**2.2 Exogenous sources of ICLs**

*DNA - Damages and Repair Mechanisms*

**124**

**ICL AGENTS**

Platinums

Carboplatin

Oxaliplatin Mitomycin

Mitomycin C

Azinomycin

Azinomycin B Chloroethylnitrosoureas

Carmustine

Synthetic

G-C base pair

Treatment of multiple

70 minutes

Liver

[33]

myelomas

(nitrogen

mustard)

**N**itrogen mustards

Cyclophosphamide

Ifosfamide Chlorambucil

**Table 1.**

*Exogenous agents of Interstrand cross-link lesions.*

Synthetic

5′ -GNC

Treatment of lymphoma,

**3 to 12 hours**.

Liver

[34]

multiple myeloma and

ovarian cancer

Treatment of sarcomas and

60–80% in

Kidney

[35]

72 hours

1.5 hours

Liver

[36]

organ cancers

Treatment of Chronic

lymphocytic leukemia,

Hodgkins lymphoma and

Non-hodgkin lymphoma

Streptomyces

5′-GNC or 5′-GNT

having antitumor activity

N.A

N.A

[32]

against P388 leukemia in

mice

sequences

sahachiroi

*Streptomyces* 

5′-CG-3*'*

Treatment of Esophagal and

Alpha-half-life of

Hepatic

[10, 31]

8.2 mins, beta-halflife of 51.8 mins

bladder carcinoma

*caespitosis*

Synthetic

Adducts: G-Pt-G and

Treatment of ovarian cancer

Treatment of colorectal

cancer

1–2 hours 26 hours or

20 hours

Kidney Kidney

[28]

[29, 30]

(made from

Pt-GG

DNA sequence: 5*'*-GC

cisplatin)

**Source**

**Adducts formed/**

**Clinical benefits**

**Elimination halflife of drug**

**Metabolism**

**References**

**Target DNA sequences**

The other sources of ICLs are exogenous in nature. They have the same mechanism of bifunctional alkylating agents but differ in their preferences for sequences, topologically restrict the DNA and need certain processing within the cell to form functioning ICL inducers [9]. In spite of the fact that they have a history of damaging DNA, their innovative uses also aid in understanding the mechanisms they follow to contribute in various therapeutic applications.

These include psoralens that belong to the family of furocoumarins, being mutagenic are still a matter of contention with their photochemotherapeutic applications in inflammatory skin diseases like psoriasis, vitiligo and eczema [22]. The Psoralens generates adducts on interaction with pyrimidines, most often with thymine and give rise to ICLs at the sequences made up of d(TpA):d(TpA) residues [23]. The several derivatives of psoralen form multiple changes in the DNA helical structural framework and exhibit their toxic nature. The DNA duplex adducted with 4′- (aminomethyl)-4,5′,8-trimethylpsoralen (AMT) exhibited 561 unwinding and 531 bending into its major groove [24].

Another chemotherapeutic agent known as cis-platinum diamminedichloride i-e CDDP, cisplatin also induces ICLs. It makes an adduct with purines, most often at the N7 position of the guanines, hence ICL forms at d(GpC): d(GpC) sequences. This is employed in various head and neck cancers, esophageal, epithelial lung, colon, gastric, bladder along with ovarian and testicular tumors. About 90% of the total defects are formed by 1,2-IaCL and 1,3-IaCL along ICL making only 5% of the total DNA lesions [23].

Apart from these anticancer agents, one of prime importance is Adriamycin which is also termed as doxorubicin. It generates a great response against a range of tumors be it as breast tumors, acute leukemia, lymphomas, stomach, sarcomas, multiple myelomas or bone tumors. It is employed as a singly or in combined form [25]. The interaction of Adriamycin is clearly understood with the help of the *in vitro* transcription assays that demonstrates the drug-induced DNA adducts at the GpC sites [26]. The electrospray mass spectral analysis revealed details of GpC drug binding regions and gives the information that the cross links are favored by formaldehyde under the certain conditions [27]**. Table 1** illustrates the exogenous agents of Interstrand crosslink lesions.
