Programmed cell death, or apoptosis, corresponds to a sequence of intracellular events that lead to cell death. It has been shown that apoptosis is necessary in some physiological conditions such as embryogenesis, homeostasis of the immune system, erythropoiesis, etc. Some xenobiotics can induce apoptosis at lower doses and necrosis at higher doses. When a cell dies, it is either by apoptosis or by necrosis, and there are many differences between these two deaths. Apoptosis begins by a pre-commitment phase, which is reversible; during this phase the cell has a high level of second messengers. The commitment phase then follows and is irreversible, even when the xenobiotic that triggered the induction is removed. Most often, apoptotic cell death requires synthesis of macromolecules, the inhibition of their synthesis can prevent it. The cell undergoes important morphological changes during apoptosis, its volume decreases when its density increases. Then chromatin becomes granular, intensively osmiophilic, it condenses along the nuclear membrane. Later, chromatin disintegrates into small granules which will be phagocytized. One of the most important characteristics of the programmed cell death is the activation of an endonuclease, that gives rise to DNA fragments of 180-200 base pairs or multiples of these numbers; then after electrophoresis, the DNA gives the appearance of a ladder. Apoptotic cells can be characterized after classic staining, and flow cytometry; they can be separated from other cells by centrifugation on a gradient of density. It has been hypothesized that cell transformation could be due to a sudden resistance to apoptosis. However, the most interesting aspect in oncology recently demonstrated is that well-known anticancer drugs are able to induce apoptosis. One can hope that the discovery of new targets for anticancer drugs could lead to discovering new drugs that could be more active.

The biological activity of spindle poisons can easily be measured using an in vitro assay based on the interaction of these substances with their cellular "receptor": tubulin. The use of this assay led us to select Navelbine and Taxotere as antimitotic substances. These compounds, as well as their natural parents: vincaleucoblastine, leurocristine and taxol respectively, have been obtained by semi-synthesis using relatively abundant natural precursors as starting materials. This paper summarizes the preparation of these important anticancer drugs.

Nurses are exposed to a variety of risks while handling cytotoxic drugs. A study was conducted in 6 different hospitals where those drugs are used. We inquired about the nurses information about their possible toxicities and the protection measures used while preparing and giving these drugs. The results showed that 50% of the 43 nurses questioned don't have complete information about these toxicities and nearly 60% of them do not apply any preventive measure for safe handling of the drugs especially the use of disposable gloves, the use of coveralls with long sleeves and the use of protective glasses.

The development of new chemotherapeutic protocols especially those cisplatin containing regimens, has lead to a dramatic improvement of remission rates in certain cancers. Nausea and vomiting seems to be the most distressing side effect from the patients point of view. A good administration of classical anti-emetic drugs should yield to at least 50% of good protection. The introduction of new drugs should even give more protection to our patients.

Activation of coagulation and of the fibrinolytic system has been identified in small cell and non-small cell cancers respectively. For the clinician this poses the diagnostic problem of a thrombosis, which is most often venous with or without pulmonary emboli, complicating the evolution of an already diagnosed cancer. The inverse is that these features may reveal an underlying neoplasm and amongst the most common of these would be bronchopulmonary cancer. Numerous laboratory studies have shown the existence of a state of hyper-coagulability, with disseminated intra-vascular coagulation, which is more or less compensated and is the more marked, the more advanced the cancer is. One should not fail to recognise that this state of hyper-coagulability may be aggravated by certain cytotoxic drugs. At the level of the tumour itself, there seems to be interactions between the cancer cells and the coagulation and fibrinolytic system: these interactions are very different according to the histological type as to whether they are small cell or non-small cell bronchopulmonary cancers.

The usual form of chemotherapy of metastatic small cell lung cancer gives a 50% objective response with a mean survival of 7-8 months. We have tested a new antimitotic drug using pirarubicin alone in 26 patients. After the second treatment we noticed a response level of 12% with moderate toxicity. Then, we undertook classical chemotherapy using cisplatin-V16. After 3 doses the response level was 50% with a median survival of 32 weeks. In our study the use of a single drug pirarubicin in metastatic small cell cancer did not appear to worsen the chance of survival in patients if polychemotherapy was carried out immediately in cases which failed on the single drug. Our monotherapy did not appear to induce resistance to affective polychemotherapy. This method applied carefully to patients with metastatic disease with a strict follow up may be utilised in the assessment of the efficacy of the newer antimitotic drugs.

A comparative study was made, in the mouse, on antiviral properties of a prodrug of n-butyric acid derived from monosaccharides: monoacetone glucose 3-butyrate (MAG = 3but), and of a free form of n-butyric acid: arginine butyrate (BuO Arg). Preventive injection of MAG = 3but protected the mice twice as effectively as BuO Arg against the lethal effect of 100 LD50 of encephalomyocarditis virus. Under the same experimental conditions, monoacetone glucose (MAG) used as carrier of the biologically active moiety, was inactive on its own. Antiviral activity of MAG = 3but was shown not to be virucidal, but rather could involve stimulation of the immune system. This capability supplements known anticellular and antitumoral properties. In total these results indicate a prime therapeutic importance for this new molecule, pharmacokinetically suitable, with its very low toxicity, for clinical application. Combined use of MAG = 3but with biological response modifiers which have similar affinity, such as Interferon, is discussed.

A bacterial extract from Vibrio cholerae, the DGZ, has been separated into two fractions by gel filtration. The effects of these two fractions and that of the crude extract are investigated and compared by two different in vitro tests. It appears that these extracts exert direct inhibition over the growth of 3LL cultured cells and that they trigger splenocytes in vitro proliferation.

During the last thirty years, the systematic screening of thousands of vegetal extracts has led to the isolation of numerous antitumor agents which belong to various chemical series. This paper only deals with some of them which are either of current clinical use or under advanced clinical experimentation, e.g., ellipticine, homoharringtonine, camptothecine, acronycine and their derivatives. The origin, the biological activity and its mechanism, and the toxicity of each of these alkaloids are described. These examples highlight the interest of the Plant Kingdom as source of biologically active new structures and the importance of a good knowledge of the mechanism of the activity and toxicity of active components. This knowledge gives a rational basis to prepare compounds of increased activity or reduced toxicity and to use them at their best in therapeutic.

The blood-brain barrier (BBB) is located between the blood and the extracellular space of the brain. This barrier is formed by the brain capillaries whose endothelial cells have tight intercellular junctions. Transcellular passage of drugs from the bloodstream to the brain occurs selectively, in a manner dependent on the ability of the molecules to penetrale through cell membranes. The blood-brain barrier is one of the main factors of chemotherapy failure in central nervous system tumors. Penetration of a molecule from the bloodstream to the brain is dependent on the compound's liposolubility, expressed by the octanol-water separation coefficient. Following intravenous administration, most drugs fail to achieve adequate levels in the central nervous system for a sufficiently long period of time. A variety of techniques have been used in an attempt to increase CNS penetration of drugs normally shut out by the blood-brain barrier: high-dose chemotherapy, intrathecal injections, intraarterial injections, induction of hyperosmolarity to make the blood-brain barrier permeable. The best results are obtained using liposoluble drugs with optimal octanol-water separation coefficients, such as fotemustine. This compound given as single drug therapy in brain metastases from malignant melanomas has yielded response rates of up to 28.2%.

Life prolongation in cancer patients is attended by a greater frequency of renal lesions associated with chemotherapy, and in the last few years cancer patients cured or in lasting remission have begun to haunt dialysis centres. Before blaming the renal toxicity of cytotoxic drugs, it is necessary to exclude all other causes of renal dysfunction (pre-renal, obstructive, iatrogenic or cancer-related). The renal toxicity of certain drugs, such as cisplatin, cyclophosphamide, ifosfamide, streptozocin, nitrosoureas, methotrexate, mitomycin C and recombinant IL2, is of importance as it is frequent and limits their use. The dangers of anticancerous drugs combinations, concomitant administration of other nephrotoxic drugs (antibiotics, non-steroidal anti-inflammatory agents) and extracellular dehydration created by gastrointestinal disorders must be borne in mind. Careful evaluation of renal function prior to chemotherapy, application of preventive measures with proven efficacy and repeated laboratory tests in short-mid- and long-term should reduce the frequency of renal complications while preserving or even improving therapeutic effectiveness.

Intra-peritoneal chemotherapy and immunotherapy are recent techniques for the treatment of tumours in the ovary. Chemotherapy is used more for the intra-peritoneal route. It is valuable because of the natural history of the disease and because of the pharmacological properties of many antimitotic drugs. Indwelling catheters have made this method easier and more acceptable to the patients. The drugs most used are cistplatinum and carboplatinum but mitoxantrone seems to be a very promising drug. The use of immunomodulators is just starting. Intra-peritoneal treatment should be at present reserved for small masses (less than 2 cm in diameter) whether used as a follow-up treatment or as a primary treatment in association with general chemotherapy.

Myelosuppression is the main limiting factor in cancer chemotherapy. The development of recombinant hematopoietic growth factors which stimulate myeloid progenitors and mainly neutrophil precursor cells leads to the evaluation of their potential activity in numerous fields of oncology. The available clinical trials have demonstrated the ability of G-CSF (granulocyte colony-stimulating factor) and GM-CSF (granulocyte-macrophage colony-stimulating factor) to accelerate neutrophil recovery following cytotoxic chemotherapy, and therefore to reduce the incidence of neutropenic febrile episodes and thereby improve the quality of life of patients receiving chemotherapy. The main goals of the future studies will be to determine to what extent the increase of dose intensity may lead to higher response rates and survival at least in patients with chemosensitive tumors.

We studied a series of 42 patients with advanced ovarian cancer who received intraperitoneal chemotherapy post second-look laparotomy. High-dose cisplatin (200 mg/m2) alone or in combination with cytarabine (2 g) achieved 47% response rate. Median overall survival from second-look laparotomy was 44 months with cisplatin (36 cases), 15 months with carboplatin (600 mg/m2, 5 cases) and not reached at 3 yrs with mitoxantrone (25 mg/m2, 8 cases). Median overall and progression-free survival from second-look laparotomy were 44 and 39 months respectively in complete responders (15 cases), 20 months and 9 months where residual tumor less than 2 cm (21 cases), 22 and 12 months where tumor greater than 2 cm (6 cases). There was a significant difference in survival (P = 0.01) and progression-free survival (P = 0.002) between complete responders and patients whose tumor was less than 2 cm. Toxicity was acceptable except for carboplatin with constant grade 4 leukocytes or platelets toxicity. It was not demonstrated that high-dose intraperitoneal chemotherapy given post second-look laparotomy will improve survival in advanced ovarian cancer. Further studies of polychemotherapy or early administration are needed.

Cerebral metastases of malignant melanoma are correlated with a very poor prognosis. Surgery of an isolated metastase can lead to a long survival but the brain lesions are frequently numerous and associated with an extracerebral diffusion. Dacarbazine (DTIC) gives a mean response rate of 21% on visceral localisations but doesn't cross the blood brain barrier (BBB). Neither do the biological response modifiers like Interleukin 2 (Il2) that leads to 25% response rate in disseminated melanoma. Nitrosoureas like carmustine (BCNU) and semustine (CCNU) have been investigated in different non randomised studies and the clinical results didn't illustrate their theorical ability to cross the BBB. Radiotherapy is also used as a palliative therapy with 7 to 16 weeks survival. Fotemustine (muphoran), a new amino acid linked nitrosourea, can give a response rate up to 28.2% in patients with cerebral metastases and the increased survival of responding patients is significant. The availability of this new drug may suggest associations with surgery and radiotherapy in the future to improve the survival of such patients.

The authors report a case of a patient dying as a result of a myocardial infarction which was probably related to the administration of vinorelbine, the vinca alkaloid recently introduced into the treatment of non small cell bronchial cancers.