
(purines)

Inhibits ribonucleotide reductase Rarely used for malignancy

Hydroxyurea Blocks formation of deoxynucleotides Used for polycythemia vera, essential thrombocytosis
Good oral bioavailability –can be used PO Used in sickle cell anemia
 Main adverse effect is myelosuppression Increases fetal hemoglobin levels (mechanism unclear)

___________________________________________________________________________________________________________

Please Consume More Fresh ACTH (says the anterior putitary to adrenal gland)

P: 6-mercaptopurine

C: Cytarabine

M: Methotrexate

F: 5-fluorouracil

A: Azathioprine

C: Cladribine

T: 6-thioguanine

H: Hydroxyurea