Effect of chlorambucil on spermatogenesis in the human with malignant lymphoma.
01 May 1970-Cancer (Wiley Subscription Services, Inc., A Wiley Company)-Vol. 25, Iss: 5, pp 1026-1030
TL;DR: It can be seen that there is a probability of azoospermia developing after ingestion of determined amounts of chlorambucil, and it has to be taken into consideration when such treatment is indicated in patients at reproductive age.
Abstract: This report is concerned with the action of chlorambucil in males. A group of 8 patients with malignant lymphoma were studied. Diagnoses of Hodgkins disease lymphosarcoma and reticulosarcoma had been established by biopsy. Ages were 18 to 38. As the sole medication chlorambucil was given in doses of .1 mg to .4 mg/Kg/day. Hormonal studies were done based on the determination of 17-ketosteroids in the urine and urinary excretion of gonadotropins. Testicular biopsies were performed by open surgery or at autopsy. After treatment 6 patients became azoospermic 1 developed sever oligospermia and 1 showed no change. With total doses up to 400 mg a progressive oligospermia developed from which the patient could recover slowly if the drug was stopped. 4 patients had elevated values of neutral 17-ketosteroids 3 had slightly low values. Gonadotropins were all within normal limits. Micropic studies showed that the germinal like disappears only Sertoli cells remain and peritubular fibrosis develops. The interstitial cells and blood vessels appeared normal. The condition of azoosperma is considered to be permanent.
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TL;DR: All samples of seminal fluid from thirty-one adult male patients who had received cyclophosphamide showed low sperm-counts or azoospermia, and preliminary studies suggest that cycloph phosphamide may also cause ovarian damage.
419 citations
TL;DR: It is concluded that steroid and chlorambucil treatment for six months favors remission of the nephrotic syndrome in adults with idiopathic membranous nephropathy and can preserve renal function for at least some years.
Abstract: We conducted a controlled trial to investigate the long-term effects of treatment with methylprednisolone and chlorambucil in patients with idiopathic membranous nephropathy. We have previously reported that after a mean of 31 months, treated patients did better. We now report the results of a longer follow-up. Eighty-one patients with proteinuria (greater than or equal to 3.5 g per day) and biopsy-proved membranous nephropathy were randomly assigned to receive either supportive therapy alone or a six-month course of corticosteroids alternated with chlorambucil (0.2 mg per kilogram of body weight per day) every other month. Methylprednisolone was first given intravenously in three pulses (1 g per day) and was then given orally (0.4 mg per kilogram per day) for 27 days. The patients were followed for 2 to 11 years (median, 5). Two patients in the control group and one in the treatment group died. At the last follow-up visit, 9 of 39 patients assigned to the control group (23 percent) and 28 of 42 patients assigned to the treatment group (67 percent) did not have the nephrotic syndrome. At five years there were more remissions of the nephrotic syndrome in treated patients than in controls (22 of 30 vs. 10 of 25; P = 0.026). Compared with base-line values, the mean reciprocal of the plasma creatinine level declined significantly in the control group (33 percent; P = 0.0002) but not in the treatment group (6 percent; P not significant). Plasma creatinine increased by 50 percent or more in 19 controls (49 percent) and in 4 treated patients (10 percent). We conclude that a six-month course of methylprednisolone and chlorambucil can bring about sustained remission of the nephrotic syndrome and help to preserve renal function in patients with idiopathic membranous nephropathy.
354 citations
TL;DR: This chapter consolidates and quantitates some deleterious effects of cancer chemotherapeutic agents in humans, including the ability to induce chromosomal aberrations, their antifertility effects, their ability to produce congenital malformations under certain conditions, and their carcinogenic potential when used to treat neoplastic and nonneoplastic diseases.
Abstract: Publisher Summary This chapter consolidates and quantitates some deleterious effects of cancer chemotherapeutic agents in humans—namely, their ability to induce chromosomal aberrations, their antifertility effects, their ability to produce congenital malformations under certain conditions, and their carcinogenic potential when used to treat neoplastic and nonneoplastic diseases. It discusses the three classes of antitumor compounds: alkylating agents, antimetabolites, and antitumor antibiotics. These compounds have been extensively studied in vitro and in vivo and they induce chromosomal aberrations; these abnormalities vary according to the agent and the test system used. Combinations of agents or agents plus irradiation also produce cytogenetic damage in human cells. It also provides information on the possible adverse effects of the antimetabolites, antitumor antibiotics, and miscellaneous synthetic agents on spermatogenesis. The current evidence indicates that these effects are related to the dose and duration of chemotherapy, both for single alkylating agents and for combination chemotherapy in which the alkylating agent is one of the components. Anticancer drugs other than the alkylating agents should be more thoroughly studied for possible effects on the fertility in the human female.
283 citations
Journal Article•
TL;DR: Reproductive function was evaluated in 16 men who had been treated with a combination of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP); a similar combination, with met...
Abstract: Reproductive function was evaluated in 16 men who had been treated with a combination of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP); a similar combination, with met...
236 citations
TL;DR: Because of the guaranteed infertility and the low frequency and unpredictability of recovery of spermatogenesis, sperm storage should be available for male patients undergoing cytotoxic therapy, since most of these patients may enjoy prolonged survival.
232 citations
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TL;DR: The quantitative estimation of urinary 17-ketosteroids has been proven of value as an aid to the clinical diagnosis of disease and its more widespread use has been hampered by the actual and assumed difficulties inherent in the chemical methods employed.
Abstract: THE quantitative estimation of urinary 17-ketosteroids has been proven of value as an aid to the clinical diagnosis of disease. Its more widespread use has been hampered by the actual and assumed difficulties inherent in the chemical methods employed. In 1947, there was proposed a simple and rapid method (1), some disadvantages of which became apparent following its use in thousands of determinations. For instance, the extraction with ether is a dangerous hazard. Adequate control throughout the various manipulative steps is difficult, since mechanical equipment cannot be readily adapted to separatory funnels. The funnels are clumsy to handle and the breakage rate is high. When large numbers of determinations have to be made, a special laboratory is a prerequisite. In view of the solubility of ether in water and water in ether, a correction factor must be used for the final aliquot. Unless special precautions are taken to reduce evaporation, considerable error may result. Over and above these problems, the...
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TL;DR: The following case concerns the possible teratogenic effect of chlorambucil on a human fetus removed from a mother receiving this drug for the treatment of Hodgkin's diseae.
Abstract: THE EFFECTS OF SODIUM AMINOPTERIN, 1 and more recently, of thalidomide, 2 on the human fetus, when administered to the mother during early pregnancy, have stressed the necessity of carefully checking all drugs for teratogenic properties. Since it is desirable that any suspicions of this nature should be reported, the following case is felt worthy of mention. It concerns the possible teratogenic effect of chlorambucil on a human fetus removed from a mother receiving this drug for the treatment of Hodgkin's diseae. Report of a Case A 27-year-old married white woman was diagnosed as suffering from Hodgkin's paragranuloma after a biopsy of a left supraclavicular lymph node in the Lynchburg General Hospital in February, 1958. Since then her illness has been characterized by fever, generalized adenopathy, pulmonary infiltration, hepatosplenomegaly, anemia, lymphopenia, and weight loss, although the degree of each of these symptoms has varied from time to time. She was
89 citations
79 citations
Journal Article•
TL;DR: Although it is perhaps still premature to attempt to assign the different reactivities of the numerous cytotoxic agents that have been tried in spermatogenesis to the different categories of damage they produce, a tentative grouping may nevertheless be considered worthwhile, if only to be criticized and proven invalid by further work.
Abstract: Although it is perhaps still premature to attempt to assign the different reactivities of the numerous cytotoxic agents that have been tried in spermatogenesis to the different categories of damage they produce, as outlined in the introduction to this review, a tentative grouping may nevertheless be considered worthwhile, if only to be criticized and proven invalid by further work.
Kinetic damage . This is difficult to recognize, since it requires a tedious examination of the distribution and proportion of the phases of the testis present in any transverse section of the tubule at different times after treatment with the drug. The only satisfactory demonstration of true kinetic damage is probably the observation of the changing pattern of mitoses observed after treatment of mice with 6-azauracil. From inadequate data, it may be inferred that this type of damage may be present after treatment with antiandrogens, bis(dichloroacetyl)diamines (WIN compounds), progestens, antimetabolites, dinitropyrrole, nitrofurans, thiophene derivatives, and cadmium salts and after elevation of testicular temperature. In none of these cases however has this type of damage been satisfactorily proven.
Cellular damage . Its presence is more clearly defined, and most of the drugs examined, especially when the effects are noted by histological examination, have shown varying degrees of this form of damage. Spermatogonial damage has been observed with certain antiandrogens, although these cells may not be the most sensitive to these agents. Certain ethyleneimine derivatives, notably ethylene urea and ethylene urethane, show gross cell destruction in the testis. Of the alkane sulphonates, Busulphan, dimethyl busulphan, methylene dimethane sulphonate, and isopropyl methane sulphonate show spermatogonial damage. Methylhydrazine derivatives as well as cadmium salts also show gross damage to this cell type. Cellular damage to primary spermatocytes seems to be a characteristic feature of temperature elevation of the testis, and several drugs which are thought to be acting on the testis by inducing this mechanism, such as the dinitropyrrole, nitrofuran, thiophene, bis(dichloroacetyl)diamine derivatives as well as cadmium salts, also exert a major action on this cell type. Bis(dichloroacetyl)diamines also exert some action on spermatids at an early stage. The final proof of cellular damage is the quantitative measurement of the extent of pycnosis and fragmentation, but this is not often observed, either because of the rapid removal of damaged cells or owing to the failure of damaged cells to develop into the normal complement of more mature forms.
Morphological damage . It is a point for discussion as to whether there should be a distinction between "cellular" and "morphological" damage, but if the cell survives for a period and leaves the testis with the spermatozoon, the damage is regarded as more persistent and classified as "morphological." Such changes in spermatid development have been noted after treatment with the alkane sulphonate derivatives, and have been described in detail in human studies after treatment with some of the bis(dichloroacetyl)diamines. Abnormal and bizarre forms of spermatozoal structure have also been described. The possibility exists that minor deformities of spermatozoa may not interfere with their viability but early or late genetic damage could not be ruled out. The most commonly observed form of morphological damage in the testis is the production of large polyploid cells during the late spermatocyte and early spermatid phases of development. A clear-cut example of morphological damage results from treatment with deuterium oxide, which is considered to induce a morphological change in the structure of the acrosome, so that the normal process of fertilization is impaired.
Early genetic damage . The most obvious form of genetic damage sustained by the germinal system is that resulting in deaths during early embryonic life. This may be due either to failure of fertilized eggs to implant or to death after implantation. Many instances of reported sterility after treatment of the male may be the result of this type of damage, and for potential antifertility agents it would be essential to know if this is so, since lower doses may induce late genetic damage. Measurement of dominant lethal action may be made in early embryos. Most of the alkylating agents produce some degree of early genetic damage. In the particular case of the simple alkyl alkane sulphonates such as methyl, ethyl, and n -propyl methane sulphonate, the main type of damage produced is directed towards the adult spermatozoa in such a way that the resulting fertilized egg fails to cleave normally, and both pre- and postimplantation deaths occur. The bis(dichloroacetyl)diamines and all antimetabolites should be suspected of causing some degree of early genetic damage, but except for some work in insect spermatogenesis, there is no satisfactory proof of such damage in the higher animals.
Late genetic damage . Damage to offspring of treated males has been conclusively demonstrated with triethyleneimine, nitrogen mustard, and methyl methane sulphonate. Owing to the very tedious nature of the experiments, very few drugs have been rigorously studied from this point of view. In general, those drugs which produce changes in DNA structure, such as the alkylating agents and some antimetabolites, as well as those which have already shown some early genetic damage at higher dose levels, may be suspected of producing late genetic damage.
Matrix damage . This occurs in some instances in association with extensive damage to the germinal epithelium, as with ethylene urea and ethylene urethane. The progestens, methylhydrazine derivatives, and cadmium salts also show extensive damage to the matrix, and in the case of the last mentioned agent, the testicular structural tissue may be the primary site of action.
An interpretation of the action of any new group of cytotoxic substances must take into account the possibilities that the effects observed may be the result of a direct action of the agent on the cell or an indirect one mediated through some of the many complex hormonal and other regulatory pathways in the whole organism. To unravel this complex question is probably easier in the testis than in any other differentiating system in the mammal, since the cellular kinetics of the spermatogenic epithelium, at least in the rodent, is now well known. The interrelationships of this system with the pituitary-gonadal axis is becoming clearer, and a way is opening to understand the mechanism by which the whole organism may control the functioning of one of its component systems. It is clear that the final definition of the mode of action of a drug must involve basic biophysical and chemical mechanisms at the level of a single molecule or a small group of molecules that are essential biochemical foci of action, whether they be at gene or cytoplasmic level.
An important technical advance in this field would be the separation of the component cells of the testis by some physical method of centrifugation, countercurrent, or filtration, destroying as little as possible of the enzyme activity, so that detailed biochemical investigations involving cell component separations may be effected. Continued study of the spectrum of drug action on spermatogenesis is desirable, however, since apart from recognizing new drug specificities of action, the potential interest to the emergency problem of population control cannot be overstressed.
37 citations