The interaction of bifunctional alkylating agents with the DNA of tumour cells

The DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT), is inactivated by reaction with the pseudosubstrate, O6-benzylguanine (BG). This inactivation sensitizes tumour cells to chemotherapeutic alkylating agents, and BG is aimed at enhancing cancer treatment in clinical trials. Point mutations in a 24 amino acid sequence likely to form the BG-binding pocket were identified using a screening method designed to identify BG-resistant mutants. It was found that alterations in 21 of these residues were able to render AGT resistant to BG. These included mutations at the highly conserved residues Lys165, Leu168 and Leu169. The two positions at which changes led to the largest increase in resistance to BG were Gly156 and Lys165. Eleven mutants at Gly156 were identified, with increases in resistance ranging from 190-fold (G156V) to 4400-fold (G156P). Two mutants at Lys165 found in the screen (K165S and K165A) showed 620-fold and 100-fold increases in resistance to BG. Two mutants at the Ser159 position (S159I and S159V) were > 80-fold more resistant than wild-type AGT. Eleven active mutants at Leu169 were also resistant to BG, but with lower increases (5-86-fold). Fourteen BG-resistant mutants were found for position Cys150, with 3-26-fold increases in the amount of inhibitor needed to produce a 50% loss of activity in a 30 min incubation. Six BG-resistant mutants at Asn157 were found with increases of 4-13-fold. These results show that many changes can render human AGT resistant to BG without preventing the ability to protect tumour cells from therapeutic alkylating agents.

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Effect of alkylating agents on the life cycle of Ehrlich tumour cells

European Journal of Cancer (1965) ◽

10.1016/0014-2964(65)90056-3 ◽

1965 ◽

Vol 1 (3-4) ◽

pp. 245-251 ◽

Cited By ~ 12

Author(s):

G. Palme ◽

E. Liss

Keyword(s):

Life Cycle ◽

Alkylating Agents ◽

Tumour Cells

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Alkylating Agents, the Road Less Traversed, Changing Anticancer Therapy

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210811105344 ◽

2021 ◽

Vol 21 ◽

Author(s):

Dipanjan Karati ◽

Kakasaheb Ramoo Mahadik ◽

Piyush Trivedi ◽

Dileep Kumar

Keyword(s):

Nitrogen Mustard ◽

Alkylating Agents ◽

Health Hazard ◽

High Reactivity ◽

Tumour Cells ◽

International Agency ◽

The Road ◽

Design And Synthesis ◽

Therapeutic Consequences ◽

Aziridinium Ion

: Cancer is considered one of the gruelling challenges and poses a grave health hazard across the globe. According to the International Agency for Research on Cancer (IARC), new cancer diagnoses increased to 18.1 million in 2018, with 9.6 million deaths, bringing the global cancer rate to 23.6 million by 2030. In 1942, the discovery of nitrogen mustard as an alkylating agent was a tremendous breakthrough in cancer chemotherapy. It acts by binding to the DNA, and creating cross linkages between the two strands, leading to arrest of DNA replication and eventual cell death. Nitrogen lone pairs of ‘nitrogen mustard’ produce an intermediate 'aziridinium ion' at molecular level, which is very reactive towards DNA of tumour cells, resulting in multiple side effects with therapeutic consequences. Owing to its high reactivity and peripheral cytotoxicity, several improvements have been made with structural modifications for the past 75 years to enhance its efficacy and improve the direct transport of drugs to the tumour cells. Alkylating agents were among the first non-hormonal substances proven to be active against malignant cells and also, the most valuable cytotoxic therapies available for the treatment of leukaemia and lymphoma patients. This review focus on the versatile use of alkylating agents and the structure activity relationship (SAR) of each class of these compounds. This could provide an understanding for design and synthesis of new alkylating agents having enhanced target specificity and adequate bioavailability.

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