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C Erlichman

Publications and source records attributed to C Erlichman.

At least 91 records · Page 5Linked to original sources
PubMed1986

Potential applications of therapeutic drug monitoring in treatment of neoplastic disease by antineoplastic agents.

Therapeutic drug monitoring of antineoplastic agents must be considered in terms of cytotoxicity to stem cells and toxicity of normal tissues. The dose-limiting toxicity which is myelosuppression is believed to be a necessary effect for maximal antitumour effect. The areas in which therapeutic drug monitoring can play a role include: predicting patients at risk of toxicity, e.g. high dose methotrexate therapy; low bioavailability, e.g. oral 6-mercaptopurine; identifying patients at risk of treatment failure, e.g. methotrexate clearance in acute lymphoblastic leukemia. Although therapeutic drug monitoring is not clinically useful at present, the potential role it can play is illustrated for cytosine arabinoside, adriamycin and cyclophosphamide. Two problems encountered with drug monitoring of antineoplastic disease are tumour heterogeneity manifested by clonal, nutritional and physical characteristics and the common practice of combination chemotherapy. These problems must be addressed in order to make therapeutic drug monitoring a practical tool in cancer chemotherapy. Future applications of therapeutic drug monitoring will require more studies to define therapeutic ranges for single agents, patient-to-patient variation, course-to-course variation and the effects of drug combinations on pharmacokinetic profiles of the drugs used.

Antineoplastic Agents↗
PubMed1986

Limitations of urinary mutagen assays for monitoring occupational exposure to antineoplastic drugs.

The sensitivity of the Salmonella reversion test of Ames as a screen for accidental absorption of 17 antineoplastic agents by drug handlers was evaluated. Dilutions of each drug were added to agar inoculated with each of two Salmonella typhimurium strains (TA98 and TA100); control plates contained no test drug. Colonies were counted after incubation at 36 degrees C for 48 hours. The drugs were tested in the presence of a liver preparation to provide metabolic activation of mutagenicity. Urine samples collected from patients after doses of three mutagenic drugs were extracted and tested with the Ames test. For 11 of the 17 drug solutions, no mutagenic activity was seen, but many of these 11 were toxic to the organisms. The most highly mutagenic drugs were doxorubicin and cisplatin, with mechlorethamine, carmustine, dacarbazine, and cyclophosphamide exhibiting less mutagenic activity. Urine from patients treated with doxorubicin or cyclophosphamide showed mutagenicity, but the results suggested that the quantity of these drugs that would have to be absorbed to produce a definite reaction in urine is unlikely to be achieved by drug handlers who use standard precautions. Because of its lack of sensitivity and the potential effects of environmental and dietary factors on the results, this bacterial mutagenicity test should not be used routinely for detection of accidental absorption of antineoplastic drugs.

Antineoplastic Agents↗
PubMed1986

Superiority of methylprednisolone sodium succinate over low dose metoclopramide hydrochloride in the prevention of nausea and vomiting produced by cancer chemotherapy.

Methylprednisolone sodium succinate and metoclopramide were compared for their efficacy, tolerance, and safety in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy in patients with cancer. Previously untreated patients about to receive at least 2 cycles of identical chemotherapy were entered into a study using a randomized, double-blind, crossover design. Patients were given either 250 mg of methylprednisolone or 10 mg of metoclopramide intravenously before the first cycle of chemotherapy and were then crossed over to receive the alternate medication before the second cycle of chemotherapy. Prochlorperazine was prescribed in both cycles for postchemotherapy nausea and vomiting. After each treatment cycle patients recorded the degree of nausea, drowsiness and anxiety, the number of episodes of vomiting experienced, and the amount of prochlorperazine taken. After the second treatment cycle patients recorded their preference for either the first or the second antiemetic medication with respect to nausea, vomiting, and overall effectiveness. Of 157 patients entered into the study, 115 were fully appraisable. Methylprednisolone was superior to metoclopramide in preventing nausea and vomiting and in decreasing anxiety and the amount of prochlorperazine used. A majority of the patients expressing a preference preferred methylprednisolone to metoclopramide for control of nausea (p = 0.003), control of vomiting (p = 0.0006), and overall effectiveness (p = 0.00004). There were few side-effects. We conclude that methylprednisolone may have some utility as an antiemetic in patients receiving moderately emetogenic chemotherapy, and who are treated as outpatients.

Antineoplastic Agents↗
PubMed1986

Treatment of advanced gastric carcinoma with mitomycin and doxorubicin.

Thirty patients with advanced gastric carcinoma were treated with doxorubicin combined with mitomycin; only four (13%) responded. Myelosuppression was the major toxic effect; there was one toxic death. The overall median survival was 14 weeks (range, 2-42), which is no different from that reported for untreated patients. The combination of doxorubicin and mitomycin alone cannot be recommended for use in patients with advanced gastric carcinoma.

Adenocarcinoma↗
PubMed1986

Plasma pharmacokinetics of 5-FU given by continuous infusion with allopurinol.

We determined the steady-state plasma levels of 5-FU when the drug was administered by continuous infusion for 5 days during 21 courses in patients with metastatic colorectal carcinoma receiving concomitant oral allopurinol given at a dose of 300 mg orally three times/day. The steady-state plasma level increased from 3.37 to 7.49 microM with dose increases from 1.25 to 2.25 g/m2/day. Clearance ranged from 1.79 to 2.41 L/min/m2. Although we observed a large day-to-day variation and a large patient-to-patient variation in plasma 5-FU levels at any given dose level, these were not significant. The plasma level of 5-FU increased linearly with dose. The difference between 5-FU plasma levels with dose was significant (P = 0.002). When the levels were adjusted for patient-to-patient and day-to-day variation the difference remained significant (P = 0.02). The results indicate that: (a) plasma levels of 5-FU may show large but insignificant variation from patient to patient and from day to day; and (b) steady-state plasma levels and 5-FU increased linearly with dose.

Allopurinol↗
PubMed1985

Phase II trial of diaziquone in patients with colon cancer.

Seventeen patients with metastatic colon cancer received diaziquone iv daily for 5 days repeated every 28 days. Based on recommended starting doses for phase II trials (6-8 mg/m2 daily X 5), the first six patients received 7 mg/m2/day X 5. Two of these patients were heavily pretreated with chemotherapy, two had received prior 5-FU alone, and two had received no prior chemotherapy. There were no responses and three septic deaths (both of the heavily pretreated patients and one 5-FU-only patient who received concurrent radiotherapy). Eleven subsequent patients received 5.5 mg/m2/day X 5. Nine had no prior therapy; two had received prior 5-FU. No antitumor responses were observed. Myelosuppression was again the major toxic effect. No further septic deaths occurred. Diaziquone in this dose and schedule had no antitumor activity in this group of patients.

Adult↗
PubMed1985

Cytotoxicity of cisplatin and cisdiammine-1,1-cyclobutane dicarboxylate in MGH-U1 cells grown as monolayers, spheroids, and xenografts.

The cytotoxicity of cisplatin and cisdiammine-1,1-cyclobutane dicarboxylate (CBDCA) was examined using the MGH-U1 human bladder carcinoma cell line, grown as monolayer cultures, multicellular tumor spheroid(s) (MTS), and xenografts in immune-deprived CBA/CaJ mice. The cell survival of exponentially growing monolayers and MTS treated with cisplatin declined in a monoexponential fashion with a concentration of drug resulting in 10% colony survival (D10) of 7.75 micrograms/ml and 9.5 micrograms/ml, respectively. MTS growth delay determination demonstrated a drug concentration-dependent increase in growth delay and a correlation between decreasing surviving fraction and increasing growth delay. In vivo treatment of MGH-U1 xenografts with cisplatin caused a modest decrease in surviving fraction although the xenografted cells treated in vitro demonstrated the same sensitivity to cisplatin as those cells maintained continuously in vitro. The D10 for CBDCA treatment was 246 micrograms/ml for exponentially growing monolayer cells and 196 micrograms/ml for MTS. Growth delay studies with CBDCA showed a concentration-dependent increase in spheroid growth delay and a correlation between decreasing surviving fraction and growth delay similar to cisplatin. The conclusions were that: 1) cisplatin and CBDCA did not have any difficulty penetrating into spheroids, 2) both agents appeared to be active against the noncycling poorly nourished cells found near the necrotic center of spheroids, 3) both cisplatin and CBDCA were cytotoxic toward MGH-U1 cells but cisplatin was 20-30 times more effective, and 4) the limited cytotoxic effect of cisplatin in vivo may be due to the low area under the concentration times the time curve achieved in vivo and not due to intrinsic cell resistance.

Animals↗
PubMed1985

A bioassay to measure cytotoxicity of plasma from patients treated with mitomycin C.

The unpredictable clinical toxicity observed in patients treated with mitomycin C and the observation that this agent must be reduced to an active form before alkylating target molecules have led to the development of a bioassay which is capable of detecting biologically active forms of mitomycin C in the plasma of drug-treated patients. The bioassay makes use of a repair-deficient mutant of Chinese hamster ovary cells, UV-20, which is 40 to 60 times more sensitive to mitomycin C than its wild-type parent. A standard curve relating in vitro cell colony-forming ability of UV-20 versus drug concentration in the plating medium has been determined. Mitomycin C levels in patient plasma as low as 1 ng/ml can be detected, compared to the 5-ng/ml limit of detection obtained with a high-pressure liquid chromatography assay for the parent compound. This assay has been utilized to detect active drug in plasma obtained from patients with colorectal cancer treated with mitomycin C as a single agent. At the completion of drug injection, serial blood samples were collected in heparinized tubes, and aliquots of plasma were extracted and assayed for mitomycin C levels by high-pressure liquid chromatography, diluted and assayed directly for their toxicity for UV-20 cells, or frozen at -20 degrees C to be assayed at a later time. The activity detected by immediate bioassay was stable up to 2 mo in frozen samples. Plasma pharmacokinetics determined by the bioassay in seven patients were no different than those determined by high-pressure liquid chromatography. No stable, cytotoxic species other than the parent compound were detected by the bioassay in the plasma of patients treated with mitomycin C.

Animals↗
PubMed1984

Antitumor activity of N-phosphonacetyl-L-aspartic acid in combination with nitrobenzylthioinosine.

N-Phosphonacetyl-L-aspartic acid (PALA) resistance may be due to the ability of tumor cells to utilize preformed circulating pyrimidine nucleosides, thereby overcoming the block of de novo pyrimidine biosynthesis which PALA causes. To test this hypothesis we examined the effects of PALA and nitrobenzylthioinosine (NBMPR) alone and in combination on B16 melanoma cells in vitro using a clonogenic assay and in vivo using growth delay. In medium containing purine and pyrimidine nucleosides at a final concentration of 28 microM, exposure to PALA (100 microM) alone or to NBMPR (10 microM) alone for periods up to 72 hr did not result in any cytotoxicity. However, exposures to PALA (100 microM) plus NBMPR (10 microM) resulted in a decrease in clonogenic survival to 0.011 at 72 hr. In medium without nucleosides, PALA (100 microM) exposure for 72 hr caused a similar decrease in survival to 0.015, whereas NBMPR (10 microM) had no effect on survival. The addition of uridine resulted in a concentration-dependent reversal of the cytotoxic effects of PALA. C57 Bl female mice bearing B16 melanoma were treated intraperitoneally daily for 4 days with PALA, the phosphate of NBMPR (NBMPR-P), or PALA plus NBMPR-P. PALA, 300 mg/kg daily X 4, resulted in a 6-day tumor growth delay but NBMPR-P, 100 mg/kg daily X 4, had no effect. PALA, 150 mg/kg daily X 4, plus NBMPR, 50 or 100 mg/kg daily X 4, resulted in a 6-day tumor growth delay also. These studies demonstrate that: (1) circulating pyrimidine nucleosides are determinants of the cytotoxic effects of PALA; (2) in vitro PALA and NBMPR combine to cause significant cytotoxicity whereas either agent alone has no effect; (3) in vivo the combination of PALA and NBMPR-P results in the same antitumor affect as PALA alone at twice the dose; and (4) due to an increase in animal toxicity, no therapeutic advantage could be demonstrated for the combination over PALA alone in vivo. We conclude that the cytotoxic effect of PALA is modulated by the levels of the preformed circulating nucleosides and that combining PALA with an inhibitor of salvage pyrimidine uptake would not increase the therapeutic efficacy of PALA because of an increase in toxicity.

Animals↗
PubMed1984

High-performance liquid chromatographic measurement of cyclophosphamide in serum.

The analysis of cyclophosphamide [N,N-bis(2-chlorethyl)-tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine -2-oxide] by high-performance liquid chromatography using ultraviolet detection is described. The method will enable measurement of serum concentrations of cyclophosphamide over a period of approximately 24 h after a dose of 150 mg, and requires 1 ml of serum. The between-day precision of the assay at concentrations of 0.3, 1.0, and 15.0 mg/L generated coefficients of variation of 11.8, 12.2, and 7.7%, respectively. Percentages of analytical recovery of cyclophosphamide and internal standard (5-ethyl-5-p-tolylbarbituric acid) were 63 and 73%, respectively. Preliminary data providing the half-life for two patients with normal renal function are presented.

Chemical Phenomena↗
PubMed1984

Male breast cancer: a 13-year review of 89 patients.

A retrospective chart review was conducted of men with the diagnosis of carcinoma of the breast seen at this institution between January 1967 and March 1981. Eighty-nine patients were available for analysis. These cases were evaluated to determine whether the natural history of this disease was similar to that of women with carcinoma of the breast and to identify prognostic variables in carcinoma of the male breast. The results of this review would suggest that many similarities exist between breast cancer in women and in men. The most common presenting symptom is a lump, the patterns of recurrence are similar for both men and women, and survival is determined by initial T stage and the presence or absence of nodes. Local postoperative radiotherapy does not influence overall survival in male breast cancer but does decrease the incidence of chest wall recurrence. Survival after recurrence is short and is similar to that observed for women with recurrent carcinoma of the breast. The differences observed in the present series were that the median age at presentation of 63.6 years is somewhat greater than that usually observed in women; no cases of lobular carcinoma were observed; and in the 44 patients who developed recurrences to date, none had evidence of liver metastases as the initial site of recurrence. In most respects the natural history of male breast cancer is similar to that of carcinoma of the breast in women. Since carcinoma of the male breast is a relatively rare malignancy. it is reasonable to recommend management of this disease be based on the greater base of knowledge available for carcinoma of the female breast.

Actuarial Analysis↗
PubMed1984

Cytotoxicity of adriamycin in MGH-U1 cells grown as monolayer cultures, spheroids, and xenografts in immune-deprived mice.

The cytotoxic activity of Adriamycin was examined in the MGH-U1 human bladder carcinoma line, grown as monolayer culture, as spheroids, and as xenografts in immune-deprived mice. The MGH-U1 cells grown as spheroids were much more resistant to Adriamycin (concentration of drug resulting in 37% cell survival, 4.5 micrograms/ml) than when treated as monolayer cultures (concentration of drug resulting in 37% cell survival, 0.9 microgram/ml). Adriamycin fluorescence was demonstrated only in the outer two layers of cells forming the spheroids, suggesting that limited drug penetration is an important factor in the resistance of spheroids to Adriamycin. Sequential trypsinization of spheroids 750 micron in diameter allowed us to determine the cytotoxic effects of Adriamycin in MGH-U1 cells derived from different depths of the spheroid. We found that cells near the surface of the spheroid had a survival similar to those of exponentially growing monolayer cells treated with Adriamycin. Cells located in the middle of the viable rim were more resistant to Adriamycin, and those found near the necrotic center were most resistant to Adriamycin. The effects of Adriamycin treatment on spheroid growth delay were determined also. In spite of a small cytotoxic effect on the clonogenic fraction of cells in MGH-U1 spheroids, the growth delay effect of Adriamycin in intact spheroids was marked. This observation is consistent with Adriamycin killing primarily the cells in the outer layers of the spheroid, where most of the proliferation in the spheroid occurs. In vivo treatment of MGH-U1 xenografts with Adriamycin followed by assessment of cell survival in vitro showed minimal evidence of cytotoxicity, consistent with the poor drug penetration observed in the spheroid model. These studies suggest that: (a) Adriamycin penetrates poorly into solid tissues; (b) in vitro clonogenic survival following Adriamycin exposure of a cell suspension may predict falsely for drug sensitivity to chemotherapy; (c) a small decrease in clonogenic survival can be translated into a long growth delay but, ultimately, the tumor regrows because some clonogenic cells are spared; and (d) for Adriamycin, the spheroid model more closely parallels the in vivo effects than does monolayer culture. The use of the spheroid model for the study of Adriamycin cytotoxicity gives further insight into the action of this drug in solid tumors.

Animals↗
PubMed1982

Combined radical radiation therapy and chemotherapy for primary squamous cell carcinoma of the anal canal.

Radical radiation therapy (5000 rads in 20 fractions in 4 weeks) combined with iv mitomycin (10 mg/m2) and 5-FU (1000 mg/m2/24 hours for 4 days) was used to treat 13 patients with locally advanced but operable squamous cell carcinoma of the anal canal. All patients achieved local control and retained anal continence, and none developed metastases. The patients were followed from 4 to 34 months (median, 12). Severe acute gastrointestinal toxic effects were seen in three patients; the same patients had significant thrombocytopenia or leukopenia. Treatment with this combined program may allow conservative management of squamous cell carcinoma of the anal canal and should be considered as an alternative to abdominoperineal resection.

Adult↗
PubMed1982

Phase I-phase II trial of N-phosphonacetyl-L-aspartic acid given by intravenous infusion and 5-fluorouracil given by bolus injection.

A phase I clinical trial of N-phosphonacetyl-L-aspartic acid (PALA) and 5-fluorouracil (FUra) was performed on 30 patients. PALA was given as a 15-minute iv infusion once daily for 5 days, and FUra was given as a bolus injection on days 2, 3, 4, and 5. Cycles of treatment were repeated every 3 weeks. Dose-limiting toxicity was manifested by stomatitis and diarrhea. Skin rash was observed also but was not dose limiting. No consistent hematopoietic or renal toxicity was observed. Seventeen patients with disseminated metastatic melanoma and measurable disease were evaluated for response. One partial response was seen; however, the response was associated with significant toxicity, and the treatment could not be repeated. Stable disease was observed in 3 patients with melanoma, 1 patient with colon carcinoma, and 1 patient with ovarian carcinoma. Our findings suggest that the clinical activity of PALA and FUra given according to the above schedule for melanoma is less than 25% (P less than 0.05). Pharmacokinetic studies of FUra revealed no consistent effect of PALA pretreatment on FUra disappearance in plasma. The mean FUra elimination half-line in plasma was 7.11 +/- 0.84 minutes (SEM), which is no different from that reported for FUra alone. The recommended doses on this schedule for phase II studies are 1,000 mg PALA/m2/day iv daily for 5 days and 200 mg FUra/m2/day iv on days 2, 3, 4, and 5.

Adult↗
PubMed1980

An overview of the clinical pharmacology of N-phosphonacetyl-L-aspartate (PALA), a new antimetabolite.

N-Phosphonacetyl-L-aspartic acid (PALA) is new synthetic antimetabolite which inhibits de novo pyrimidine biosynthesis. Its significant activity against Lewis lung carcinoma, B16 melanoma, and glioma 26 suggested that it might be useful in the treatment of human solid tumors. Phase I trials revealed that dose-limiting toxicity included skin reactions, diarrhea, and stomatitis. Pharmacologic studies demonstrated rapid renal excretion of more than 70% of the unmetabolized drug in 24 h. Peak plasma levels correlated with dose of PALA administered. Partial responses to PALA were seen in one patient with melanoma, one with chondrosarcoma, and one with colon carcinoma. The potential for PALA's use in combination chemotherapy, particularly with 5-fluorouracil, is discussed.

Animals↗