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PubMed1982

Damaging effects of fourteen chemotherapeutic drugs on mouse testis cells.

The harmful effects of 14 chemotherapeutic drugs on spermatogenesis in the mouse have been evaluated by studies of testicular cell killing and morphological and genetic damage produced. Male mice were given drugs as single injections at various doses up to the toxic levels. Prednisone and 6-mercaptopurine produced little or no cytotoxicity. All other drugs tested killed differentiated spermatogonia. Of these, methotrexate, cyclohexylchlorethylnitrosourea, cis-platinum, and mechlorethamine did not show significant stem cell killing. Bischlorethylnitrosourea, chlorambucil, 5-fluorouracil, mitomycin C, antinomycin D, and procarbazine showed some stem cell killing. Triethylenethiophosphoramide (thio-TEPA) was the only drug in this group which killed large numbers of stem cells. Only 5-fluorouracil and cis-platinum killed spermatocytes, and only cis-platinum killed spermatids. Several drugs induced chromosome breaks in treated spermatocytes. Thio-TEPA was effective in inducing chromosome translocations in treated spermatocytes and probably also in spermatocytes which originated from surviving treated stem cells. It had been our hypothesis that the cytotoxic effects of these drugs on mouse testicular stem cells would correlate with the duration of azoospermia observed in patients. This was shown not to be the case. Thus, the cytotoxic effects of single injections of single chemotherapeutic agents on the mouse testis did not appear to be predictive of which drugs will cause long-term azoospermia in humans.

Animals↗
PubMed1981

A system for determining the pharmacology of indirect radiation sensitizer drugs on multicellular spheroids.

We have characterized some of the physiology of multicellular spheroids of different sizes grown from Chinese hamster lung fibroblast (V79) cells. Among the parameters studied were oxygen tension distributions within the spheroid. This was achieved using ultramicroelectrodes with tip diameters of 1-5 mu and a perfusion system whereby environmental conditions such as flow, temperature, and chemical makeup of the milieu could be measured and controlled. Plateau pO2 values of less than 10 mm Hg were consistently obtained from spheroids under various conditions. We were able to modify these distributions by use of indirect radiation sensitizer drugs such as mechlorethamine HCl (mustargen) at nontoxic doses. We have also made determinations of the inhibitory capacities of several other drugs on the respiration rate of constituent cells of multicellular spheroids in single-cell suspensions. We have concluded that there are indeed hypoxic cells in spheroids whose radioresistance may be modified by essentially nontoxic levels of indirect radiosensitizer drugs and that the system described shows great promise for screening agents which may modify radiation response.

Animals↗
PubMed1980

[Membrane transport of antineoplastic drugs and its relevance to tumour chemotherapy (author's transl)].

The permeation of cell membranes by several antineoplastic drugs (AD) exhibits characteristics of carrier-mediated transport processes (facilitated diffusion or active transport); the main representatives among these AD are mechlorethamine, cyclophosphamide, melphalan, methotrexate, 6-mercaptopurine, 5-fluorouracil, cytarabine, 5-fluorodeoxyuridine, vincristine, vinblastine, adriamycin, daunorubicin and dactinomycin. Inhibition or stimulation of the membrane transport of AD influences absorption, distribution, elimination, therapeutic effectiveness and toxicity. The choice of certain combination therapies may increase the selectivity of AD by influencing membrane transport. A change in the properties of transport systems is one possible reason for the resistance of tumour cells to various AD.

Animals↗
PubMed1976

Combination chemotherapy with DTIC (NSC-45388) in advanced malignant melanoma, soft tissue sarcomas, and Hodgkin's disease.

The results of three controlled studies with multiple-drug regimens which included DTIC are reported for advanced melanoma, soft tissue sarcomas, and Hodgkin's disease. In malignant melanoma, no statistical difference was observed between (a) DTIC, BCNU, and vincristine, and (b) DTIC, BCNU, and actinomycin D in terms of response rate, median duration of response, and survival. In sarcomas, the combination of adriamycin and DTIC produced a higher incidence of complete plus partial responders when compared to cyclophosphamide, vincristine, and methotrexate. However, no significant difference was seen in the median duration of response or survival. In Hodgkin's disease, a new four-drug combination including adriamycin, bleomycin, vinblastine, and DTIC (ABVD) produced an incidence of complete remissions and a median duration of response comparable to that achieved with mechlorethamine, vincristine (Oncovin), predinisone, and procarbazine (MOPP). Preliminary data indicate that ABVD is not cross resistant to MOPP. It is concluded that DTIC can be successfully and safely employed in combination with conventional agents in susceptible neoplastic diseases.

Antineoplastic Agents↗
PubMed1976

Southeastern Cancer Study Group trials with nitrosoureas in Hodgkin's disease.

A decade of studies with the nitrosoureas in the Southeastern Cancer Study Group has shown that they are active agents for the treatment of Hodgkin's disease and that they may be combined with other chemotherapeutic agents in regimens which have acceptable toxicity to produce excellent response rates. Further more, six monthly cycles of treatment with a combination of either BCNU, vinblastine, cyclophosphamide, procarbazine, and prednisone or mechlorethamine, vincristine, prednisone and procarbazine(MOPP), following the achievement of a clinical CR, produce significantly superior durations of remission and survival in previously untreated patients. Our studies with BCNU given orally have indicated that it is not a clinically useful drug. Finally, studies with methyl-CCNU given orally have indicated no particular place for this agent in the treatment od Hodgkin's disease when compared to CCNU and BCNU.

Administration, Oral↗
PubMedDate not supplied

Similarity of the effects of tosyl-L-arginine methyl ester, atropine, caffeine and antitumour alkylating agent on some biological functions of thrombin and platelet 12-lipoxygenase.

The effect of the synthetic thrombin substrate (TAME) and three compounds exerting an opposite effect on Ca-PPI and AdC (caffeine, atropine and meta-tolyl derivative of mechlorethamine (TDM)) on hormone-like and catalytic functions of thrombin was studied. It is shown that both TAME and other drugs under test block effectively the thrombin-induced platelet aggregation, as well as protect the active site of the enzyme from denaturation by dithiothreitol. The same compounds inhibit thrombin in thrombin-fibrinogen reaction and platelet 12-lipoxygenase. These data suggest identity of thrombin moieties which determine its enzymatic and hormone-like activities.

Alkylating Agents↗
PubMed1977

Splenectomy, chemotherapy, and survival in Hodgkin disease.

The question was raised whether routine splenectomy might, by virtue of its effects on the receipt of subsequent chemotherapy, offer long-term benefits to patients with advanced Hodgkin disease. Therefore, we compared followup data from a group of patients who were receiving mechlorethamine hydrochloride, vincristine sulfate, procarbazine hydrochloride, and prednisone (MOPP regimen) and who had had splenectomies to a group of similarly treated, carefully matched control patients on the MOPP regimen who had not had splenectomies. Our results indicate no important difference in duration of survival or long-term remission status. There was only a suggestion that splenectomy in such patients may be followed by impaired resistance to subsequent infections. Therefore, although early splenectomy can be important in the assessment of splenic disease, it must not be considered to be a therapeutic procedure per se.

Dactinomycin↗
PubMed1993

The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin's disease. A single-center eight-year study of 155 patients.

Although high-dose chemotherapy and autologous bone marrow transplantation (ABMT) are increasingly being used for the treatment of relapsed and resistant Hodgkin's disease, there have been few large, single-center studies reported with adequate follow-up to allow full evaluation of this therapeutic modality. We present 155 poor-risk Hodgkin's disease patients who received high-dose BEAM (BCNU, etoposide, cytosine arabinoside, and melphalan) chemotherapy and ABMT who have been studied over a period of 8 years. All patients had either not attained a remission on mechlorethamine, vincristine, procarbazine, prednisone-type therapy and had poor prognostic features at presentation, not attained a complete remission or relapsed within 1 year of an initial alternating regimen, or not attained remission with two or more lines of treatment. At the time of ABMT the relapse status of the patients was as follows: 46 patients were primarily refractory to induction therapy, 7 were good partial responders, 52 were in first relapse, 37 in second relapse, and 13 in third relapse. Seventy-eight patients had chemoresistant disease, 33 had chemosensitive disease at the time of ABMT, and 44 were untested for chemosensitivity at latest relapse. The procedure related mortality in the first 90 days post-ABMT of 10% overall. At 3 months 43 patients (28%) were assessed as complete responders, 72 patients had a partial response (46%), and 24 patients (16%) had no response or progression of disease. However, by 6 months, 53 (24%) patients were assessed as complete responders and 51 (33%) patients had nonprogressive disease. Forty-five patients had received radiotherapy post-ABMT to residual masses (41 patients) or to previous sites of bulk disease (4 patients). The actuarial overall and progression-free survival at 5 years was 55% and 50%, respectively. On multivariate analysis patients with bulk (masses > 10 cm), heavily pretreated patients (those receiving three or more lines of treatment) and females had a significantly poorer prognosis. Relapse status was also significant for progression-free survival in that patients in second (60%) and third relapse (70%) had a better prognosis than those in first relapse (44%) or with primary refractory disease (33%). Response to prior chemotherapy did not predict for progression-free survival. These results enable comparisons to be made between high-dose chemotherapy with ABMT and conventional dose salvage therapy. Furthermore, although the results as a whole are highly encouraging, certain groups carry an unfavorable prognosis.

Adolescent↗
PubMed1993

Acute leukemia after the treatment of Hodgkin's disease.

The risk of developing a secondary acute leukemia or myelodysplastic syndrome after the treatment of Hodgkin's disease is discussed on the basis of the results reported from large series with prolonged follow-up. It appears that the risk mainly depends upon the treatment strategy and certain host-related factors such as older age. Radiation therapy used alone is associated with the lowest risk, combination mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy plus irradiation with the highest risk, and the risk of MOPP chemotherapy alone being in between the two. Splenectomy and probably splenic irradiation may also add to the risk. In long-term, surviving patients continuously free of Hodgkin's disease, the cumulative probability of second leukemia is low, with a high risk period which can be limited to the 10 years following the end of curative therapy. Finally, the impact of secondary leukemia on long-term survival is limited and far less than that of second tumors.

Acute Disease↗
PubMed1995

DNA topoisomerase II alpha expression is associated with alkylating agent resistance.

Increased expression of DNA topoisomerase II alpha has been associated with resistance to certain DNA-damaging alkylating agents, but no causal relationship or mechanism has been established. To investigate this observation, we developed a model of topoisomerase II overexpression by transfecting a full-length Chinese hamster ovary topoisomerase II alpha into EMT6 mouse mammary carcinoma. Topoisomerase II alpha-transfected cell lines demonstrated continued topoisomerase II alpha mRNA and protein expression, which were undetectable in vector-only lines, in stationary phase (G0-G1). The topoisomerase II transfectants were approximately 5-10-fold resistant to the alkylating agents cisplatin and mechlorethamine. Upon release from G0-G1, the topoisomerase II transfectants demonstrated more rapid thymidine incorporation and shorter cell-doubling times than control cells. Purified topoisomerase II and nuclear extracts with topoisomerase II-decatenating activity bound to cisplatin-treated DNA with significantly greater affinity than to untreated DNA in a cisplatin concentration-dependent manner. These observations suggest that expression of topoisomerase II alpha may have a role in cellular resistance to antineoplastic alkylating agents. The mechanism for this may involve increased binding of topoisomerase II alpha to alkylating agent-damaged DNA.

Animals↗
PubMed1977

Characterization and responsiveness of the Madison 109 lung carcinoma to various antitumor agents.

The Madison 109 (M109) tumor was discovered in 1964 in the lung of a BALB/c mouse. This experimental carcinoma is maintained in vivo by sc passage in the right axillary region. When implanted im (5 X 10(5) cells) into the right hind leg of BALB/c mice for testing, the primary progresses with metastases to the lung, spleen, and liver. The metastases to the lung are visible within 3 weeks and result in the death of the host in about 35 days after tumor implant. Implantation of a lung nodule is tumorigenic and lethal. Pyran polymer therapy delayed the appearance of lung metastases, inhibited the growth of the primary tumor, and significantly increased the lifespan of BALB/c mice inoculated with the M109 tumor. No spontaneous regression has been observed and very few "no takes" have occurred in untreated BALB/c mice inoculated with at least 500 M109 cells. Of the 82 agents tested so far, the M109 model has selected active agents such as actinomycin D, adriamycin, daunorubicin, DNA, procarbazine, and pyran polymer. It has not shown sensitivity as tested to several standard therapeutic agents including cytosine arabinoside, BCNU, hydroxyurea, mechlorethamine, melphalan, triethylenemelamine, and vincristine.

Animals↗
PubMed1998

Long-term results from MOPPEBVCAD chemotherapy with optional limited radiotherapy in advanced Hodgkin's disease.

The purpose was to verify the 5-year results of the MOPPEBVCAD chemotherapy regimen with limited radiotherapy in relation to the promising preliminary data. Mechlorethamine, vincristine, procarbazine, prednisone, epidoxorubicin, bleomycin, vinblastine, lomustine, melphalan, and vindesine were delivered according to a schedule derived through hybridization, intensification, and shortening of the corresponding alternating CAD/MOPP/ABV regimen. Radiotherapy was restricted to sites of bulky involvement or to areas that responded incompletely to chemotherapy. This multicenter, controlled, nonrandomized trial involved 145 eligible patients. Radiotherapy was administered to 47 patients, 46 of whom were in complete remission after chemotherapy. Remissions were complete in 137 patients (94%), partial in 4 (3%), and null in the remaining 4. Tumor-specific, overall, relapse-free, and failure-free survival at 5 years were 0.89, 0.86, 0.82, and 0.78, respectively. Hematologic toxicity was considerable, whereas nonhematologic side effects were fully acceptable. Most of the unfavorable prognostic factors lost their clinical weight. Only age and lymphocyte depletion histologic type were statistically correlated with major follow-up endpoints; performance status and bone marrow involvement were subordinate to age. Seven patients developed a second cancer (including 3 myelodysplasias). MOPPEBVCAD with selected radiotherapy is a highly effective regimen in advanced Hodgkin's disease. Early and late toxicity are no more severe than what would be expected with other alternating or hybrid regimens. A comparison with ABVD, which is currently considered the standard regimen for advanced Hodgkin's disease, is needed.

Adolescent↗
PubMed1998

Repair of DNA alkylation damage.

Alkylation damage of DNA is one of the major types of insults which cells must repair to remain viable. One way alkylation damaged ring nitrogens are repaired is via the Base Excision Repair (BER) pathway. Examination of mutants in both BER and Nucleotide Excision Repair show that there is actually an overlap of repair by these two pathways for the removal of cytotoxic lesions in Escherichia coli. The enzymes removing damaged bases in the first step in the BER pathway are DNA glycosylases. The coding sequences for a number of methylpurine-DNA glycosylases (MPG proteins) were cloned, and a comparison of the amino-acid sequences shows that there are some similarities between these proteins, but nonetheless, compared to other DNA glycosylases, MPG proteins are more divergent. MPG proteins have been purified to homogeneity and used to identify their substrates ranging from methylating agents to deamination products to oxidatively damaged bases. The ligation-mediated polymerase chain reaction has been used to study the formation of alkylation damage, and its repair in mammalian cells. We have studied DNA damage in the PGK1 gene for a series of DNA alkylating agents including N-methyl-N'-nitro-N-nitrosoguanidine, Mechlorethamine, and Chlorambucil and shown that the damage observed in the PGK1 (phosphoglycerate kinase 1) gene depends on the alkylating agent used. This report reviews the literature on the MPG proteins, DNA glycosylases removing 3-methyladenine, and the use of these enzymes to detect DNA damage at the nucleotide level.

Alkylation↗
PubMed1998

Mammalian 3-methyladenine DNA glycosylase protects against the toxicity and clastogenicity of certain chemotherapeutic DNA cross-linking agents.

DNA repair status is recognized as an important determinant of the clinical efficacy of cancer chemotherapy. To assess the role that a mammalian DNA glycosylase plays in modulating the toxicity and clastogenicity of the chemotherapeutic DNA cross-linking alkylating agents, we compared the sensitivity of wild-type murine cells to that of isogenic cells bearing homozygous null mutations in the 3-methyladenine DNA glycosylase gene (Aag). We show that Aag protects against the toxic and clastogenic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea and mitomycin C (MMC), as measured by cell killing, sister chromatid exchange, and chromosome aberrations. This protection is accompanied by suppression of apoptosis and a slightly reduced p53 response. Our results identify 3-methyladenine DNA glycosylase-initiated base excision repair as a potentially important determinant of the clinical efficacy and, possibly, the carcinogenicity of these widely used chemotherapeutic agents. However, Aag does not contribute significantly to protection against the toxic and clastogenic effects of several chemotherapeutic nitrogen mustards (namely, mechlorethamine, melphalan, and chlorambucil), at least in the mouse embryonic stem cells used here. We also compare the Aag null phenotype with the Fanconi anemia phenotype, a human disorder characterized by cellular hypersensitivity to DNA cross-linking agents, including MMC. Although Aag null cells are sensitive to MMC-induced growth delay and cell cycle arrest, their sensitivity is modest compared to that of Fanconi anemia cells.

Animals↗