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PubMed1975

Bone changes in young mice with impaired lymphoid system.

Disturbances of osseal growth were observed in young mice with their lymphoid system affected by antihymocyte serum or mitolactol (dibromodulcitol) treatment. These bone changes were similar to those observed in germ-free and neonatally thymectomized mice as well as in mice suffering from a graft vs. host reaction. Their severity was in direct correlation with the disturbance of the thymus dependent lymphoid system. Not only immunological adaptation but also normal bone growth appears to require an intact thymus and thymus dependent lymphoid system.

Animals↗
PubMed1983

In vivo drug sensitivity assay of clonogenic human melanoma cells and correlation with treatment outcome.

In vitro tests of tumor cell drug sensitivity have been suggested as a means of selecting more appropriate clinical strategies against human cancer and improving preclinical drug development. The lack of biotransformation in these in vitro assays precludes the meaningful assessment of several major chemotherapeutic agents, including dacarbazine and cyclophosphamide. In vivo drug exposure of tumor cells in agar diffusion chambers placed in mice offers a possible solution to problems of drug biotransformation and pharmacokinetics. We have prospectively used this system as an assay for sensitivity of clonogenic human melanoma cells. Tumor cells were tested fresh, cryopreserved, and/or cultured in vitro before or after clinical use of dacarbazine, semustine, and mitolactol in 41 patient-drug combinations in which a clinical correlation could be made. Tumor cell drug sensitivity in the assay using fresh or cryopreserved tumor cells was highly correlated with clinical response and resistance with clinical nonresponse. Cultured melanoma cells exhibited enhanced plating efficiency in comparison to both fresh and cryopreserved cells of the same tumor. Cultured cells also showed increased drug sensitivity which did not correlate with drug sensitivity of the same fresh or cryopreserved tumor or with clinical response. Tumor cell drug sensitivity assays carried out in vivo provide a possible basis for preclinical evaluation of drugs which are unsuitable for in vitro testing.

Animals↗
PubMed1996

A comparative study of preoperative B-V-M-M chemotherapy and irradiation in advanced squamous cell cancer of the oral cavity.

From January 1976, 50 patients with squamous cell cancer of the head and neck were treated with telecobalt preoperative irradiation followed by appropriate surgery. Another group of 50 patients, who matched in risk factors and stage of disease, were treated with preoperative chemotherapy and surgery. Chemotherapy consisted of bleomycin, vincristine, mitolactol and methotrexate. All patients received 3 courses. Surgery was performed 2-3 weeks post-chemotherapy or 4-6 weeks postradiotherapy. Forty-four percent of the patients in the radiotherapy group showed recurrences, while 30% of the patients had recurrence in the chemotherapy group. The overall 3-year survival rate was 66% in the chemotherapy group and 57% in the radiation therapy group, with no statistical difference.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1979

Intra-arterial chemotherapy of head and neck tumours.

The benefits and complications of regional chemotherapy in the treatment of head and neck tumours are discussed. Intra-arterial chemotherapy has been employed in 72 cases of preoperative, postoperative and palliative management. Cytostatic treatment consisted of combined Vincristine, bleomycin, methotrexate, and mitolactol administration by a Watkins-USCI or Sharp chronofusor. In cases of preoperative treatment the tumour regression was in the range of 50-80%. Tumours of the gingiva, parotid gland, maxilla and tonsil responded very well, tumours of the tongue less well to the treatment. The most dangerous complication is thrombosis of the common carotid artery; to avoid this complication the prothrombin index was reduced and kept at the 30-40% level.

Antineoplastic Agents↗
PubMedDate not supplied

Chemotherapy of advanced and recurrent cervical carcinoma.

Chemotherapy is used primarily to treat advanced or recurrent cervical cancer. There are three major applications: primary therapy, as a radiation sensitizer, and neoadjuvant therapy. Primary chemotherapy is employed in advanced and disseminated cervical carcinoma (Stage VB). The four best single drugs with moderate activity against cervical cancer are: cisplatin, ifosfamide, dibromodulcitol (mitolactol), and Adriamycin (doxorubicin). Cisplatin and ifosfamide appear to be the best combination therapy: they provide an objective response rate of 33%. However, because the overall survival was not significantly improved with combination therapy, single-agent therapy with one of the above active drugs is acceptable. For stages IIB, III and IVA, the primary therapy is still radiation. Concomitant chemotherapy with hydroxyurea or a combination of cisplatin and 5-fluorouracil (5-FU) have been shown to enhance radiation response in several randomized trials. Hydroxyurea is the preferred radiation sensitizer because it offers less toxicity, ease of administration, and equivalent results. Chemotherapy in neoadjuvant setting produces promising results. Various cisplatin combinations of mitomycin C, 5-FU, vincristine, and bleomycin have been employed to shrink locally advanced cervical cancer and permit safe, radical excision. Early results with these combinations in small trials are encouraging but further studies are needed to fully evaluate their potential.

Antineoplastic Agents↗
PubMed1988

A combined treatment for advanced oral cavity cancers.

Effects of preoperative chemotherapy with three courses of a combination of bleomycin, vincristine, mitolactol, prednisone, and methotrexate, with a leucovorin rescue, followed by surgery were studied in 43 patients with advanced squamous cell carcinoma of the oral region. Before chemotherapy 34 patients (79%) had Stage III or IV carcinomas whereas nine patients had Stage II lesions. The clinical response was very encouraging: 20 patients (46%) achieved a clinical complete response and 23 patients (54%) were judged as partial responders. Side effects of this chemotherapy were minimal and reversible. Between 15 and 22 days after the last course of chemotherapy patients went to surgery. Wound healing complications did not occur. The surgical specimens were tested microscopically. The microphotographs showed small tumor rests with giant cells bordered by fibrous scar tissue and separated from the healthy tissues. With a median follow-up of 36 months (range, 21-58 months) 74% of patients are alive and 70% remain disease-free. Eleven patients died but only five (11%) because of the failure of therapy. This combined therapy appears both safe and promising treatment for advanced squamous cell carcinomas of the oral cavity. A further follow-up study needed to confirm the promising 5-year results.

Actuarial Analysis↗
PubMed1992

Treatment of recurrent gliomas and metastatic brain tumors with a polydrug protocol designed to combat nitrosourea resistance.

PURPOSE: The study was undertaken to evaluate a chemotherapy protocol against recurrent malignant gliomas that was designed to combat presumed chloroethyl-nitrosourea (NU) resistance. PATIENTS AND METHODS: All patients had malignant gliomas and had failed prior therapy. Patients were stratified as having either glioblastoma multiforme (GM) or anaplastic gliomas (AG) and as having failed radiotherapy (RT) only or both RT and chemotherapy. Chemotherapy consisted of six drugs: before lomustine (CCNU), thioguanine (TG), dibromodulcitol (mitolactol; DBD), and procarbazine (PCB) were given to enhance CCNU-induced tumor-cell kill and to reduce alkyltransferase repair of ethylated DNA. A fluorouracil-hydroxyurea (FUHU) combination was given 2 weeks later to kill cells that began to cycle after the challenge of the first four drugs (TPDC-FUHU chemotherapy). RESULTS: Of the 88 assessable patients, 37 had GM, 38 had AG, and 13 had other primary and metastatic brain tumors. For GM patients, 61% had a partial response (PR) or stable disease (SD) for a median of 9.3 months if RT only failed, and 58% had a PR or SD for a median of 5.1 months if they had previously been treated with an NU. For AG patients, 92% had a PR or SD for a median of 15 months if RT only had failed, but only 38% had a PR or SD for a median of 10.6 months if they had been previously treated with a NU. Activity was also seen against other recurrent or progressive primary and metastatic brain tumors. CONCLUSIONS: TDPC-FUHU chemotherapy is a highly effective form of chemotherapy for both recurrent GM and AG patients. This study suggests but does not prove that this combination may be superior to other NU-based treatments for recurrent malignant glioma patients who fail RT. Because of the activity of this chemotherapy, we intend to evaluate more fully this approach in a randomized study.

Adolescent↗
PubMed2006

Treatments for astrocytic tumors in children: current and emerging strategies.

Strategies for the treatment of childhood cancer have changed considerably during the last 50 years and have led to dramatic improvements in long-term survival. Despite these accomplishments, CNS tumors remain the leading cause of death in pediatric oncology. Astrocytic tumors form the most common histologic group among childhood brain tumors. They are a heterogeneous group that from a practical therapeutic point of view can be subdivided into low-grade astrocytomas (LGA), optic pathway gliomas (OPG), high-grade astrocytomas (HGA), and brainstem gliomas (BSG). This article focuses on the practical application of treatments that lead to long-term survival, improved quality of life, and reduced long-term complications. Improvement in therapy has led to better outcomes for patients with LGA and OPG. Careful follow-up without any treatment is indicated for a small percentage of patients diagnosed with LGA with an indolent course including children with neurofibromatosis type 1 (NF1). Surgery is the main recommended treatment for children with resectable LGA. Radiation therapy is generally recommended for children with progressive LGA, or after failure of chemotherapy, accomplishing tumor control at 10 years in over 60% of patients. Cytotoxic chemotherapy is usually reserved for children who have had treatment failure with surgery and radiation therapy. It is also offered for children who are too young to be treated with radiation or to defer or avoid radiotherapy. Carboplatin and vincristine achieve 5% complete and 28% partial responses but the use of vincristine is criticized due to poor penetration of the CNS. A regimen of tioguanine, procarbazine, mitolactol, lomustine, and vincristine is frequently administered as an alternative to carboplatin and vincristine in LGA. The introduction of temozolomide has allowed better responses, including a 24% complete response rate compared with 0-5% complete response rates with the previous regimens. OPG are usually histologically LGA, and are treated with similar chemotherapy regimens. OPG is the most common type of brain tumor associated with NF1. Tumor growth in some of these patients is slow with no treatment recommended for an extended period of time. The prognosis for children with the remaining types of astrocytomas remains poor. Surgical resection is typically the first step in the treatment of HGA followed in older children by radiation therapy. The data regarding chemotherapy are mixed. Combination chemotherapy before or after radiation, including cisplatin, carmustine, cyclophosphamide, and vincristine or carboplatin, ifosfamide, cyclophosphamide, and etoposide has provided disappointing results. Clinical trials with temozolomide and agents directed against single targets have not shown substantially better results, but it is hoped that currently conducted studies will provide better outcomes. Diffuse intrinsic BSG are among the most difficult-to-treat brain tumors. Surgical treatment is not recommended for diffuse intrinsic BSG and standard radiation therapy is typically given in children aged >3 years. None of the numerous chemotherapy regimens, including temozolomide, has provided a significant response rate or an improvement in survival. It is expected that newer agents affecting multiple targets such as AEE-788 and antineoplastons, and combinations of single-targeted agents with chemotherapy will provide better results. Careful evaluation of histology, location of the tumor, patient age, and consideration of treatment-related morbidity play an important part in selecting between clinical observation, surgery, radiation, chemotherapy, or investigational agents. The goals of treatment for astrocytic tumors should extend well beyond objective responses and increased survival. Improvement of quality of life is an equally important objective of treatment. Radiation therapy and chemotherapy result in serious late toxicities.

Astrocytoma↗
PubMed1992

[Comparative study of preoperative chemotherapy and radiotherapy in squamous cell carcinoma of the oral cavity].

The results of the preoperative Co 60 irradiation and BVMM (bleomycin, vincristine, mitolactol, methotrexate) chemotherapy were compared. Both treatments were used in 50-50 advanced squamous cell cancer of the oral cavity. The general condition, size of lesion and age of the patients were similar. Surgery in the irradiated group was significantly more radical at the primary sites. Local recurrences during a three-year follow-up period were diagnosed in 36% from the radiotherapy group, whilst 8% such recurrences diagnosed in the chemotherapy group. There was no significant difference in the radicality of lymph node surgery. Lymph node recurrences occurred in 8% from the irradiated group, whilst 22% was diagnosed in the chemotherapy group. The main opinion is that BVMM chemotherapy and irradiation can be used to support one another in the interest of better result, like preoperative chemo- and postoperative radiotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1975

Cytostatic treatment of polycythaemia rubra vera. Comparison of the effects of some cytostatics in 100 patients in a period of five years.

Experience with cytostatic treatment performed in patients with polycythaemia rubra vera is reviewed. The effectivity and side effects of the drugs applied are evaluated. Mannosulfan and mitobromitol were the drugs most sutiable for treatment. In certain special cases, 5-hydroxyurea was also satisfactory, while mitolactol was the least suitable.

Adolescent↗
PubMed1989

[Non-differentiated carcinoma of the nasopharynx in children].

The authors deal in their paper with the problem of nondifferentiated carcinoma in childhood. They draw attention to data in the literature which report an incidence of 1-15% and compare with these data their own experience according to which in 158 patients with carcinoma of the nasopharynx there were seven children. They emphasize the inexpressive character of symptoms and thus the relatively long time which elapses before causal anti-tumourous treatment is started in child patients. They emphasize the importance of a uniform diagnostic protocol where they accentuate the directoscopy of the Rosenmüller fossa, tympanometry, computed tomography and draw attention to the advantages of EBV serology and mapping according to the HLA system. As far as treatment is concerned, they recommend radiotherapy, supplemented by adjuvant administration of the transfer factor and Mitolactol. In the conclusion the authors emphasize the necessity of team work to ensure correct interpretation of results from the diagnostic sphere and to ensure treatment in the initial stages when therapy gives the most permanent results.

Adolescent↗
PubMed1985

Cross-resistance of vinblastine- and taxol-resistant mutants of Chinese hamster ovary cells to other anticancer drugs.

Stable mutants resistant to the anticancer drug vinblastine (VinR mutants) have been isolated after a single selection step from Chinese hamster ovary cells. Of the two types of VinR mutants which are obtained, one class exhibits specific cross-resistance to only some of the microtubule inhibitors. However, the second type of mutants, which is affected in membrane permeability, exhibits cross-resistance to a wide variety of unrelated compounds. Both classes of VinR mutants showed codominant expression in cell hybrids formed between resistant and sensitive cells. The cross-resistance patterns of the VinR mutants and a single-step mutant resistant to the anticancer drug taxol (TaxR mutant) toward various anticancer drugs have been determined. The mutants resistant to both of these drugs showed significantly increased resistance toward aclarubicin, dactinomycin, doxorubicin, bisantrene, bruceantin, chromomycin A3, demecolcine, colchicine, daunorubicin, ellipticine, emetine, ethidium bromide, maytansine, mithramycin, mitoxantrone, nitidine chloride, olivomycin, podophyllotoxin, puromycin, taxol, vinblastine, vincristine, vindesine, teniposide, and etoposide. Interestingly, either one or both of the above mutants exhibited somewhat enhanced sensitivity toward vidarabine, acivicin, bleomycin, cisplatin, cytarabine, alpha-difluoromethyl-ornithine, 5-FU, tegafur, and tiazofurin. For a number of other anticancer drugs which were examined (chlorambucil, mitolactol, IMPY, hexamethylmelamine, hydroxyurea, diglycoaldehyde, methotrexate, mitoguazone, mitomycin, nocodazole, and 6-thioguanine), the level of resistance of these mutants was found to be unaltered. The information regarding cross-resistance and collateral sensitivity patterns of VinR and TaxR mutants should prove to be very useful in the design of drug combinations which could prove more effective in cancer chemotherapy.

Alkaloids↗
PubMedDate not supplied

Chemotherapy for inoperable, non-small cell bronchogenic carcinoma: EST 2575, generation II.

Between 1976 and 1978 the Eastern Cooperative Oncology Group tested ten regimens in 415 patients with histologically documented, inoperable non-small cell bronchogenic carcinoma. Most patients were ambulatory (69%) and had extensive disease (69%). Patients were stratified by cell type: squamous cell carcinoma (SQ), large cell anaplastic carcinoma (LC), or adenocarcinoma (AD). Ineffective single agents (including cell types tested and percent complete and partial responses) were dactinomycin (SQ, 6%), dianhydrogalactitol (SQ, 0), ftorafur (AD and LC, 3%), and piperazinedione (AD and LC, 7%), Ineffective combination regimens included the contemporary standard regimen cyclophosphamide (CYT) plus CCNU (SQ, AD, and LC, 9%), methotrexate plus doxorubicin (ADR) plus CYT plus CCNU (MAC) (SQ and AD, 12%), and mitolactol plus ADR (AD and LC, 8%). When compared to CYT plus CCNU the following regimens demonstrated significant activity: CYT plus bleomycin plus cisplatin (SQ, 23%; P = 0.02) and ADR plus 5-FU plus cisplatin (AD and LC, 24%; P = 0.006). Mitomycin demonstrated marginal activity in squamous cell cancer (19%, P = 0.06). Neither "active" regimen improved survival although responders to any regimen had a significant prolongation of median survival (31.6 vs 15.7 weeks, P = 0.002). The MACC regimen, piperazinedione, and mitomycin were substantially more toxic than the two effective regimens, which were adequately tolerated. Ambulatory performance status, limited disease, and prior surgery were significant positive prognostic variables whereas prior radiation and pretreatment weight loss adversely affected response or survival.

Adenocarcinoma↗
PubMed1994

Salvage chemotherapy in recurrent or refractory squamous cell cancer of the uterine cervix.

Squamous cell cancer of the cervix is a relatively drug-resistant tumor. Therefore, chemotherapy is predominantly reserved for cervical cancer patients with recurrent or refractory disease following surgery and/or radiation therapy or for patients who present with far advanced, incurable disease. Objective responses to salvage chemotherapy are generally short lived (4 to 6 months) with few patients surviving more than 1 year. Complete clinical remissions primarily occur at extrapelvic sites (eg, lung, lymph node, and soft tissue metastases). Bulky pelvic tumor in an area of prior irradiation remains largely refractory to further therapy. At present, no chemotherapy regimen has proven superior to single-agent cisplatin, which is associated with an approximately 30% objective response rate. The most effective nonplatinum agents appear to be doxorubicin, ifosfamide, mitolactol, and vincristine. Multiple studies have documented improved partial response rates with platinum-based multiagent chemotherapy, but no regimen has been associated with an improved survival duration. To improve the poor prognosis of this patient group, identification of new agents with at least equivalent activity to cisplatin is mandatory. The development of new platinum-based regimens using currently available agents is unlikely to substantially improve patient survival, although better palliative therapy may result from this approach.

Antineoplastic Agents↗
PubMed1981

Clinical trials with the hexitol derivatives in the U.S.

Three hexitol derivatives, dibromomannitol (DBM), dibromodulcitol (DBD), and dianhydrogalactitol (DAG), originally investigated in Hungary, have been evaluated as anticancer agents in the United States. Their principal mechanism of action is attributed to alkylation via actual or derived epoxide groups. Their preclinical spectrum includes activity against murine leukemias and against the murine ependymoblastoma, which is particularly noteworthy for DAG. Dibromomannitol trials were targeted to chronic myelogenous leukemia but no advantage over busulfan therapy was demonstrable. Dibromodulcitol and DAG were sequentially evaluated for their usefulness against a wide variety of tumors. The activity of DBD against breast cancer has stimulated several continuing trials in this disease. On the other hand, DAG was disappointing in breast cancer and in several other malignancies, but some activity has been noted against lung cancer. Both DBD and DAG are being investigated for possible usefulness in the management of patients with intracranial neoplasms. The present clinical experience does not allow firm judgment on the advantage of one analogue over another. Such comparative analysis does point out the desirable direction of future studies as well as the limitations of current preclinical systems for the selection of analogues.

Animals↗
PubMed1984

Adriamycin, dibromodulcitol, and mitomycin combination chemotherapy for patients with metastatic breast carcinoma previously treated with cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone.

Twenty-six evaluable patients with metastatic breast carcinoma previously treated with a combination of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP) were treated with a combination of doxorubicin (Adriamycin), dibromodulcitol, and mitomycin (ADM). Four patients (15%) achieved complete remission, and 10 patients (39%) had a partial response. Five patients (19%) had stable disease, and seven patients (27%) experienced disease progression. The median time to disease progression was 10 months for responding patients (range, 4-44 months) and 5 months (range, 2-13 months) for patients with stable disease. The median survival duration was 15 months (range, 6-44+ months) for responders, 11 months (range, 2-27 months) for patients with stable disease, and 4 months (range, 2-41 months) for nonresponders. Two of the four patients with complete remission are alive and in continued remission at a follow-up of 44 and 40 months. Seventy-one patients with greater than or equal to two sites of metastasis responded, whereas 23% of patients with greater than or equal to three metastatic sites responded. Although higher responses were seen with soft tissue and osseous metastasis, responses were observed in all three sites of metastasis. This combination chemotherapy regimen with ADM is an effective second-line program for patients who have previously received CMFVP chemotherapy.

Adult↗
PubMed1984

Multivariate analysis of factors associated with outcome of treatment for adults with acute myelogenous leukemia.

Utilizing multivariate logistic regression statistical analysis, the authors evaluated prognostic features associated with achievement of complete remission (CR) and remission and survival duration in acute myelogenous leukemia (AML). These clinical variables were analyzed in 77 consecutive adult patients who underwent 108 courses of remission induction therapy with daunomycin, cytosine arabinoside, and 6-thioguanine (DAT) chemotherapy for newly diagnosed and first relapse of AML. Eight patients had developed leukemia in the setting of other malignant or immunologic diseases (therapy-linked AML) and 69 patients had not (primary AML). Sixty-three percent of patients with primary AML achieved CR with median remission and survival durations of 11 and 24 months, respectively. Significant unfavorable predictive features for achievement of CR were splenomegaly, and elevated leukocyte count or serum alkaline phosphatase levels. Patients who had leukocyte counts of less than or equal to 10,000/mm3 at diagnosis or less than or equal to 40,000/mm3 at the start of therapy, and those who received greater than 120 mg/m2 of daunomycin had significantly longer remissions and survival than those who did not. Fifty-seven percent of patients in first relapse also achieved CR; however, relative to first remissions, second remission durations were significantly shorter (median, 4.6 months). Sixty-two percent of patients with therapy-linked AML achieved CR, but remission durations (median, 2.8 months) were significantly shorter than first remissions of primary AML patients. These data identify clinical features associated with increased risk of failure to achieve CR and potential for short remission duration and survival. Alternative forms of therapy should be considered for such high-risk patients.

Adolescent↗
PubMed1988

Central nervous system involvement in malignant melanoma.

One hundred consecutive patients with cerebral metastases from malignant melanoma were studied in relation to survival from the time of diagnosis of central nervous system (CNS) involvement, response to treatment, characteristics of their primary lesion, and the course of the disease from initial diagnosis to the development of intracranial tumor. After treatment, clinical and investigational evidence of objective regression of cerebral lesions was demonstrable in ten patients who survived with a median of 11.5 months from diagnosis of CNS involvement. In 11 additional patients, CNS disease remained clinically stable for a median period of 7 months. Median survival for the entire group of 100 patients was 2.5 months. However, eight patients (8%) survived longer than 1 year from the time of diagnosis of cerebral metastases, four of whom (4%) survived longer than 2 years; the longest survivor being disease-free and incomplete neurologic remission at more than 82 months. Patients with malignant melanoma metastatic to the brain should be informed of the therapeutic options available for their disease.

Antineoplastic Combined Chemotherapy Protocols↗