Differentiating agents

Differentiating agents are treatments that cause cancer cells to differentiate into a less malignant phenotype or undergo apoptosis.

Types:
1. Retinoids
2. Arsenic trioxide
3. Histone deacetylase Inhibitors HDACs.
4. Vitamin D
5. Cytokines: GCSF, GM,-CSF.
 

1. Retinoids:
Retinoids are natural or synthetic derivatives of vitamin A (retinol).
Retinoid receptors:
Retinoids exert their effect through the interaction with their specific receptors that include:
1. Retinoid acid receptors (RARs)
2. Retinoid X receptors (RXRs)
Theses receptors are DNA binding transcription factors that regulate the expression of other genes that mediate the cell division regulatory effect of Retinoids.

Mechanism of action:
1. Induce cellular differentiation, especially granulocytic
2. Suppress carcinogenesis
3. Inhibit the proliferation of certain cell lines like melanoma, breast, neuroblastoma, leukaemia, germ cell tumours and bone.

Examples for Retinoids used in practice:
1. All –Trans Retinoic Acid (ATRA: Vesanoid capsule 10 mg).
It is used in the treatment of acute promyelocytic leukaemia APL associated with the fusion protein PML-RAR α that blocks cellular differentiation.
It is given PO at a dose of 45mg/kg /day till complete remission.
Maintenance is given in the form of the same dose for 2 weeks every three month for 2 years.
2. 9 cis Retinoic Acid (9-cis RA: Panretin PO and Topical). It is used in the treatment of APL and as a topical treatment in AIDS associated Kaposi’s sarcoma.
3. 13 cis Retinoic Acid (13-cis RA: Bexarotene PO). It is used in the treatment of CTCL (MF), epidermoid skin cancer and in the prevention for oral leukoplakia in tobacco users.
4. N4-hydroxil retinamide (4HPR: Fenretinide). It is used mainly in the prevention of tumours like breast prostate bladder and the oral cavity.

2. Arsenic trioxide:
It is used in the treatment of APL and induces higher rate of complete molecular remission (negative PML-RAR-α BY PCR) compared to ATRA.
It is given as intravenous infusion daily till complete remission at a dose of 0.15 mg/kg/day. After 3 weeks of discontinuation, additional courses for 25 days treatment are given.

3. Histone Deacetylase Inhibitors:
Histones are protein molecules that keep the DNA folded and not accessible for interaction with different proteins essential for cell cycle regulation and transcription. Histone Deacetylase Inhibitors HDAC inhibitors inhibit histone deacytlation process essential for many biological activities like transcription and cell growth. Thus, they prevent cellular oncogenes from directing the cell into replication and or proliferation. Experimentally exposure of cancer cells to HDAC inhibitors resulted in transcriptional control, changes in protein–DNA interaction to cellular differentiation, growth arrest and apoptosis.

Examples for HDACIs used in cancer treatment:
1. Azacytidine (Vidaza) is used is approved by the Food and Drug Administration (FDA) to treat myelodysplastic syndromes (MDS).

For more information, visit the NCI web site at: http://www.cancer.gov/cancertopics/druginfo/azacitidine

2. Butyrates (Sodium phenylbutyrate) is used in the treatment of MDS, APL, refractory solid tumours and thalassemia.
 

3. Hybrid polar compounds (Hexamethylene bisacetamide) is used in the treatment of MDS.

4. Vitamin D:
It is used in the treatment of MDS.
Vitamin D induces its effect by different mechanisms as follows:
• It decreases the growth of different cell lines like breast, colon, and prostate cell lines.
• It induces the differentiation of hematopoietic cells towards monocytes and macrophages.

5. Cytokines:
• Colony- Stimulating factors: G-CSF, GM-CSF.
• Interferons.