| emise of cells by programmed cell death referred to | | | | apoptosis-triggering drugs. A large number of |
| as apoptosis, a Greek word that means | | | | adenoviral agents are being constructed, including |
| “dropping off“ or “falling | | | | replication-incompetent and replication-selective |
| off“ as in leaves from a tree, has been | | | | oncolytic adenoviruses. One of them is ONYX-015, a |
| recently a topic of intense interest in biomedical | | | | replication-competent virus genetically engineered to |
| sciences. Apoptosis is a well-defined sequence of | | | | selectively replicate in and lyse p53-deficient cancer |
| morphological changes of cells that shrink and | | | | cells. Other agent, INGN 201, was shown to deliver a |
| condense and then fragment, releasing small | | | | p53 expression. |
| membrane-bound apoptotic bodies, which are | | | | Preclinical studies in human cell lines and animals with |
| phagocytosed by other cells. Importantly, the | | | | head and neck cancers have shown that the p53 |
| intracellular constituents are not released into the | | | | gene is transcribed and translated into p53 protein. |
| extracellular milieu where they might have deleterious | | | | Respectively, 5% and 58% of patients receiving |
| effects on neighboring cells. On the contrary, cells | | | | three intratumoral injections of INGN 201 in |
| that die in response to tissue damage or other | | | | conjunction with radiation therapy for over 6 weeks |
| reasons exhibit very different morphological changes | | | | were shown to have achieved complete and partial |
| generally called necrosis. The cells that undergo this | | | | responses. Other example may be a gene encoding |
| process swell and burst, releasing their intracellular | | | | the proapoptotic Vpr protein that was successfully |
| contents, which can damage surrounding cells and | | | | transferred into cancer cells by the HIV-1 virion. |
| often cause inflammation. Apoptosis refers to a | | | | These agents are introduced by intravascular infusion |
| particular morphology in which a chromatin condenses | | | | or intratumoral or epitumoral injections. An example |
| or coalesces to a heterochromatin in one or more | | | | of a target therapy against cancer is an intravenous |
| masses in the nucleus. It usually settles along | | | | administration of liposomal form of tretinoin (ATRA). |
| still-intact nuclear membrane referred to as | | | | Treatment of acute promyelocytic leukemia (APL) |
| margination of the chromatin. One of the essential | | | | with ATRA alone or in combination with |
| functions of apoptosis is the elimination of cells in | | | | chemotherapy results in an almost complete remission |
| which DNA damages, faulty proliferation or improper | | | | rate as high as 85% to 95%. |
| adhesion to extracellular matrix that cannot be | | | | Other proapoptotic anticancer therapeutics is |
| repaired. In cancer cells, the mechanism of apoptosis | | | | Genasense developed by the Genta Company. |
| induction is broken. Therefore, more and more ideas | | | | Genasense is a phosphothioate oligonucleotide |
| and hypotheses for selective inducing apoptosis in | | | | consisting of 18 modified DNA bases. First, the |
| cancer cells are tested in a growing number of | | | | single-stranded DNA molecule must be incorporated |
| laboratories all over the world. The subject of | | | | into a cancer cell and then target the mRNA by |
| programmed cell death has been recently discussed in | | | | having a complementary sequence to it. |
| almost 80 000 publications. As it is known, cell | | | | This drug inhibits the production of a protein known |
| apoptosis may be induced by various stress factors | | | | as Bcl-2 that is widely expressed in many types of |
| (e.g. hypoxia, expression of oncogenes, mutations, | | | | cancer. This up-regulation of Bcl-2 blocks the release |
| DNA damages). On the other hand, apoptosis may be | | | | of cytochrome C from the mitochondria thereby |
| induced via internal or external signals, for instance | | | | preventing apoptosis. Furthermore, Bcl-2 appears to |
| proteins. Some of such endogenous and exogenous | | | | be a major contributor to both inherent and acquired |
| proapoptotic proteins have been found and described. | | | | resistance to current anticancer treatments. By |
| Their genes may be used in modern anticancer | | | | inhibiting production of Bcl-2, Genasense enables the |
| therapies. | | | | cancer cells to be killed by apoptosis when treated |
| For example, introducing into cancer cells proapoptotic | | | | with current state of the art therapy. Interesting |
| genes as Bax, Bcl-X5 or E2F-1 significantly increases | | | | apoptosis-inducing drug is Velcade jointly developed |
| induction of apoptosis. Some clinical trials concern | | | | by NCI and Millenium Pharmaceuticals. Activity of |
| therapeutic application of a 121-amino acids apoptin | | | | Velcade is mainly associated with reversible inhibition |
| originated from chicken anemia virus (CAV). Recent | | | | of the proteasome and building up many proteins |
| data suggest that apoptosis induced by this protein | | | | including BAX. In the normal cells, the BAX protein |
| involves caspases, a family of cysteinyl | | | | induces apoptosis by blocking the activity of Bcl-2. |
| aspartate-specific proteinases. In vitro results show | | | | When BAX level increases, BAX inhibition of Bcl-2 also |
| that apoptin is very active against cancer cells | | | | increases and the cells undergo apoptosis. Non-clinical |
| without inducing toxicity to normal cells. This | | | | studies have demonstrated that cancer cells are |
| tumor-specific effect may be explained by the | | | | more sensitive to the effects of the proteasome |
| nuclear localization of the protein in tumor cells | | | | inhibition than normal cells. |
| required for its action. Moreover, apoptin is equally | | | | Selected references |
| active, such as p53-mutant, Bcl-2-overexpressing or | | | | Adachi, S.L.L., Carson, D.A., Nakahata, T., 2004. |
| BCR-ABL-expressing tumor cells. Other investigations | | | | Apoptosis induced by molecular targeting therapy in |
| showed that E4orf4 induces apoptosis in cancer cells | | | | hematological malignancies. Acta Haematologica 111, |
| by linking with 2A (PP2A) phosphatase. Unfortunately, | | | | 107-123. |
| induction of apoptosis by introducing genes encoding | | | | Ferreira, C.G., Epping, M., Kruyt. F.A.E., Giaccone, G., |
| proapoptotic proteins has been little known. | | | | 2002. Apoptosis: Target of Cancer Therapy. Clinical |
| One possible mechanism is associated with | | | | Cancer Research 8, 2024-2034. |
| destruction of mitochondrial membranes and, in | | | | Ghobrial, I.M., Witzig, T.E., Adjei, A.A., 2005. Targeting |
| consequence, disturbing electrons transport, oxidative | | | | Apoptosis Pathways in Cancer Therapy. CA: A |
| phosphorylation and ATP synthesis. Finally, the cell | | | | Cancer Journal for Clinicians 55, 178-194. |
| dies but the death is slightly different than that during | | | | Hengartner, M.O., 2000. The biochemistry of |
| typical apoptosis induced by caspases due to | | | | apoptosis. Nature 407, 770-776. |
| prolonged time of this process. | | | | Lowe, S.W., Lin, A.W., 2000. Apoptosis in cancer. |
| Proapoptotic proteins cannot be directly introduced | | | | Carcinogenesis 21, 485-495. |
| to cancer cells because there are no specific | | | | Tamm, I., Dorken, B., Hartmann G., 2001. Antisense |
| receptors. They are transported through membranes | | | | therapy in oncology: new hope for an old idea? |
| in complexes by special fusion proteins called ligands. | | | | Lancet 358, 489-197. |
| Other method is introducing them as genes by | | | | Tamm, I., Schriever, F., Dorken, B., 2001. Apoptosis: |
| vectors and this approach has been already | | | | implications of basic research for clinical oncology. |
| successfully applied. Clinical trials are presently | | | | Lancet Oncology 2, 33-42. |
| underway to test efficiency of new | | | | |