Table 1 Common biological agents used for topical treatment of CIN

5-fluorouracil

5-Fluorouracil is a pyrimidine analogue (cytotoxic agent) used in the treatment of cancer. 5-FU acts through inhibition of the target enzyme thymidylate synthase (TS) by the 5-FU metabolite, FdUMP, and Incorporation of this metabolite into DNA, resulting in inhibition of DNA synthesis and function. It stops the cells making and repairing DNA. Topical 5-FU appears to be an effective medical therapy for CIN [13, 14]

Beta-glucan

Beta glucans are sugars that are found in the cell walls of bacteria, fungi, yeasts, algae, lichens, and plants, such as oats and barley. They are sometimes used as medicine. They might stimulate the immune system by increasing chemicals which prevent infections. They mediate their antitumour activity by activation or augmentation of the host’s immune system, via activation of leukocytes and production of inflammatory cytokines. Beta-glucan has been shown to increase the spontaneous regression rate of low-grade cytologic abnormalities as well as cervical findings [15].

Cidofovir 2%

The acyclic nucleoside phosphonate cidofovir has proved efficacious in the treatment of different clinical manifestations of HPV-induced epithelial cell proliferation. As an antiviral drug, it is incorporated in viral DNA and preferentially inhibits DNA, reduce capacity of HPV positive cells to repair DNA damage. Cidofovir 1% gel is able to inhibit partially or completely cervical dysplasia lesions [16, 17].

Curcumin

Curcumin (diferuloylmethane), a yellow substance from the root of the plant Curcuma longa Linn., has been demonstrated to inhibit the transcription of HPV16 E6/E7 proteins as early as six hours after treatment and restores the expression of tumor suppressor proteins p53, retinoblastoma protein, and PTPN13.

Imiquimod 5%

Imiquimod is an immunomodulator with antiviral and anti-tumor effects. It is a toll-like receptor 7 agonist and induces up regulation of interferon and activation of dendritic cells. Imiquimod (5% cream) has been shown to be safe and effective in the treatment of genital warts caused by low-risk HPV infections. The mechanism for the eradication of genital verrucous lesions with imiquimod may involve the induction of both innate and cellular immunity. Antiviral activity may be stimulated through the induction of cytokines, such as interferon-a (IFN-a), tumor necrosis factor-a (TNF-a), and interleukins (ILs) [18, 19].

Interferon alpha and beta

Interferons (IFNs) are a family of glycoproteins and are natural body defenses against viral infections and play important roles in combating tumors and regulating immunity. IFNs perform their effects through binding to cell surface receptors and activating members of the JAK kinase family.

The antitumor effects result from direct action on the proliferation or antigenic composition of tumor cells, or from the effect of modulation on immune effector cell populations with tumor cell specificities.

In addition to this, they can have indirect effects, such as modulation of the immune response and inhibition of tumor angiogenesis.Some studies have shown good results from the use of IFN-β for treating CIN cases [20, 21].

Trans-retinoic acid

Retinoids are essential for cell growth, differentiation, and cell death. Various retinoids have been shown to inhibit cellular proliferation in cervical cancer cells in several studies.

All-trans retinoic acid (atRA) is an active metabolite of vitamin A under the family retinoid. Retinoids, through their cognate nuclear receptors, exert potent effects on cell growth, differentiation and apoptosis.

Retinoic acid either decreases or increases EGF-stimulated growth and EGF-R expression depending on the cell line and culture conditions. HPV-containing cell lines overexpress EGF-R and are more sensitive to retinoïds than normal cells. Increased sensitivity of HPV-containing cells may explain the reversal of premalignant lesions and dysplasias of the cervix by retinoic acid [22]

Trichloroacetic acid

Trichloroacetic acid is an analogue of acetic acid in which the three hydrogen atoms of the methyl group have all been replaced by chlorine atoms. It is a chemically destructive acid that burns, cauterizes and erodes the skin and mucosa, resulting in the physical destruction of warty tissue through protein coagulation. The destructive nature of the product frequently extends beyond the superficial wart to encompass the underlying viral infection.