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.

The recent treatment protocols used in the management of children with brain tumors have greatly improved the survival rate in these patients. The authors present a review of the endocrine dysfunctions associated with the different types of treatment. Cranial irradiation is the first cause of endocrine disorders, growth failure being the main risk. A simplified protocol for endocrine evaluation and treatment of the disorders is suggested.

Serotonin (5-Hydroxytryptamine) seems to play a dominant role in triggering vomiting induced by cytotoxic agents through the stimulation of 5-HT3 receptors. They have been observed in the GI tract as well as in the brain (area postrema). Ondansetron is a specific antagonist of 5-HT3 serotonin receptors. Its anti-emetic activity is very powerful in the ferret. The availability of an injectable or oral form of this product allows the overall treatment of acute and delayed emesis and its administration is in accordance with different schedules: single IV injection or a continuous 24 hour infusion or repeated IV injection followed by oral treatment. The pharmacokinetics of the drug are as follows: absorption begins about 30 minutes after the administration per os, its biodisponibility is about 60%, its clearance: 20 ml/minute and its elimination half life about 3 hours. Different double blind studies, carried out in parallel groups or in cross over, demonstrated the superiority of ondansetron over metoclopramide in the control of nausea and vomiting, whether or not the chemotherapy contained cisplatin; a more recent study shows also that ondansetron was superior to alizapride and methylprednisolone in combination. Side effects of ondansetron do not include extrapyramidal symptoms but only headaches and constipation. The use of ondansetron improves the well-being of patients receiving chemotherapy and increases protocol compliance.

The photodynamic therapy of cancer (PDT) by porphyrins is now at a turning point with the advent of phase III clinical trials. The transport of photofrin II and its delivery to tumor cells and vasculature is believed to be a determinant of tumor necrosis by suppressing the oxygen supply. However, this treatment must be improved by increasing the selectivity of the photosensitizer uptake by tumors and also by using photosensitizers absorbing in the 700-800 nm range where tissues have the highest transmittance. In addition, these new photosensitizers (chlorines, phthalocyanines...) should be rapidly excreted to avoid the only secondary effect of the PDT: the long-lasting photosensitivity of the patient skin. Finally, the combination of PDT with other therapies or its chemopotentiation by "bioreductive" drugs which interfere with the metabolism of hypoxic cells resulting from the PDT are potential means for improving the effectiveness of this new modality for cancer treatment.

Germinal cells are particularly sensitive to cancer chemotherapy in males. This toxicity is difficult to evaluate. It is the most frequently observed in young patients treated for curable cancers, by alkylants, specially if the treatment is intense and long. Depending on the patient and his age, on the cancer and its treatment, recovery of a normal spermatogenesis may be observed in a minority of cases and sometimes lately. This hazard must be told to the patient who is invited to preserve his sperm which is not always of enough good quality. There is no proved means to protect gonadal function. Therefore modifications of chemotherapy are desirable to decrease its toxicity.