Cytotoxic agents used in various therapies (anticancer treatments in particular) are known to be very deleterious to male fertility. In these situations, both quantitative (oligo and azoospermia) and qualitative alterations of the male reproductive system occur. What are the various possibilities to protect male reproduction? Sperm cryo-storage, prior to the beginning of chemotherapy and/or radiotherapy, is one possibility. However this possibility can only be offered to a relatively limited number of patients, due to the fact that the disease itself often causes gonadal abnormalities. Another possibility is the substitution of the most cytotoxic drugs by less deleterious agents, as well as, the reduction of the doses used in the therapeutic regimens. Progress in this field however remains very slow. Therefore, the use of various protective agents appears to be necessary. Of all the agents so far tested (anti-oxidants, GnRH analogs, FSH, steroids), the combination of medroxyprogesterone acetate and testosterone (MPA+T) is the one which has been the most studied both in men (contraception) and in rodents (contraception and protection). From a series of experiments using MPA+T in male rats, it appears that both qualitative and quantitative protection of fertility can be achieved against chemo- and radiotherapy. Progress in this field should be the prelude of clinical trials. This transfer from animals to men, should result as one of the activities of a pluri-disciplinary group supported by INSERM and entitled "Prosperm". The dialogue established in this group between researchers and physicians offers new perspectives in the domain of protection of spermatogenesis, at a time when this is most needed.(ABSTRACT TRUNCATED AT 250 WORDS)

Antimitotic chemotherapy and radiation therapy can induce temporary or permanent infertility in men, transitory amenorrhea or premature ovarian failure in women, and genetic mutations responsible of fetal deaths or congenital malformations in the progeny. Alkylating agents and radiotherapy can provoke definitive male infertility and ovarian failure, but individual susceptibility seems quite variable. In man, return of spermatogenesis can still be observed more than 10 years after treatment and pregnancies are obtained with very low sperm counts. In women, the progressive depletion of the follicular pool explains the increasing frequency of ovarian failure, with lower doses of treatment. Antimitotic and immunosuppressive therapy can also induce irreversible lesions in children's gonads.

A prospective comparative study of the alveolar bone resorption after teeth extraction was achieved in a series of 79 patients in order to analyze macroscopically the possible consequences of radiotherapy and chemotherapy on the toothless edges. After quarterly coronal and sagittal X-rays for two years, this study enhances quite a similar vertical resorption for the radiation and chemotherapy-treated patients as well as for the witness patients. The alveolar bone resorption progression also appears unaltered by anti cancerous treatments. In both cases, a resorption stabilisation can be clearly seen after 6 months according to dental extractions. The vertical alveolar bone resorption is more important in incisor and canine regions. The anti cancerous treatments may not have significant disastrous consequences as far as available bone amount is concerned, on a post prosthetic restoration.

The LDH cytotoxicity test is able to emphasize the stabilisation of human embryo fibroblast membranes, in vitro, by two amphiphilic drugs: the metomidate and the thymolol. The membrane stabilisation is emphasized by the reduced LDH externalization as compared with the untreated cells. The use of the LDH test for the selection of some natural complexes or synthetic drugs with membrane stabilising and potential antiviral activity is proposed. The inhibition of LDH by metomidate was recorded, as decreasing of the enzyme activity with increasing metomidate concentration. This fact explains the known lactic acid accumulation, under metomidate treatment of human subjects. The use of metomidate in classical cancer treatment potentiation is proposed instead of lactate externalization inhibitors, already used for this aim.

An ever-growing number of children with malignant diseases can today be cured and will have prolonged survival. Their quality of life, which can be altered by a substantial number of late effects of the disease or its treatment, is a prominent field of long-term assessment. In a cross-sectional study based on clinical and paraclinical parameters and covering 59 children and young adults treated between 1981 and 1986 for a childhood malignant disease, we investigated late effects in the long-term survivors. Late effects were found in 36 (61%) of these patients; their spectrum is wide, but most often affected are the CNS and the musculoskeletal system. Two thirds of the patients have mild or moderate and one third severe problems. The frequency of the late effects and the type of problem vary greatly according to the initial diagnosis; our results show a significant difference of severity according to the number of affected systems (p < 0.05). The results of our study match those of other similar reports and confirm the high frequency of late effects in survivors of pediatric cancer. A prospective study, assessing a large population of patients, is needed to determine the underlying causes and to develop primary and secondary prevention strategies.

Anthracyclines have greatly contributed to improvement in the prognosis of certain cancers, but their beneficial effect is impaired by an unquestionable toxicity affecting notably the heart. Changes in blood pressure or electrocardiograms, benign pericardial reactions and rare but severe myocarditis may occur at an early stage of treatment. The cumulative toxicity of anthracyclines limits their use. With a cumulative dose of 550 mg/m2 the mean incidence of toxicity varies from 5 to 10 percent. The occurrence of toxicity largely depends on the total dose, but other factors such as patient's age and general condition, and previous treatments with chemo- or radiotherapy must be taken into account. The best methods to monitor the cardiotoxicity of anthracyclines are echocardiography, radionuclide study of ejection fraction and myocardial biopsy for histological study. The rational use of these three types of examination must be adjusted to each individual patient. It should reduce the incidence of severe myocarditis which sometimes cancels all the beneficial effects of the anticancer treatment.

Certain drugs can induce ventricular tachycardia (VT) by creating reentry, ventricular after potentials or exaggerating the slope of phase 4. These may or may not be symptomatic, sustained or non-sustained and have variable ECG appearances: monomorphic or polymorphic, bidirectional, torsades de pointes. They risk degenerating into ventricular flutter of fibrillation and have been held responsible for the increased mortality observed unexpectedly in some long-term treatments. The drugs responsible are mainly those used in cardiology, probably due to predisposing circumstances (cardiomegaly, cardiac failure, previous severe ventricular arrhythmias, therapeutic associations, metabolic abnormalities). These include primarily the antiarrhythmic drugs (IA, IC, sotalol and bepridil), digitalis, sympathomimetics and phosphodiesterase inhibitors. These complications may be toxic or idiosyncratic, in patients with or without cardiac disease, and may also occur with other drugs: vasodilators and anti-anginal drugs (lidoflazine, vincamine, fenoxedil), psychotropic agents (phenothiazine and imipramine), antimitotics, antimalarials (chloroquine) or antibiotics (erythromycin, pentamidine). The prognosis is severe and the treatment is often difficult which makes prevention, helped by repeated surface ECG (or Holter monitoring), very important with careful assessment of patients at risk.

The dose of anticancer drugs is currently adjusted to the body surface area of the patient, although for a given body surface, patients have different distribution and metabolism for a given drug. The dose adjustment to the tumour drug content was studied, we noted that it is not always possible to obtain a tumour sample; the sample and its drug content may not be representative of the whole tumour content, this measured drug content is neither indicative for the evaluation of the dose to be administered, nor indicative of the chemotherapy efficacy. The best criterion for the dose adjustment seems to be the plasma concentration of the drug. Correlations between drug plasma concentration and clinical data are examined. The relationship between plasma concentration and efficacy cannot be excellent, since it depends on the presence of resistant cells and on the blood flow through the tumour. A relationship between plasma concentration and toxicity has been reported with many anticancer drugs. The drug plasma concentration and the area under the curve (AUC) give better correlations than the administered dose with efficacy and toxicity. Different methods of dose adjustment are reported. They use mathematical models which allow to decrease the number of blood samples, without losing precision in the pharmacokinetic parameter evaluation. In conclusion, the dose adjustment to the drug plasma concentration or to the AUC can play an important role in improving the chemotherapy efficacy, while toxicity is reduced.

S9788, a new triazinoaminopiperidine derivative, was 250-fold more active than verapamil in sensitizing DC-3F/AD cells to actinomycin D. This multidrug-resistance modulating activity of S9788 was confirmed on DC-3F/AD, P388/ADR-10, P388/VCR-20, KB/A1, K562/R, S1/tMDR, and COLO320DM cells, with respect to actinomycin D, doxorubicin, vincristine, vinblastine and etoposide. S9788 is 2-255-fold more active than verapamil, depending on the cell line and the cytotoxic agent used, potentiating preferentially the cytotoxicity of the vinca-alkaloid derivatives. S9788 only had a slight effect on vincristine accumulation and retention by parental sensitive cells, as well as on their sensitivity to cytotoxic drugs. S9788 fully restored vincristine accumulation and retention by S1/tMDR cells (S1 cells transfected by the mdr 1 gene) to a level similar to that measured in S1 cells, leading to a blockade in the G2 + M phase of the cell cycle. Therefore, S9788 enhances vincristine activity by restoring its cellular accumulation in resistant cells. After a short incubation period of cells with vincristine (4 h), a condition close to the clinical administration of this cytotoxic agent, a post-incubation for 20 hours more with 5 microM S9788, fully restored the sensitivity of S1/tMDR cells to vincristine. After an exposure of 4 hours at equal concentrations, the accumulation of S9788 was 13-fold that of verapamil in S1/tMDR cells, and 20 hours after the removal of the modulators, S9788 was retained at a concentration 20-fold that of verapamil. S9788 is therefore a powerful new modifier of the P-gp-mediated multidrug-resistance, which by its pharmacological properties (cellular kinetics and activity), might be used in combination with existing chemotherapy against tumors displaying the MDR phenotype.

Taxotere [N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol] is a new chemical entity obtained by semisynthesis from 10-deacetylbaccatin III, a non cytotoxic precursor extracted from the needles of the European yew Taxus baccata. Taxotere retains the unique mechanism of action of taxol and inhibits the depolymerisation of microtubules into tubulin. In vitro, Taxotere is cytotoxic against murine and human tumor cells with IC50 values ranging from 4 to 35 ng/ml. Taxotere inhibits the clonogenic properties of fresh human tumor cells at clinically relevant concentrations. Taxotere is highly active in vivo against several experimental models: it is 2.7-fold more active than taxol on a log cell kill basis against B16 melanoma; ten out of the twelve models of grafted murine tumors tested respond to Taxotere; it is active with 80% complete regressions against advanced C38 colon adenocarcinoma and PO3 pancreatic ductal adenocarcinoma. Finally, Taxotere is active against several human xenografts implanted in nude mice. Safety studies were performed in dogs and mice according to NCI guidelines. Toxicological effects are observed mostly is tissues with high cell turnover (bone marrow in mice and dogs, gastrointestinal tract in dogs only) or in those where microtubules play an important role (peripheral nerves in mice only). Because of its availability, due to an efficient process using a renewable source of natural precursor, its preclinical profile (higher antitumoral activity than taxol with a comparable toxicological profile) and its unique mechanism of action, Taxotere has entered Phase I clinical trials in Europe, United States and Japan. The dose limiting toxicity is a neutropenia. Evidence of clinical activity has been noted (breast, ovarian, lung). Taxotere is now in Phase II clinical trials.

Fibrosis in oncology concerns iatrogenic pathology, after radiotherapy or bleomycin, and also after surgery or neoadjuvant chemotherapy. Specificity of certain etiologic conditions are described in detail. Some therapeutic attitudes are discussed. Corticoids are useful in the management of inflammatory fibrosis attacks. Other drugs under study are used in an attempt to reduce the late fibrotic process, namely liposomal superoxide dismutase.

The only factor limiting the use of anthracyclines (very powerful antimitotic antibiotics) is their cardiotoxicity. The cardiac involvement is irreversible, dose-dependent and may be detected at an early stage by non-invasive (echocardiography, myocardial scintigraphy) or invasive investigations (endomyocardial biopsy). The mechanism of cardiac toxicity involves the oxidative metabolism of the cardiac myocyte and liberation of oxygen free radicals and is different from the antitumoral effect. Protocols of administration over 6 to 24 hours have enabled the use of higher total doses and the reduction of cardiotoxicity without affecting the therapeutic efficacy. The use of "antioxidants" such as ICRF 187 has given promising results in myocardial protection. The strategy of surveillance (screening) of cardiotoxicity, of the mode of administration of the anthracyclines, results from the essential coordination of the efforts of the chemotherapist, taking into account the pathology, the sensitivity of the tumor to anthracyclines therapy, enabling personalization of the prescription and the abandon of the concept of maximal dosage.

The available data regarding the impact of pregnancy on the course of gynecologic cancers and the effects of the malignant processes and their treatments on both the mother and the fetus are analyzed in the present work. The incidence of specific gynecologic cancers in pregnant women parallels that in woman of child bearing age in general. Cervical cancer is the most common followed by breast and ovarian cancer. The review of the recent literature indicates that for equivalent clinical stage, maternal age and lymph node involvement, survival rate of patients affected with gynecologic cancer during pregnancy is similar to those of non-pregnant women. A conflict between maternal therapy and fetal well-being is frequently observed in cases of invasive gynecologic cancer and a multidisciplinary approach is crucial to optimal treatment of the mother and her fetus.

Acral erythema (AE) is a painful, erythematous bullous eruption of the palms and soles which is chemotherapy-induced. To the numerous chemotherapies which induce AE we must add, perhaps, a new drug, Vépéside. AE is followed by graft-versus-host-disease in all patients receiving bone marrow transplantation. AE and early GVH disease being very similar, we discuss the differential diagnosis which can be very difficult.