[Anticancer drug research in Hungary, 1950-2000]. / Daganat-kemoterápiás kutatások Magyarországon az 1950−2000 közötti években.

The present review about the history of anticancer drug research in Hungary intends to call attention to the importance of studies on their mode of action. Several lines of evidence suggest that clinically usable oncopharmacological properties could be revealed by this way. Among the numerous compounds certain alkylating sugar alcohols and 2'-deoxyuridine derivatives were submitted to detailed investigations concerning their mode of action. Myelobromol with selective action on the myeloid elements of bone marrow has been justified for its application in chronic myeloid leukemia therapy and also in bone marrow ablation before transplantation. Mitolactol is able to cross bloodbrain barrier, consequently could control certain brain tumors. 5-etil-2'-deoxyuridine by reducing dihydropyrimidine dehydrogenase activity is able to increase 5-fluorouracil concentration in the blood, resulting in improved antitumor effect. In contrast, 5-hexil-2'-deoxyuridine, as an inhibitor of glycoconjugate pathway by reducing heparan sulfate production, has the ability to prevent metastasis. Noteworthy, the remarkable effects of vinca alkaloids, antiestrogens, and GNRH analogues were also presented in this review.

[A case of adult primitive neuroectodermal tumor(PNET)with multiple lung metastases effectively treated with ADM, IFM(AI)regimen].

The patient was a 48-year-old male with a right subclavicular tumor. The pathological diagnosis showed primitive neuroectodermal tumor(PNET)because of the rosette formation and the positive neurogenic marker.Radiation was administered at a total dose of 50 Gy, because surgical resection would induce the loss of right arm function. CT examination demonstrated a reduction of the primary tumor and new multiple lung metastases. The patient received intravenous AI regimen(ADM and IFM). After the 7th course, both the primary tumor and multiple lung metastases decreased. AI regimen might be effective for PNET.

Phase II TPDCV protocol for pediatric low-grade hypothalamic/chiasmatic gliomas: 15-year update.

To report long-term results for children with low-grade hypothalamic/chiasmatic gliomas treated on a phase II chemotherapy protocol. Between 1984 and 1992, 33 children with hypothalamic/chiasmatic LGGs received TPDCV chemotherapy on a phase II prospective trial. Median age was 3.0 years (range 0.3-16.2). Twelve patients (36%) underwent STRs, 14 (42%) biopsy only, and seven (21%) no surgery. Twenty patients (61%) had pathologic JPAs, nine (27%) grade II gliomas, and four (12%) no surgical sampling. Median f/u for surviving patients was 15.2 years (range 5.3-20.7); 20 of the 23 surviving patients had 14 or more years of follow-up. Fifteen-year PFS and OS were 23.4 and 71.2%, respectively. Twenty-five patients progressed, of whom 13 are NED, two are AWD, and 10 have died. All children who died were diagnosed and first treated at age three or younger. Age at diagnosis was significantly associated with relapse and survival (P = 0.004 for PFS and P = 0.037 for OS). No PFS or OS benefit was seen with STR versus biopsy/no sampling (P = 0.58 for PFS, P = 0.59 for OS). For patients with JPAs and WHO grade II tumors, the 15-year PFS was 18.8 and 22.2% (P = 0.95) and 15-year OS was 73.7 and 55.6% (P = 0.17), respectively. Upfront TPDCV for children with hypothalamic/chiasmatic LGGs resulted in 15-year OS of 71.2% and 15-year PFS of 23.4%. No survival benefit is demonstrated for greater extent of resection. Age is a significant prognostic factor for progression and survival.

[Expression of MDR1 and GST-pi in osteosarcoma and soft tissue sarcoma and their correlation with chemotherapy resistance].

OBJECTIVE: To explore the expression of multidrug resistance gene 1 ( MDR1), glutathione-S-transferases-pi (GST-pi) in osteosarcoma and soft tissue sarcoma tissues from 34 patients and their correlation with chemotherapy resistance. METHODS: MDR1 and GST-pi expressions were analyzed by real-time fluorescence quantitative polymerase chain reaction (FQ-PCR) and flow cytometry (FCM) at mRNA and protein levels, respectively. Chemotherapy sensitivity on adriamycin, cisplatinum, fluorouracil, mitomycin C, dacarbazine, vincristine, methotrexate in tumor tissues were detected by MTT assay. RESULTS: The nonsensitive rates on adriamycin, cisplatinum, fluorouracil, mitomycin C, dacarbazine, vincristine, methotrexate in tumor tissues were 41.18%, 17.7%, 47.1%, 50.0%, 76.5%, 61.8% and 52.9%, respectively. The expression of P-glycoprotein (P-gp) and GST-pi in tumor tissues was 1.54 and 2.58 (relative fluorescence intensity). Chi2 analysis showed that there was a positive correlation between P-gp expression and drug resistance on ADM, GST-pi expression and resistance on ADM, DDP and MMC (P < 0.05). There was not seen obvious correlation between expression of MDR1, GST-pi and age, gender, pathological type, tumor size in osteosarcoma and soft tissue sarcoma patients (P > 0.05). The expression of GST-pi was increased in patients receiving preoperative chemotherapy. The rate of postoperative recurrence was higher in patients with higher GST-pi expression level than those with lower GST-pi expression level before operation (P < 0.05). CONCLUSION: Individual differences exist in chemotherapy sensitivity and expression of MDR1 and GST-pi in osteosarcoma and soft tissue sarcomas patients. Chemotherapy can induce up-regulation of GST-pi protein expression. Primary high expression of GST-pi is the main mechanism of resistance of osteosarcoma and soft tissue sarcomas to chemotherapy and is related to poor prognosis.

Evaluation of adriamycin and dibromodulcitol in metastatic breast carcinoma.

A phase 1 to 2 evaluation of a combination of adriamycin (ADR) and dibromodulcitol (DBD) was performed in patients with progressive, metastatic breast carcinoma. All but one patient had been treated previously with chemotherapy. ADR was given on Day 1 or Days 1 and 8, and DBD was given on Days 1 to 10 of each 21- to 28-day treatment cycle. Side effects were evaluable in 54 patients, and 50 patients were evaluable for therapeutic response. The dose-limiting toxicities were leukopenia and thrombocytopenia. The severity of both toxicities increased as both the ADR and DBD doses increased; however, the effect of increases in DBD dose was much more profound. The mean white blood cell count and platelet nadirs occurred, respectively, on Days 15.3 and 15.9; both nadirs were delayed for 0.6 day by each 30-mg/sq m/day increase in the DBD dose and delayed for 1.7 to 3.9 days using the Day 1, 8 rather than the Day 1 ADR schedule Recovery of the peripheral counts by Day 29 was prolonged by the Day 1, 8 ADR schedule and by increasing the DBD dose. A tolerable dose schedule for previously treated patients was considered to be ADR, 40 mg/sq m on Day 1, and DBD, 135 mg/sq m on Days 1 to 10 repeated every 28 days. Responses were observed in 46% (23 of 50) of the patients. There were 1 complete remission, 19 partial remissions, and 3 improvements. Thirteen patients showed no change and 14 developed progressive disease. There were responses in 13 of 37 (36%) with visceral dominant disease as compared to 7 of 8 (87%) with osseous and 3 of 5 (60%) with soft tissue-dominant disease. There were 22 of 48 (46%) responses in patients previously exposed to alkylating agent therapy. Twnety-two patients had responded and 19 had failed to respond to prior alkylating agent-containing regimens; the response rates to DBD in these groups were respectively, 45 and 42%. The median time to remission was 29 days. The median time to therapeutic failure was 5.1 months for responders, 2.3 months for patients with no change, and 29 days for progressors. The combination of ADR and DBD appears to be an active and well-tolerated program in patients with previously treated metastatic breast carcinoma.

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.

A phase II evaluation of mitolactol in patients with advanced squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study.

Sixty patients with advanced squamous cell carcinoma of the cervix (SCC) who had received no prior chemotherapy were entered onto a study of mitolactol (dibromodulcitol [DBD]). The drug was administered orally at an initial dose of 180 mg/m2 per day for 10 days and repeated every 4 weeks. There were 55 evaluable patients, of whom one (2%) had a complete response (CR), and 15 (27%) had a partial response (PR), (CR plus PR, 29%). A 95% confidence interval for the true response rate is 18.8% to 42.1%. Myelosuppression was appreciable at this dose and schedule, with 13 patients experiencing life-threatening thrombocytopenia and two drug-related deaths. The level of activity in this disease encourages us to determine a tolerable dose of this drug in combination with cisplatin for further study.

Phase II study of 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine chemotherapy with radiotherapy for treating malignant glioma in children.

We conducted a single-arm phase II study to evaluate the efficacy and safety of radiotherapy combined with 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine (TPDCV) chemotherapy for treating malignant astrocytoma in children and anaplastic ependymoma in patients of all ages. Between 1984 and 1992, 42 patients who had malignant astrocytomas (glioblastomas multiforme, anaplastic astrocytomas, or mixed anaplastic oligoastrocytomas) were treated with TPDCV chemotherapy and radiation therapy. Of these patients, 40 were younger than 18 years, but 2 were older (22 and 23 years) when treated. Cranial radiation averaged 58 Gy. TPDCV chemotherapy was given for 1 year or until progression. Between 1989 and 1991, 17 patients with malignant ependymoma were treated with TPDCV chemotherapy and craniospinal radiation. Radiation was given at an average dose of 54 Gy to the tumor, 28 Gy to the whole brain, and 31 Gy to the spinal axis. TPDCV chemotherapy was given for 1 year or until tumor progressed. Of the patients with glioblastoma multiforme, 13 of 17 died; the median time to progression was 49 weeks, and median survival was 85 weeks. The four patients surviving at this writing were followed a median 537 weeks (range 364-635 weeks). Of the patients with nonglioblastoma malignant astrocytoma, 14 of 25 died; the median time to progression was 224 weeks. Median survival was not reached in this group. The median follow-up for those surviving was 494 weeks. For the patients with ependymoma, 11 of 17 died with a median time to progression of 141 weeks. The median follow-up for the eight who survive was 469 weeks. Nine patients died with a median survival of 183 weeks. The combination of TPDCV and radiotherapy has activity against childhood anaplastic astrocytoma, glioblastoma multiforme, and anaplastic ependymoma. The results of this study for children with glioblastoma were comparable to results in the literature, while the results for children with anaplastic astrocytoma appeared better than most reports. The combination of TPDCV chemotherapy and radiation therapy for anaplastic ependymomas appears to be active and at least as good as published reports using radiation therapy alone.

Dibromodulcitol plus bleomycin compared with bleomycin alone in head and neck cancer.

Advanced recurrent squamous cell head and neck cancer patients were prospectively randomized to receive or not receive dibromodulcitol 10 mg/kg PO weekly for 8 consecutive weeks in addition to bleomycin chemotherapy. Patients initially entered in the study received bleomycin 15 mu/m2 three times weekly for 8 weeks. This was later changed to 15 mu/m2 twice weekly for 8 weeks because of unacceptable stomatitis. Most patients had relapsed following surgery and/or radiotherapy, but none had received prior chemotherapy. A2 : 1 randomization in favor of the dibromodulcitol-containing therapy was used. There were 12 partial responses in the 44 evaluable patients receiving the combination (27%), and 4 partial responses in the 18 patients receiving single-agent bleomycin chemotherapy (22%). This difference was not statistically significant. Response durations were also relatively short for both therapies. Within the limitations of this study, we were unable to demonstrate that patient benefit resulted from the addition of dibromodulcitol to bleomycin chemotherapy for this patient population.

Chemotherapeutic approaches to brain tumors. Experimental observations with dianhydrogalactitol and dibromodulcitol.

Dianhydrogalactitol (DAG) or its active cell-killing moiety has a relatively long biological half-life in 9L cells cultured in vitro. The shape of the DAG dose-response curves was similar to that of those observed for most oncolytic agents. The prominent shoulder on the 24-h dose-response curve indicates that 9L cells can accumulate a reasonable amount of DAG-induced sublethal damage before they are killed. The appearance of 9L colonies in petri dishes was delayed 3-5 days after a DAG treatment that killed more than 99% of the cells, an observation not previously made with radiation, hyperthermia, the nitrosoureas, or other chemotherapeutic agents. Comparison of the in vitro exposure integral and the in vivo tumor tissue integral indicated that DAG would have to be administered at a dose in excess of its LD10 to achieve an in vivo 2 log cell kill. The lack of a significant increase in lifespan after a LD10 dose confirmed this prediction. While DAG alone is active against IC ependymoblastoma, it had very limited activity against IC glioma 26; however, the combination of DAG with BCNU was curative in 85%-100% of animals at 120 days. BCNU alone achieved no more than 4%-16% survival at 120 days. The combination of DBD and BCNU was not consistently better than BCNU alone against IC glioma 26. It appears that DAG may have a limited place in CNS chemotherapy for specific kinds of tumors. BCNU-DAG combination studies suggest that we may, under the right conditions, enhance the antitumor activity of the hexitol epoxides by drug combination therapies, although the mechanism for this enhanced antitumor activity is presently unknown.

Combined radiotherapy and chemotherapy with dibromodulcitol and CCNU in the postoperative treatment of malignant gliomas.

Within 4 weeks after definitive surgery, 91 patients with supratentorial glioblastomas and malignant astrocytomas were randomized to one of three treatment arms: Group 1 received radiotherapy alone; Group 2 received dibromodulcitol (DBD) during radiotherapy, and treatment was then continued with DBD; and Group 3 received DBD during radiotherapy, followed by combination chemotherapy of CCNU and DBD. No severe myelotoxicity occurred, but combined treatment with CCNU and DBD occasionally caused a transient myelosuppression. Statistical analysis of 84 evaluable patients showed a significantly longer survival period in those who received chemotherapy during and after irradiation. Median survival times in the three groups were 40, 57, and 60 weeks, respectively; the corresponding p value for Groups 2 and 3 was 0.025 and 0.0015. The ratio of patients surviving over 18 and 24 months was highest in Group 3. This study suggests that the administration of DBD during irradiation might have been the main factor in improving survival times.

A phase II study of dibromodulcitol (DBD) in stage IV melanoma.

Twenty-four patients were evaluated in a non-randomized study to assess the effectiveness of dibromodulcitol (DBD) in Stage IV melanoma. Patients received 100 mg/m2 of DBD orally for 35 days. The dose was escalated to 130 mg/m2 and then to 160 mg/m2 if no significant hematologic toxicity occurred. There were no objective responses, including six patients who had had no prior chemotherapy. Five patients (21%) remained stable. Median survival was 151 days. Survival favored females, nonvisceral involvement pretherapy, and patients with a disease-free interval (DFI) of greater than 1 year. None of these advantages was statistically significant. Toxicity was predominantly hematologic, but nausea, vomiting, shortness of breath, and diarrhea were also seen. Oral DBD, using this dose and schedule, does not appear efficacious in advanced disseminated melanoma.

Dibromodulcitol in the treatment of metastatic hemangiopericytoma.

Hemangiopericytoma is an uncommon sarcoma arising from the pericapillary cells. While the rarity of this lesion precludes randomized investigation, metastatic hemangiopericytoma has been noted to respond to a variety of agents, including vincristine, adriamycin, actinomycin, and high-dose methotrexate. We wish to report an unusual case of this disease which failed to respond to the above but then exhibited a marked response to dibromodulcitol. In light of the unusual nature of this response, we would like to suggest a controlled trial of the use of dibromodulcitol in patients with this rare tumor.

Randomized clinical trial of doxorubicin alone or combined with mitolactol in women with advanced breast cancer and prior chemotherapy exposure.

One hundred fifty-one women with advanced breast cancer who had failed prior chemotherapy were randomized to monthly courses of doxorubicin (60 mg/m2 I.V. day 1, observation after 500 mg/m2) or doxorubicin (40 mg/m2 I.V. day 1; maximum 500 mg/m2) and mitolactol (135 mg/m2 orally, days 1-10; 180 mg/m2 after maximum doxorubicin). Median survival times were 232 days for doxorubicin and 225 days for doxorubicin + mitolactol, and median times to progression were 112 days and 97 days, respectively. Results are inconsistent with a 25% improvement in survival or time to progression for doxorubicin + mitolactol (p = 0.04 and 0.02, respectively, adjusted for stratification factors but not multiple testing). Regression rates for all patients, both measurable and evaluable, were 30% for doxorubicin alone and 26% for doxorubicin + mitolactol. Regression rates were significantly higher in patients with measurable indicator lesions. Cardiac toxicity was seen in four patients, all of whom were receiving doxorubicin alone. It appears that the combination of doxorubicin + mitolactol is not substantially more effective than doxorubicin alone in women with advanced breast cancer and prior chemotherapy exposure.

Phase II evaluation of dibromodulcitol, ICRF-159, and maytansine for sarcomas.

Patients with objectively measurable soft tissue sarcomas, osteosarcomas, chondrosarcomas, and mesotheliomas were treated with dibromodulcitol (DBD) (180 mg/m2 p.o. days 1-10 q4 wks.). ICRF-159 (300 mg/m2 p.o. tid days 1-3 q4 wks), or maytansine (MAYT) (1.5 mg/m2 I.V. q3 wks.). Forty-five evaluable patients received DBD, 47 MAYT, and 37 ICRF-159. Only patients who had had their histopathologic diagnoses confirmed by a pathology reference panel were included in the final analysis. Two patients had objective partial responses: a patient with osteosarcoma who responded to DBD and a patient with fibrosarcoma who had a partial response of brief duration to ICRF-159. Approximately 70% of the patients treated with each drug were of ECOG performance status 0 or 1, and over half had moderate or worse toxicity. It seems unlikely that these drugs have significant therapeutic activity for common mesenchymal malignancies.

The effect of dibromodulcitol (Elobromolr, Mitolactolr, nsc 104 800) on the postoperative recurrences of the Guerin carcinoma of the rat.

In all cases of Guerin carcinoma of the rat the recurrence of the tumor in 7-10 days can be observed following surgical removal. Local treatment with Dibromodulcitol combined with intraperitoneal administration of the same drug results in delayed occurrence of tumor recurrences, the growth of which is slower, and in a significant increase of life span of the animals. In exceptional cases no recurrence appeared. The local treatment combined with intraperitoneal administration was the most effective. Peroral treatment was also effective although in a lesser degree.

Preliminary experience with Mitolactol in advanced tumors of the orofacial region and the larynx.

Mitolactol (Dibromodulcitol "DBD"; RlobromolR) an alkylating agent was applied in a clinical series of twenty advanced or relapsing cases of malignant tumors of the orofacial region and the larynx. It was administered orally in a mean total dose of 127 mg/kg/30 days. In 45% of the patients the treatment resulted in a diminution of tumors by more than 50%, with remission lasting 1-4 months. 30% of the patients responded by a retreat of the tumor volume smaller than 50%, while no therapeutic effect was noted in 25% of the patients, or the objective finding proved to be worse. Subsequent radiotherapy improved the results, and remissions which followed combined chemo-radiotherapy were prolonged up to 9 months. The effect of DBD treatment proved better in orofacial than in laryngeal carcinoma.

Randomized phase III trial of single versus multiple chemotherapeutic treatment following surgery and during radiotherapy for patients with anaplastic gliomas.

In 81 patients with anaplastic supratentorial gliomas, single versus multiple chemotherapeutic agents were selected for treatment following surgery and during radiotherapy in a prospective randomized study. Time to treatment failure and survival were not significantly enhanced by multiple agent chemotherapy, as administered in this study.

Cytochemical characterization of Yoshida sarcoma cells resistant to dibromodulcitol.

Two Yoshida ascites sarcoma cell populations, one of them originally sensitive and another rendered resistant to the alkylating agent dibromodulcitol (DBD), were compared for doubling time, labeling index, survival time, morphological features, cellular DNA content and modal DNA value. Cross-resistance studies were carried out on bilaterally growing solid tumours derived from the sensitive and resistant Yoshida cell populations. Glycogen-containing granules appeared in the cytoplasm of the DBD-resistant sarcoma cells; these were not present in the sensitive tumour. The growth parameters of the sensitive tumour were throughout the 10-day observation period characteristic of rapidly proliferating tumours, whereas those of the DBD-resistant tumour was characteristic of slowly proliferating systems. As compared to the mean DNA values for normal somatic cells (lymphocytes), those found for both tumours indicated that the cells were hyperdiploid aneuploid. The DNA stem line in the resistant tumour proved to be significantly smaller than that in the sensitive tumour. These results indicate that a reduction of malignancy in the Yoshida tumour is associated with a developed resistance to dibromodulcitol. The resistant tumour showing cross-resistance to dianhydrogalactitol, diacetyl-dianhydrogalactitol and to nitrogen mustard retained full sensitivity to cyclophosphamide and adriablastin (Adriamycin), and proved to be collaterally sensitive to vincristin.

[Pharmacokinetic study of dibromodulcitol in children with brain tumors]. / A dibrómdulcit farmakokinetikai vizsgálata agytumoros gyermekekben.

Systemic pharmacokinetics of high-dose (500 mg/m2), orally administered dibromodulcitol (Elobromol) were studied in 16 chemotherapeutic courses administered to 5 patients. Cerebrospinal fluid dibromodulcitol levels were also analysed in two patients. Bromoepoxydulcitol, dianhydrodulcitol are cytotoxic, whereas bromoanhydrodulcitol, andhydroepoxydulcitol are inactive metabolites detectable during the biotransformation of dibromodulcitol. The HPLC method, developed by our team, is suitable for the determination of both dibromodulcitol and its main metabolites (dianhydrodulcitol and bromoanhydrodulcitol). Our publication is the first in the literature to describe the pharmacokinetic properties of these three hexite-derivatives in pediatric patients. With the exception of one patient, concentration-time curves were analysed by the one-compartment model. From the 30th minute following administration, dibromodulcitol was detectable in all plasma samples for at least 12 hours, its concentration however was usually undetectable by the 24th hour. Though highly variable in value, dianhydrodulcitol concentrations were detectable during all but one therapeutic courses. The following peak concentrations were observed: dibromodulcitol: 3.46-30.63 microM; dianhydroldulcitol: 1.70-6.17 microM; bromoanhydrodulcitol: 0-5.63 microM. The correlation of area under the curve for bromoanhydrodulcitol and dibromodulcitol was exponential up to 200 microMxh with no additional increase detectable above this limit; the distribution of dianhydrodulcitol values were described by a maximum-curve. The possibility of enterohepatic recirculation could not be excluded for any of the compounds studied. Each of the three hexitol derivatives were detectable in the cerebrospinal fluid even if the concentration of the individual metabolite remained undetectable in plasma. The cerebrospinal fluid concentrations of dibromodulcitol were almost constant in the period from 2.5 to 8 hours following administration.(ABSTRACT TRUNCATED AT 250 WORDS)