Prodrugs In Cancer Chemotherapy Research Articles

Macromolecular Co-Conjugates of Methotrexate and Ferrocene in the Chemotherapy of Cancer

Novel anticancer “as reported by Neuse (Synthetic Polymers as Drug-Delivery Vehicles in Medicine, Hindawi Publishing Corporation, Cairo, 2008) and Mufula (Macromolecular Derivatives of Methotrexate and Ferrocene as Potential Prodrugs in Cancer Chemotherapy, MSc. Dissertation, School of Chemistry, Wits University, Cambridge, 2010)” drugs with enhanced therapeutic effectiveness were synthesized through the concept of drug co-conjugation with polymer carriers. The expected benefits are synergistic effects, which can potentially lead to reduction in doses and side effects caused by high dose of single drug, and the prevention of the development of multi-drug resistance. Multidrug-binding ability of polyaspartamide-type carriers was demonstrated by the co-conjugation with ferrocene and methotrexate (MTX) to the polymer carriers as well as the co-conjugation of ferrocene and folic acid in a two step process involving the HBTU coupling method. The degree of MTX incorporated was found in the range of 10–19% by mass and the degree of Fe found was in the range of 6–13% by mass for the first step of coupling. The degrees MTX, Fe and FA were found to be in the range of 17–27%, 15–16% and 24–26% respectively for the second step.

Intramolecular cyclization of N-phenyl N′(2-chloroethyl)ureas leads to active N-phenyl-4,5-dihydrooxazol-2-amines alkylating β-tubulin Glu198 and prohibitin Asp40

The cyclization of anticancer drugs into active intermediates has been reported mainly for DNA alkylating molecules including nitrosoureas. We previously defined the original cytotoxic mechanism of anticancerous N-phenyl- N′-(2-chloroethyl)ureas (CEUs) that involves their reactivity towards cellular proteins and not against DNA; two CEU subsets have been shown to alkylate β-tubulin and prohibitin leading to inhibition of cell proliferation by G 2/M or G 1/S cell cycle arrest. In this study, we demonstrated that cyclic derivatives of CEUs, N-phenyl-4,5-dihydrooxazol-2-amines (Oxas) are two- to threefold more active than CEUs and share the same cytotoxic properties in B16F0 melanoma cells. Moreover, the CEU original covalent binding by an ester linkage on β-tubulin Glu198 and prohibitin Asp40 was maintained with Oxas. Surprisingly, we observed that Oxas were spontaneously formed from CEUs in the cell culture medium and were also detected within the cells. Our results suggest that the intramolecular cyclization of CEUs leads to active Oxas that should then be considered as the key intermediates for protein alkylation. These results will be useful for the design of new prodrugs for cancer chemotherapy.

The Cytotoxic Activity of Macromolecular Ferrocene Conjugates Against the Colo 320 DM Human Colon Cancer Line

Water-soluble and biocompatible polymers containing bioreversibly attached ferrocene units as side chain terminals have in recent years attracted interest in drug research. In preliminary screens, polymers of this type have shown high antiproliferative activity against selected human carcinoma cell lines, paired with low in vivo toxicity. They may thus lend themselves as efficacious prodrugs in cancer chemotherapy. Cancers of the intestinal system are known to resist chemotherapeutic treatment. This general lack of sensitivity of the colorectal malignancies prompted us to investigate the in vitro behavior of selected carrier-bound ferrocene prodrugs against the Colo 320 DM cell line, a representative human adenocarcinoma of the colon. The findings of this investigation are reported in the present communication. The carriers 1 to 10 used for conjugation with the metallocene are water-soluble aliphatic polyamides featuring primary or secondary amine functionality as side chain terminals or main chain constituents. By previously developed methodology these amino groups are coupled with the ferrocenylation agent, 4-ferrocenylbutanoic acid, generating the target conjugates 1-Fc to 10-Fc, in which the metallocene is bound through amide or hydrazone links. Cell culture tests are performed by established protocol against the Colo line and, for comparison, also against the HeLa cells. Significantly, while outstanding performance is observed for most of the conjugates against both cell lines, the results indicate activities in the Colo screens to be higher on average than determined in the sensitive HeLa tests.

Prodrugs in Cancer Chemotherapy.

At present, chemotherapy is not very effective against common solid cancers especially once they have metastasised. However, laboratory experiments and studies on dose intensification in humans have indicated that some anti-cancer agents might be curative but only if the dose given was very much higher than that presently obtainable clinically. Prodrugs, activated by enzymes expressed at raised level in tumors, can deliver at least 50-fold the normal dose and can cure animals with tumors normally resistant to chemotherapy. This approach has not yet proved to be practicable clinically because of the rarity of human tumors expressing a high level of an activating enzyme. However, new therapies have been proposed overcome this limitation of prodrug therapy. Enzymes that activate prodrugs can be directed to human tumor xenografts by conjugating them to tumor associated antibodies. After allowing for the conjugate to clear from the blood a prodrug is administered which is normally inert but which is activated by the enzyme delivered to the tumor. This procedure is referred trials are promising and indicate that ADEPT may become an effective treatment for all solid cancers for which tumor associated or tumor specific antibodies are known. Tumors have also been targeted with the genes encoding for a prodrug activating enzymes. This approach has been called gene-directed enzyme prodrug therapy (GDEPT) or VDEPT (virus-directed enzyme prodrug therapy) and has shown good results in animal models. These new therapies may finally realise the potential of prodrugs in cancer chemotherapy.

Prodrugs in cancer chemotherapy.

At present, chemotherapy is not very effective against common solid cancers, especially once they have metastasized. However, laboratory experiments and studies on dose intensification in humans have indicated that some anticancer agents might be curative, but only if the dose given was very much higher than that attainable clinically. Prodrugs activated by enzymes expressed at a high level in tumors can deliver at least 50-fold the normal dose and can cure animals with tumors normally resistant to chemotherapy. The approach is not practicable clinically because of the rarity of human tumors expressing a high level of an activating enzyme. However, new therapies have been proposed that overcome this limitation of prodrug therapy. Enzymes that activate prodrugs can be directed to human tumor xenografts by conjugating them to tumor-associated antibodies. After allowing for the conjugate to clear from the blood a prodrug is administered which is normally inert, but which is activated by the enzyme delivered to the tumor. This procedure is referred to as ADEPT (antibody-directed enzyme prodrug therapy). Using different combinations of antibody, enzyme and prodrug, many classes of human tumor xenograft have been shown to be very sensitive to this procedure although in most cases they are quite resistant to conventional chemotherapy. Early clinical trials are promising and indicate that ADEPT may become an effective treatment for all solid cancers for which tumor-associated or tumor-specific antibodies are known. Tumors have also been targeted with the genes encoding for prodrug activating enzymes. This approach has been called virus-directed enzyme prodrug therapy (VDEPT) or more generally GDEPT (gene-directed enzyme prodrug therapy) and has shown good results in laboratory systems. These new therapies may finally realize the potential of prodrugs in cancer chemotherapy.

Prodrugs in cancer chemotherapy.

Prodrugs in cancer chemotherapy.

Prodrugs in cancer chemotherapy.

At present, chemotherapy is not very effective against common solid cancers especially once they have metastasised. However, laboratory experiments and studies on dose intensification in humans have indicated that some anti-cancer agents might be curative but only if the dose given was very much higher than that presently obtainable clinically. Prodrugs, activated by enzymes expressed at raised level in tumors, can deliver at least 50-fold the normal dose and can cure animals with tumors normally resistant to chemotherapy. This approach has not yet proved to be practicable clinically because of the rarity of human tumors expressing a high level of an activating enzyme. However, new therapies have been proposed overcome this limitation of prodrug therapy. Enzymes that activate prodrugs can be directed to human tumor xenografts by conjugating them to tumor associated antibodies. After allowing for the conjugate to clear from the blood a prodrug is administered which is normally inert but which is activated by the enzyme delivered to the tumor. This procedure is referred to as ADEPT (antibody-directed enzyme prodrug therapy). Early clinical trials are promising and indicate that ADEPT may become an effective treatment for all solid cancers for which tumor associated or tumor specific antibodies are known. Tumors have also been targeted with the genes encoding for a prodrug activating enzymes. This approach has been called genedirected enzyme prodrug therapy (GDEPT) or VDEPT (virus-directed enzyme prodrug therapy) and has shown good results in animal models. These new therapies may finally realise the potential of prodrugs in cancer chemotherapy.