Biomedical subjects

B S Yap

Publications and source records attributed to B S Yap.

At least 19 recordsLinked to original sources

PubMed1988

Phase I study of weekly-administered iproplatin [cis-dichloro-trans-dihydroxy-bis-isopropylamine platin (chip, JM9)].

Iproplatin [cis-dichlor-trans-dihydroxy-bis-isopropylamine platinum (CHIP, JM9)] is a new antineoplastic platinum analogue with an octahedral conformation. It has more water solubility than does cisplatin and was found to have less neurotoxicity and nephrotoxicity in experimental animals than cisplatin. Like cisplatin, it has been demonstrated to have a broad spectrum of activity in experimental tumor systems. A phase I study of iproplatin was conducted in 28 patients (12 with melanoma, 8 with sarcoma, 6 with breast cancer, and 2 with colon cancer). All patients had failed prior chemotherapy. Four consecutive doses of iproplatin were administered at weekly intervals followed by a rest period of two weeks for hematologic recovery (one course). One hundred forty-two weekly doses were administered with all patients except three receiving at least one full course. The weekly starting dose of 40 mg/m2 was increased to 120 mg/m2 given over 30 minutes without hydration. Myelosuppression predominantly thrombocytopenia, was the dose-limiting toxicity at weekly doses of greater than or equal to 95 mg/m2 per course. With iproplatin doses 75 mg/m2, 95 mg/m2, and 120 mg/m2, the lowest median granulocyte counts were 2.6 x 10(3)/mm3, 2.2 x 10(3)/mm3, and 1.8 x 10(3)/mm3, respectively. Similarly, at iproplatin doses of 75 mg/m2, 95 mg/m2, and 120 mg/m2, the lowest median platelet counts were 144 x 10(3)/mm3, 99 x 10(3)/mm3, and 31 x 10(3)/mm3, respectively. Mild to moderate nausea and vomiting were observed in the majority of patients. No significant neurotoxicity, nephrotoxicity, or ototoxicity was observed. Objective tumor regression was not observed in this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗

PubMed1986

Clinical pharmacokinetics of 9, 10-anthracenedicarboxaldehyde-bis [(4,5-dihydro-1 H-imidazol-2-yl)hydrazone]dihydrochloride.

We studied the clinical pharmacokinetics of the anthracene derivative bisantrene using high-performance liquid chromatographic analysis. We administered the drug to ten patients at 120-250 mg/m2 IV; one of these patients also received a second dose of 120 mg/m2 6 weeks later, and another received 150 mg/m2 weekly for three doses. Bisantrene disappeared from the plasma biphasically, with an initial t1/2 of 0.6 +/- 0.3 h and a terminal t1/2 of 24.7 +/- 6.9 h after single doses. The apparent volume of distribution according to the area under the curve was 42.1 +/- 5.9 l/kg, and the total clearance was 1045.5 +/- 51.0 ml/kg/h. The 96-h cumulative urinary excretion was 3.4% +/- 1.1% of dose; thus, renal excretion was a minor route of elimination for this agent. Bisantrene pharmacokinetics in the patient who received a second dose after 6 weeks showed insignificant changes. However, in the patient who was given this drug weekly for 3 weeks, the plasma t1/2 of the drug during the terminal phase became increasingly longer, while the total clearance was significantly reduced. These results suggest that bisantrene may accumulate in the body and that caution is essential in the event of frequent administration.

Adult↗

PubMed1985

A phase II trial of PCNU in patients with malignant melanoma and central nervous system metastases.

Twelve patients with malignant melanoma metastatic to the central nervous system (CNS) were treated with PCNU. All patients had prior chemotherapy and/or radiation therapy and had progressive brain metastases, documented by computerized tomography. PCNU was given as a single intravenous infusion of 90-110 mg/m2 every 6-8 weeks. There was one partial response and four patients had stable disease. Although no episodes of sepsis or bleeding occurred, seven of 17 courses led to significant granulocytopenia or thrombocytopenia. Nonhematopoietic toxicities were mild. These results indicate that systemic PCNU is unlikely to be more effective than other currently used chemotherapy in patients with malignant melanoma and CNS metastases.

Brain Neoplasms↗

PubMed1984

Phase II evaluation of PALA in patients with refractory metastatic sarcomas.

The efficacy of PALA was evaluated in 22 patients with metastatic soft tissue and bone sarcomas. The 20 evaluable patients had received a median of three prior chemotherapeutic regimens, including an adriamycin combination, to which eight had shown response. PALA was administered at 2-week intervals. Sixteen patients received 6 g/m2 over 1 hour intravenously as their initial dose, while six patients received 5 g/m2. The major side effects were skin rash, stomatitis, diarrhea, nausea, and vomiting. Significant myelosuppression was not seen. Two patients had stabilization of disease for periods of 10 and 13 weeks. At the dose and schedule used in this trial, PALA was not effective against advanced adult sarcoma.

Adult↗

PubMed1984

Phase I study of tricyclic nucleoside phosphate using a five-day continuous infusion schedule.

A Phase I trial of tricyclic nucleoside phosphate (1,4,5,6,8-pentaazaacenaphthylene-3-amino-1, 5-dihydro-5-methyl-1-beta-D-ribofuranosyl 5'-phosphate ester; NSC 280594) was conducted using a 5-day continuous infusion schedule. Thirty-seven patients with advanced cancer were entered on the study, of whom 33 patients were evaluable for response and toxicity. Dose levels ranged from 10 mg/sq m/day X 5 days to 40 mg/sq m/day X 5 days. Initially, courses were repeated every 3 to 4 weeks. As cumulative toxicity became manifested, the interval between courses was changed to every 6 weeks. Major toxicities included hyperglycemia, hepatotoxicity, and thrombocytopenia. Patients with a prior history of diabetes mellitus, extensive radiation therapy, or significant liver metastases were prone to severe toxicity. Other toxicities noted were nausea and vomiting, abdominal discomfort, anemia, and reduction in serum calcium, phosphorus, and albumin levels. Rare side effects included hypertriglyceridemia, hyperamylasemia, diarrhea, and stomatitis. Antitumor activity observed include improvement in s.c. metastases in a patient with papillary thyroid carcinoma, stabilization of disease in a patient with mesothelioma, and mixed responses in three patients (colon cancer, sarcoma, and tonsillar squamous cell cancer). Recommended schedule for Phase II studies is 20 mg/sq m/day for 5 days every 6 weeks.

Acenaphthenes↗

PubMed1983

Clinical pharmacology of 2,5'-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (AZQ).

2,5'-Diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (AZQ) is an alkylating compound which has exhibited a broad spectrum of antitumor activity against a variety of experimental tumors, particularly those implanted intracranially. We have studied the clinical pharmacology of AZQ in 11 patients with various types of tumors. AZQ was administered at 1-12 mg/m2 daily for 5 days by i.v. infusion in 10-30 min. 14C-labelled AZQ was given on day 1 only. Blood and urine specimens were analyzed radiochemically and chromatographically. The plasma disappearance of unchanged AZQ was essentially biphasic, with an initial plasma t 1/2 of 1.4 +/- 0.4 hr and a terminal t 1/2 of 45.5 +/- 3.1 hr. The apparent volume of distribution was 14.2 +/- 3.0 l/kg. The cumulative urinary excretion of unchanged AZQ was 4.3% in 24 hr and 8.6% in 96 hr. The total clearance of the drug was 200 ml/kg/hr. Cerebrospinal fluid AZQ concentration peaked 45-90 min after drug administration, reaching about 70% of that in plasma, and then declined at nearly the same rate.

Antineoplastic Agents↗

PubMed1983

A randomized study of continuous infusion vindesine versus vinblastine in adults with refractory metastatic sarcomas.

A randomized study was conducted in 33 adult patients with refractory metastatic sarcomas to compare the therapeutic efficacy of continuous vindesine versus continuous vinblastine. Of 30 evaluable patients, 15 patients received vindesine as a continuous 5-day infusion at 1.2 mg/m2 repeated every 3 weeks, and 15 patients received vinblastine at 1.5 mg/m2/day every 3 weeks. Ten patients had stable disease, while 20 patients showed progressive disease. No objective responses were observed. There was adequate myelosuppression and both drugs were well tolerated with few catheter-related problems. It does not appear that vindesine or vinblastine, given by continuous 5-day infusion, is active in the treatment of metastatic sarcomas in adults.

Adult↗

PubMed1983

Bisantrene, an active new drug in the treatment of metastatic breast cancer.

Forty-four patients with metastatic breast cancer who had previously received extensive conventional systemic therapy, including combination chemotherapy with doxorubicin, were treated with Bisantrene, a new anthracene derivative. The dose schedule was 250 to 300 mg/sq m body surface administered as a 1- to 2-hr i.v. infusion. Of 40 evaluable patients, there were nine partial responses, and 18 patients had stable disease. Responses were seen in all major sites of organ involvement with a median time to progression of 28 weeks. Moreover, responses were seen among patients who had either failed to respond or had demonstrated refractoriness to prior therapy with doxorubicin, suggesting an apparent lack of cross-resistance between doxorubicin and Bisantrene. Except for myelosuppression and one incidence of acute anaphylactoid reaction, Bisantrene was generally well tolerated by most patients. We believe that Bisantrene may ultimately have a major role in the effective treatment of metastatic breast cancer, and further clinical trials are warranted.

Adult↗

PubMed1983

Prednisone pulse therapy for refractory myeloma.

The utility of vindesine and a frequent prednisone schedule was evaluated in 70 patients with refractory myeloma. No patient responded to vindesine alone, but about one-fourth achieved significant tumor reductions from intermittent high-dose prednisone, either alone or in combination with vindesine. Forty-seven percent responded when prednisone pulses were combined with vincristine and doxorubicin, providing the best results yet achieved in our patients with refractory myeloma. In responding patients, remissions were of excellent quality and survival was prolonged significantly. These results supported the utility of a more frequent corticosteroid schedule with increased doxorubicin dose in patients with advanced and resistant multiple myeloma.

Bone Marrow↗

PubMed1982

Treatment for meningeal carcinomatosis in breast cancer.

Forty breast cancer patients with meningeal carcinomatosis were treated with a combined program of whole brain irradiation therapy with intrathecal and intraventricular methotrexate and citrovorum factor rescue. Responses were seen in 26 patients (65%); 13 patients (35%) failed to respond. The median survival time for the responding patients was six months, and for the nonresponders, one month. Factors affecting response and survival included pretreatment spinal fluid glucose, protein, and duration of CNS-related symptomatology prior to onset of therapy. In contrast, pretreatment CSF tumor cell count, CEA and initial CNS functional status did not appear to have prognostic significance. The authors conclude that following intensive therapy there can be much improvement in the quality of life and disease-free survival in breast cancer patients with meningeal carcinomatosis.

Brain↗

PubMed1982

Clinical pharmacology of bruceantin by radioimmunoassay.

During the phase I clinical trial of a new antitumor agent, bruceantin, the pharmacology was studied in 18 cancer patients. The drug was infused intravenously (IV) for 3 h at doses ranging from 1 to 3.6 mg/m2 per day for 5 days. The plasma drug disappearance curves were biphasic, with a fast initial half-life of less than 15 min. The second half-life (t1/2 beta) varied from 0.7 to 38 h among different patients and was not dose-related. The difference between the t1/2 beta on day 1 and that on day 5 was not significant. In patients with normal liver function, the mean plasma concentration at the end of infusion was 22 ng/ml, and the value of the area under the concentration X time curve (AUC) was 111 (ng/ml)h. In contrast, in patients with abnormal liver function the corresponding values were 115 ng/ml and 830 (ng/ml)h, respectively. In addition, these patients had a slower elimination half-life of 10.9 h and a decreased total clearance of 157 ml/min/m2, as compared with 2.6 h and 671 ml/min/m2, respectively, for the normal group. All these differences were statistically significant. Patients with abnormal liver function developed more severe toxicity, including fever, severe nausea, vomiting, and hypotension. Two patients with severe hepatic dysfunction received a reduced dose and developed no toxicity. These results demonstrated the importance of the effects of liver dysfunction on drug disposition and showed that the dosage should be reduced in patients with hepatic dysfunction.

Antineoplastic Agents, Phytogenic↗

PubMed1982

AZQ therapy in patients with disseminated malignant melanoma.

Twenty-eight patients with disseminated malignant melanoma, who had failed prior therapy, were treated with aziridinylbenzoquinone (AZQ) administered on a 5-day I.V. schedule repeated every 4 weeks. The starting doses were 8 or 6 mg/m2/day x 5 days for good-and-poor-risk patients respectively. There were no complete or partial responses among 23 evaluable patients but four patients had stabilization of disease. The dose-limiting toxicity was thrombocytopenia. Other toxicities included weakness, nausea, vomiting, anorexia, dizziness, abdominal pain, and constipation. AZQ, given on a 5-day schedule, is ineffective in the treatment of patients with metastatic malignant melanoma.

Adult↗

PubMed1982

Phase I clinical evaluation of 9,10-anthracenedicarboxyaldehyde[bis(4,5-dihydro-1H-imidazol-2-yl)hydrazone]dihydrochloride (bisantrene).

9,10-Anthracenedicarboxyaldehyde[bis(4,5-dihydro-1H-imidazol-2-y1)-hydrazone ]dihydrochloride (bisantrene) is one of a series of anthracenedicarboxyaldehyde compounds that has significant antitumor activity similar to that of doxorubicin in experimental mouse tumor systems. A phase I clinical study was conducted using a weekly x 3 schedule. Twenty-six patients with a wide variety of advanced malignant solid tumors received a total of 39 courses of the drug at doses ranging from 40 to 180 mg/m2/week x 3. Leukopenia was the dose-limiting toxic effect. Other toxic effects included malaise, which was observed in 49% of the courses, nausea and vomiting in 36%, fever in 21%, and phlebitis in 21%. No responses were observed in this study. For phase II studies, using this schedule, a starting dose of 150 mg/m2/week x 3 repeated every 4-5 weeks is recommended. In patients who have received minimal or no therapy, the starting dose should be 180 mg/m2.

Adult↗

PubMed1981

A phase II evaluation of methyl CCNU and actinomycin D in the treatment of advanced sarcomas in adults.

Twenty-nine patients with metastatic sarcoma were treated with a combination of methyl CCNU and actinomycin D. Patients with adequate bone marrow reserve received methyl CCNU 100 mg/m2 orally on day 1 and actinomycin D 0.3 mg/m2/day intravenously for five days. Both drugs were repeated every four weeks. Patients with inadequate bone marrow reserve received methyl CCNU 75 mg/m2 and actinomycin D 0.2 mg/m2/day for five days. All patients had received prior chemotherapy and had progressive disease at the start of the study. There was one complete response in a patient with peritoneal mesothelioma which lasted 18 months and the patient is still alive at 38+ months. Ten patients had stable disease including three patients who had responses between 25% to 50%. No responses were seen in 18 patients. The median time to progression for patients with stable disease was five months and for those with progressive disease was two months (P = 0.001). The median survival for patients with stable disease was 20 months compared with three months for patients with progressive disease (P = 0.001). The combination was generally very well tolerated and myelosuppression was insignificant. However, with the dosages and schedule used in this study, the combination of methyl CCNU and actinomycin D does not appear to have significant activity in advanced soft tissue sarcomas. Further studies with this combination are indicated in patients with mesothelioma.

Adult↗

PubMed1981

Chemotherapy for postmastectomy lymphangiosarcoma.

Twenty-two patients with postmastectomy lymphangiosarcoma have been seen at M. D. Anderson Hospital during the past 20 years. Of these, 13 received chemotherapy, either regionally, systemically, or both. Six patients were treated with regional chemotherapy using either methotrexate alone, a combination of melphalan, nitrogen mustard, and actinomycin D, or a combination of melphalan with nitrogen mustard or actinomycin D; 3 achieved a partial or complete response. Eleven patients received 19 trials of systemic chemotherapy; one complete and seven partial responses were observed, giving an overall response rate of 42% (8/19). Responses occurred with 5-fluorouracil, methotrexate, a combination of vincristine, actinomycin D, and cyclophosphamide, and a combination of Adriamycin and dacarbazine with or without vincristine. The median survival time of the six patients who responded to at least one chemotherapeutic trial was 26.5 months compared with four months for the five patients who failed to respond. These data indicate that chemotherapy may play a significant role in the treatment of patients with this rare but distinctive tumor.

Adult↗

PubMed1981

Asparaginase and methotrexate combination chemotherapy in relapsed acute lymphoblastic leukemia in adults.

We have treated 37 adults with acute lymphoblastic leukemia (ALL), who have relapsed on previous intensive chemotherapy, with a combination of L-asparaginase and methotrexate (MTX) +/- ifosfamide. The initial study included 26 patients who received the two-drug combination of L-asparaginase and MTX given sequentially. Of the 26 patients, 15 (58%) achieved complete remission (CR), while 3 patients had a partial remission (PR), resulting in an overall response rate of 69%. The median duration of CR was 17.5 weeks. The median survival of complete responders was 39 weeks compared with 10 weeks for failures (P=0.001). The regimen was generally well tolerated and it was possible to give MTX doses of up to 400 mg/m2 with minimal myelosuppression, and severe stomatitis was infrequent. A further study involved the use of this regimen combined with ifosfamide in 11 patients. In this continuing study, there were six CR's (55%) and two PR's, with an overall response rate of 73%. The median duration of CR was 14+ weeks, and the median survival was 40+ weeks. Combination chemotherapy with asparaginase and MTX is effective in inducing remission in adults with ALL in relapse. It should now be considered for inclusion as part of induction therapy of previously untreated adults with ALL.

Adolescent↗

PubMed1981

Pharmacokinetics of [14C]methylglyoxal-bis-guanylhydrazone) in patients with leukemia.

Methylglyoxal-bis(guanylhydrazone) (MGBG; NSC 32946), a competitive inhibitor of S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50), currently being reevaluated for its clinical antileukemic activity. MGBG labeled with 14C in the guanylhydrazone moiety was administered i.v. (150 microCi; specific activity, 1.9 microCi/mumol; 20 mg total) to six patients with leukemia. All patients in the study had normal renal and hepatic function. [14C]MGBG underwent no in vivo metabolism; it disappeared from the plasma with an average terminal t 1/2 of 4.1 hr. The 72-hr cumulative urinary excretion was only 14.5 +/- 2.2% (S.E.M.) of the total radioactive dose. The apparent volume of distribution was 661 ml/kg and the total clearance rate was 21.2 ml/kg/min. The low urinary excretion rate and the relatively rapid plasma clearance suggest that MGBG may be sequestered in the body. Therefore, if MGBG is administered by a frequent treatment schedule, the prolonged biological half-life in humans may significantly contribute to its clinical toxicity.

Drug Evaluation↗

PubMed1981

Penetration of methylglyoxal bis(guanylhydrazone) into intracerebral tumors in humans.

Methylglyoxal bis(guanylhydrazone) (MGBG; NSC 32946) is currently being reevaluated for its clinical antineoplastic activity against both hematological and solid tumors. MGBG (100 to 200 mg/sq m) was administered by slow infusion over 3 hr to six patients during surgical resection of intracerebral tumors. Excised tumor tissue and plasma were assayed for MGBG by high-pressure liquid chromatography. In all cases, MGBG penetrated rapidly into brain tumor tissue. Viable tumor tissue contained greater concentrations of MBGB than did necrotic tumor tissue. In two patients with glioblastoma multiforme, MBGB concentrations in brain tumor tissue were five- to 19-fold higher than concurrent plasma samples. However, MGBG did not penetrate well into the cerebrospinal fluid of two patients with Ommaya reservoirs given i.v. MGBG (200 mg/sq m). The highest MGBG concentration in cerebrospinal fluid reached only 22% of the concurrent plasma levels. These studies suggest that MGBG may be a useful agent in the treatment of intracerebral tumors but may not be effective against meningeal leukemia and meningeal carcinomatosis.

Blood-Brain Barrier↗