N2,N4,N6-tri(hydroxymethyl)-N2,N4,N6-trimethylmelamine (trimelamol) is an efficient DNA cross-linking agent in vitro

Jackson, Claire; Hartley, John A.; Jenkins, Terence C.; Godfrey, Russell; Saunders, Richard H.; Thurston, David E.

doi:10.1016/0006-2952(91)90343-4

Cited by 10 publications

(5 citation statements)

References 13 publications

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“…Hartley and Thurston have addressed the concern that ISC formation by trimelamol (and HMM by induction) may result not from covalent attachment of the drug to DNA, but rather from formaldehyde-mediated cross-linking (resulting from deformylation of 137 , Scheme ) . That formaldehyde cross-links 5‘ ApT 3‘ via methylene bridging of the two N 6 exocyclic amines of deoxyadenosine has been demonstrated by Hopkins et al Indeed, an analogous situation has recently been disclosed in the case of ISC formation by the anthracycline drugs doxorubicin and daunorubicin (section 5.3).…”

Section: 2 Nnn ‘N ‘N ‘N ‘-Hexamethylmelamine and Related Structuresmentioning

confidence: 94%

“…That trimelamol mimics the mechanism of action of hexamethylmelamine and structurally related congeners has been stipulated by the known metabolic pathway leading to demethylation of each trimelamine exocyclic nitrogen via P-450-mediated carbinolamine formation . Little is known about the mechanism of action of the parent compound HMM; however, some data (in vitro) have been generated pertaining to the reaction of trimelamol with linearized plasmid PBR322 DNA …”

Section: 2 Nnn ‘N ‘N ‘N ‘-Hexamethylmelamine and Related Structuresmentioning

confidence: 99%

“…The viability of interstrand cross-linking via formaldehyde was probed in two ways . First, it was demonstrated that in the presence of thiophenol, trimelamol gave rise exclusively to the trisubstituted thioether adduct.…”

Section: 2 Nnn ‘N ‘N ‘N ‘-Hexamethylmelamine and Related Structuresmentioning

confidence: 99%

“…That the two alkylation events leading to ISC generation proceed in rapid succession and perhaps simultaneously has been suggested. Like mechlorethamine, the second alkylation (typically rate limiting for many cross-linking agents) appears too fast to be measured, thus suggesting that monoalkylation brings the highly activated imminium species of the “second arm” in close enough proximity to the second strand such that almost immediate reaction occurs, presumably with little or no structural perturbation of the target duplex …”

Section: 2 Nnn ‘N ‘N ‘N ‘-Hexamethylmelamine and Related Structuresmentioning

confidence: 99%

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DNA Cross-Linking Agents as Antitumor Drugs

1998

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Section: 2 Nnn ‘N ‘N ‘N ‘-Hexamethylmelamine and Related Structuresmentioning

confidence: 94%

Section: 2 Nnn ‘N ‘N ‘N ‘-Hexamethylmelamine and Related Structuresmentioning

confidence: 99%

Section: 2 Nnn ‘N ‘N ‘N ‘-Hexamethylmelamine and Related Structuresmentioning

confidence: 99%

Section: 2 Nnn ‘N ‘N ‘N ‘-Hexamethylmelamine and Related Structuresmentioning

confidence: 99%

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DNA Cross-Linking Agents as Antitumor Drugs

1998

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“…Meeting the life-year (QALY) threshold will require substantial reductions in primary immunotherapy. As a result, NICE does not recommend routine use of some IO drugs in the NHS [22][23][24][25].…”

Section: Cost Of Immuno-oncology Therapiesmentioning

confidence: 99%

Immunological Compounds for Cancer Therapy

Garg

2024

IJHMP

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In recent years, cancer therapy has envolved from traditional methods such as surgery, radiotherapy, chemotherapy, targeted therapies, including immuno-oncology (IO) This innovative approach uses the body the immune system’s role in fighting cancer cells has shown exceptional success. Biomarker testing, particularly PD-L1, is now mandatory before treatments such as pembrolizumab (Keytruda) for lung, stomach, head and neck cancer, and atezolizumab (Tecentriq) for cervical and endometrial cancer cancer but PD-L1 is important for other cancers is uncertain and Despite progress, challenges in managing the side effects and high costs of IO persist, causing concern for the NHS and other healthcare systems. Furthermore, the IO pipeline includes promising CAR-T cell therapies and cancer therapies, although these present unique toxicity and cost challenges. Immunotherapies can be used as a delivery mechanism by attaching a monoclonal antibody to a chemotherapy drug to make an antibody drug conjugate (ADC). The antibody seeks out and hones in on a specific molecule on the tumor cell, bringing the chemotherapy with it.

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Alkylating Agents and Platinum Antitumor Compounds

Siddik

2017

Holland‐Frei Cancer Medicine

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Overview Alkylating agents and platinum‐based compounds are highly potent antitumor drugs used in the treatment of a variety of cancers. These drugs target DNA (deoxyribonucleic acid) but require activation by spontaneous or metabolic transformation to induce formation of DNA monofunctional adducts and interstrand and intrastrand crosslinks. As a result of this damage, the DNA unwinds and/or bends, and such distortions are then recognized by specialized DNA damage recognition proteins to activate checkpoints, which arrest the cell cycle to allow cells time to repair the damage and survive. If the DNA damage is extensive and repair cannot be completed, then cells activate p53‐dependent or independent apoptosis (programmed cell death) to affect antitumor drug response. As activated species from alkylating agents and platinum compounds are not tumor‐selective, they will also interact with DNA and other endogenous macromolecules in normal cells to induce severe side effects; at times the toxicity can be irreversible and cumulative and, thereby, presents a dose‐limiting barrier. Another limitation is that genetic changes in tumors that are either intrinsic or acquired can inhibit apoptosis and induce resistance to alkylating and platinating drugs. Resistance mechanisms may be observed in the form of reduced drug accumulation, increased drug inactivation, increased DNA repair, failure of DNA damage recognition system to recognize the damage, and aberrant apoptotic signal transduction pathways. Rational strategies to circumvent resistance mechanisms are, therefore, needed desperately to enhance patient care.

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N2,N4,N6-tri(hydroxymethyl)-N2,N4,N6-trimethylmelamine (trimelamol) is an efficient DNA cross-linking agent in vitro

Cited by 10 publications

References 13 publications

DNA Cross-Linking Agents as Antitumor Drugs

DNA Cross-Linking Agents as Antitumor Drugs

Immunological Compounds for Cancer Therapy

Alkylating Agents and Platinum Antitumor Compounds

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