Also the prodrug to drug differential needs to be

Also, the prodrug to drug differential needs to be very high. Whereas the differential of the prodrug/drug pairs for CPG2 was about 100:1, Tietze et al. have reported a series of glycosidic prodrugs that are up to million times less toxic than the drug that showed IC50 of 110fM [13]. In addition, they have reported a glucuronide prodrug that was 1000–5000 fold less toxic than the parent duocarmycin drug [66]. These are most encouraging studies and should be developed for clinical investigations.
Conflicts of interest Funding for ADEPT research over the years included Cancer Research UK, Post Natal Choriocarcinoma Trust, Royal Free Cancer Research Trust, AstraZeneca and National Translational Cancer Research Network.
A major limitation of the use of cancer chemotherapy results from the lack of tumour specificity shown by most anticancer drugs. Many clinically used agents act predominantly through an antiproliferative mechanism which leads to damage of normally multiplying ganciclovir such as those of the bone marrow and gut. Therefore, chemotherapy is often linked to severe side effects due to the destruction of healthy tissue. One strategy to overcome this problem involves the use of non-biologically active prodrug derivatives of cytotoxic agents that can be selectively activated at the tumour site. In the antibody directed prodrug therapy (ADEPT) approach, an antibody–enzyme conjugate is used to localize an enzyme at the tumour site. A prodrug form of a cytotoxic agent, that can be converted to the active agent by the antibody-linked enzyme, is then administered systemically leading to selective release of the cytotoxic agent at the tumour site. An important feature of this system is that the releasing enzyme is of non-human origin (e.g., bacterial), thus avoiding release of the cytotoxic agent at other sites in the body. It has also been suggested that a bystander effect may enhance the efficacy of treatment, with the cytotoxic agent produced within the tumour diffusing out to neighbouring cells. One such system is presently in clinical trials and involves a fusion protein conjugate of the A5B7 F(ab’)(2) antibody and the enzyme carboxypeptidase G2 (CPG2) targeted against colorectal carcinoma expressing carcinoembryonic antigen (CEA). This is being used in conjunction with a nitrogen mustard prodrug ZD2767P (, ). However, with this combination of agents, therapeutic efficacy may be limited due to rapid repair of the DNA adducts formed after release of the cytotoxic agent, a commonly occurring phenomenon with mustard-based drugs. To address this issue, we have designed and synthesized two novel families of pyrrolobenzodiazepine (PBD)-based prodrugs (, and ,; ) that are not only more potent (i.e., picomolar) compared to mustard-based prodrugs but their adducts may be more resistant to repair,, thus reducing the probability of clinical resistance developing. The pyrrolo[2,1-][1,4]benzodiazepines (PBDs) are a family of antitumour antibiotics that includes the natural products anthramycin and DC-81. They exert their cytotoxicity by covalently bonding to the exocyclic C2–NH group of guanine residues in the minor groove of DNA through their N10–C11 imine functionality. This leads to a number of biological effects including the inhibition of transcription, and of enzymes binding to cognate sites., The PBD monomers have significant in vitro cytotoxicity, and it has been demonstrated that joining two PBD moieties through a linker (via their C8-positions) leads to PBD dimers capable of interstrand DNA cross-linking., , One example of a PBD dimer, SJG-136 (, ), is now being evaluated in Phase 1 clinical trials., One interesting property of PBD dimers is that the interstrand cross-linked adducts they form in the minor groove of DNA appear to be highly resistant to repair,, and it is this feature that may lead to ADEPT prodrugs with distinct advantages over ZD2767P (, ). To explore the potential of using these extremely cytotoxic molecules in prodrug systems, we initially demonstrated the possibility of converting PBD monomers into nitroreductase-sensitive prodrugs. We now report the design, synthesis and evaluation of four model self-immolative CPG2 PBD prodrugs (, and ,, ) formed from the PBD monomer and dimer (Pentamethylene linker between PBD units), respectively, potentially suitable for use in CPG2-based ADEPT therapy. Prodrugs of this type should have an advantage over existing mustard-based prodrugs both in terms of potency and/or resistance to DNA repair.