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M R Pfeffer

Publications and source records attributed to M R Pfeffer.

33 records · Page 2Linked to original sources
PubMed1990

Effect of acidic pH on radiosensitization of FSaIIC cells in vitro by misonidazole, etanidazole, or cis-diamminedichloroplatinum (II).

Because acidic regions may coexist with hypoxic regions in solid tumors, we have studied the effect of acidic extracellular pH on the abilities of misonidazole, etanidazole, and cis-diaminedichloroplatinum(II) (CDDP) to radiosensitize hypoxic FSaIIC cells in vitro. For 1-h exposures to misonidazole prior to and during irradiation, the sensitizer enhancement ratios (SERs) were 2.10 +/- 0.18 at 1 mM drug and 2.50 +/- 0.16 at 5 mM drug at pH 7.40 but only 1.90 +/- 0.14 and 2.30 +/- 0.14, respectively, at pH 6.45. For etanidazole the SERs at pH 7.40 at 1 and 5 mM drug were 1.90 +/- 0.13 and 2.40 +/- 0.18, respectively, but only 1.25 +/- 0.13 and 1.70 +/- 0.17, respectively, at pH 6.45. The decrease in the SERs for both 2-nitroimidazole compounds was statistically significant (P less than 0.01). When CDDP at concentrations of 1 and 5 microM was tested, SERs of 1.30 +/- 0.15 and 1.60 +/- 0.18, respectively, were observed at pH 7.40, and the increase was not significant at pH 6.45 (1.35 +/- 0.15 and 1.80 +/- 0.19, respectively). The cellular levels of misonidazole, etanidazole, and CDDP did not vary significantly at the environmental conditions tested. These results demonstrate that pH is a potentially important variable in the action of hypoxic cell radiosensitizing drugs and suggest that future evaluations of such agents should test the effects of pH.

Animals↗
PubMed1989

Interaction of PtCl4(Fast Black)2 with hyperthermia.

We are developing complexes of negatively charged PtCl4 with positively charged nuclear dyes as new antitumor agents for use alone and in conjunction with hyperthermia and/or radiation. Elemental analysis has shown that the complex PtCl4(Fast Black)2 is a tight ion pair. In experimentally growing EMT6 cells in vitro, PtCl4(Fast Black)2 killed cells in a log-linear manner which increased as the temperature of the exposures was increased from 37 to 42 degrees C or 43 degrees C. In addition, cell kill was also increased under conditions of low pH (6.45), especially in hypoxic cells treated at elevated temperature. Measurement of intracellular platinum levels after exposure to 25 microM cisplatin or PtCl4(Fast Black)2 demonstrated that platinum levels were between 170- and 200-fold higher after exposure to PtCl4(Fast Black)2. In vivo studies in the FSaIIC murine fibrosarcoma showed, again, that PtCl4(Fast Black)2 killed in a log-linear manner. Treatment of tumors placed in the thigh with 43 degrees C, 30-min hyperthermia immediately following i.p. injection of PtCl4(Fast Black)2 was dose modifying. One hundred mg/kg of PtCl4(Fast Black)2 produced a 4.6-day tumor growth delay which increased to 6.4 days with 43 degrees C, 30-min hyperthermia immediately following i.p. injection of PtCl4(Fast Black)2 was does modifying. One hundred mg/kg of PtCl4(Fast Black)2 produced a 4.6-day tumor growth delay which increased to 6.4 days with 43 degrees C, 30-min hyperthermia (growth delay for hyperthermia alone was 1.4 days), and 500 mg/kg produced a 5.6-day delay which increased to 11.0 days with hyperthermia. In contrast, cisplatin (5 mg/kg) produced a 4.4-day delay which increased to 5.9 days with hyperthermia. PtCl4(Fast Black)2 was well tolerated by animals, and the maximally tolerated dose was approximately 650 mg/kg. This new complex appears quite active as an antitumor agent alone and in conjunction with hyperthermia, and, since other studies have shown it to interact positively with radiation, this agent seems a very appropriate candidate for further development as a clinical anticancer drug.

Animals↗
PubMed1989

A phase I-II trial of cisplatin, hyperthermia and radiation in patients with locally advanced malignancies.

A Phase I-II trial testing the addition of systemic cisplatin (CDDP) to local hyperthermia and radiation was conducted to determine the dose of cisplatin that is tolerable once weekly for 6 weeks and to estimate the therapeutic potential of this trimodality combination in patients with locally advanced malignancies. Cisplatin at 20 mg/m2 (4 patients), 30 mg/m2 (8 patients), and 40 mg/m2 (12 patients) was given rapidly (over 5-10 min) i.v. after prehydration with 1 liter of normal saline. After approximately two-thirds of the cisplatin dose had been delivered, microwave hyperthermia was begun and continued for 60 min; the target minimum tumor temperature was 43 degrees C. Following hyperthermia, a 400 cGy fraction of radiation was delivered to the tumor. On other days during the treatment weeks, additional 200 cGy fractions were given to total doses of 6,000-6600 cGy in patients with full radiation tolerance or 2400-3600 cGy in patients with limited radiation tolerance. The 24 patients in this trial had a median age of 57 years and the predominant sites/tumor types were head and neck/squamous cell carcinoma (9) and chest wall/breast adenocarcinoma (9). Seventeen of the 24 treated tumors (70%) had previously been irradiated. Eighteen patients (75%) had received prior chemotherapy and nine patients (38%) had previously been treated with cisplatin. Bone marrow suppression was dose limiting in patients heavily pretreated with chemotherapy and chest wall radiation. No significant toxicities were observed at the 20 and 30 mg/m2 dose levels, but 5 of the 12 patients (42%) treated at 40 mg/m2 required modification of the cisplatin dose because of blood count suppression in four patients and mild renal dysfunction in one patient. Each of the patients with bone marrow suppression, however, had been heavily pretreated except for one patient with thrombocytopenia due to hypersplenism. Nausea and vomiting were mild with use of a standard, multiagent antiemetic regimen. Twelve patients (50%) attained a complete regression (CR) and 12 patients (50%) a partial regression (PR). Complete regression appeared to correlate with small tumor volumes (115 cc for CR versus 199 cc for PR patients) and higher tumor temperatures (4.6 average minimum equivalent minutes at 43 degrees C in CR versus 2.0 min in PR patients). Local toxicities included second degree burns in 12 patients (50%) and third degree burns in 6 (25%), but all burns healed in 4-12 weeks without surgical intervention.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1988

Antibiotic therapy for infected Ommaya reservoir systems.

The major complication of prolonged use of a permanently implanted Ommaya reservoir system is bacterial infection, encountered in 3 to 15% of patients. The best therapeutic approach to ventriculitis and meningitis occurring in the presence of this device is still a subject of debate. We reviewed our experience in 66 consecutive patients receiving intraventricular therapy via the Ommaya reservoir for leptomeningeal metastases or for subacute sclerosing panencephalitis. Eight episodes of infection occurred during the period of treatment, and all of them responded to systemic antibiotics with or without intraventricular treatment. Removal of the Ommaya reservoir was avoided, and therapy via the device for the underlying disease was resumed as soon as the infection was controlled. No relapse of infection occurred during a minimal follow-up of 40 days. On the basis of our experience and review of the literature, we challenge the concept that the Ommaya device, as a foreign body, must be removed to treat such infections successfully.

Adolescent↗
PubMed1986

Adriamycin, vinblastine and mitomycin C as second-line chemotherapy in advanced breast cancer.

Thirty-six evaluable patients with metastatic measurable breast carcinoma previously treated with CMF or CMFVP were given second-line chemotherapy with Adriamycin, vinblastine, and mitomycin C (AVM), as follows: Adriamycin 20 mg/m2 and vinblastine 6 mg/m2 by i. v. push on days 1, 8, and 15, and mitomycin C 10 mg/m2 i. v. on day 1, every 6 weeks. Ten patients (28%) achieved partial remission (PR) lasting a median of 10 months, and eight patients (22%) experienced improvement of a lesser level than PR. An additional nine patients (25%) had disease stabilization; in the remaining nine patients (25%), persistent disease progression was observed. The median survival from the onset of AVM was 7 months for all patients; patients with PR survived a median of 13 months. Myelotoxicity was substantial and frequently interfered with the optimal administration of AVM, especially in patients with skeletal metastases; four patients were hospitalized with leukopenia and fever; all recovered promptly; one death was probably related to thrombocytopenia and CNS bleeding. Our results with AVM are similar to the average response rate published in the literature with the use of Adriamycin as a single agent in previously treated patients with advanced breast cancer.

Adult↗
PubMed1984

Treatment of advanced soft tissue sarcomas with a modified CYVADIC protocol.

33 consecutive patients with metastatic or locally recurrent soft tissue sarcoma were treated with a modification of the CYVADIC (cyclophosphamide, vincristine, Adriamycin, dacarbazine) protocol. In an attempt to enhance the response rate without increasing the toxicity, the dose of Adriamycin was raised to 60 mg/m2 and the dose of cyclophosphamide to 600 mg/m2 in each cycle. The dose of dacarbazine was decreased to 150 mg/m2/day for 5 days. Of 31 evaluable patients there were 4 complete responses (13%) and 9 partial responses for a total response rate of 39%. 11 patients (33%) had minimal response or stable disease. The response achieved with our dose modification was no better than that achieved in several series with conventionally dosed CYVADIC.

Adult↗
PubMed1983

Successful chemotherapy of recurrent intracranial germinoma with spinal metastases.

A recurrent CNS germinoma with subependymal and spinal metastases was treated by combination of cis-platinum, bleomycin, and vinblastine, resulting in disappearance of intracranial and spinal tumor. Second intracranial relapse responded again to the same combination chemotherapy. Response of spinal metastases to this combination chemotherapy has not been reported previously.

Adult↗
PubMedDate not supplied

Interaction with hyperthermia of platinum complexes of triaminotriphenylmethane dyes.

Complexes of the tetrachloroplatinum(II) dianion PtCl4 with positively charged nuclear dyes have been designed in an effort to create new anticancer drugs for use with hyperthermia and/or radiation. The PtCl4 complexes with the monocationic triaminotriphenylmethane dye basic fuchsin [Pt(basic fuchsin)2] and the dicatrionic triaminotriphenylmethane dye methyl green [Pt(methyl green)], as well as the free dyes, were tested in exponentially growing EMT6 cells in vitro. Both the platinum complexes and free dyes were only moderately cytotoxic at pH 7.40 and 37 degrees C in normally oxygenated and hypoxic cells where cell killing by these drugs ranged from 0.5 to 1.5 logs at 500 microM. Each agent, however, became more cytotoxic at hyperthermic temperatures and pH 7.40. Pt(methyl green) and Pt(basic fuchsin)2 were slightly more cytotoxic to euoxic as opposed to hypoxic cells. Both platinum complexes became even more cytotoxic at pH 6.45 and 43 degrees C. Under these conditions, Pt(basic fuchsin)2 killed more hypoxic than euoxic cells (4.5 versus 2.5 logs at 500 microM), but Pt(methyl green) killed more euoxic than hypoxic cells (4.5 versus 2.5 logs at 100 microM). Methyl green was less cytotoxic than Pt(methyl green) at pH 6.45 and 43 degrees C, but basic fuchsin was the most cytotoxic drug under these conditions (cell kill of 3.5 logs in both euoxic and hypoxic cells at 100 microM). Intracellular platinum levels measured after 1 h exposure to 25 microM cisplatin, K2PtCl4, PT(methyl green), and PT(basic fuchsin)2 showed that approximately 1 ng of platinum per 10(6) cells was present after treatment with CDDP at pH 7.40 and pH 6.45 and at 37 degrees C and 42 degrees C; and approximately 0.2 ng was present after exposure to K2PtCl4 under each of these conditions. After exposure to Pt(methyl green), approximately 2.5 ng of platinum per 10(6) cells at pH 7.40, 37 degrees C, and 42 degrees C were present but increased to about 6.5 ng at pH 6.45 and 42 degrees C. With Pt(basic fuchsin)K, 726 ng of platinum were present at 37 degrees C, pH 7.40; 920 ng at 42 degrees C, pH 7.40; 313 ng at 37 degrees C, pH 6.45; and 413 ng at 42 degrees C, pH 6.45. Since Pt(methyl green) was more cytotoxic to cells at pH 6.45 and 42 degrees C, some of this effect could be attributed to increased uptake under these conditions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Schedule dependent tumour growth delay, DNA cross-linking and pharmacokinetic parameters in target tissues with cis-diamminedichloroplatinum(II) and etanidazole with or without hyperthermia or radiation.

It has been reported previously that striking increases in tumour growth delay and cytotoxicity are seen when cis-diamminedichloroplatinum(II) (CDDP) is combined with mild local hyperthermia (43 degrees C, 30 min) and/or etanidazole (ETA). This paper reports a study of CDDP pharmacology and the in vivo tumour DNA cross-linking produced by these combinations. In C3H mice bearing the FSaIIC murine fibrosarcoma, Pt plasma pharmacokinetics were not significantly altered by any of the combination of treatments. Although ETA caused no significant change in CDDP tissue pharmacokinetics, treatment of the tumour-bearing limb with hyperthermia immediately following an i.p. injection of CDDP (10 mg/kg) resulted in an increased peak Pt concentration (3.5 versus 2.8 micrograms Pt/g tumour wet weight) and doubled the t1/2 elimination of Pt (15 to 30 h) from the tumour. Similar heat-induced changes were observed in the Pt pharmacokinetics in skin. There was about a three-fold increase in the Pt area under the curve (AUC) for the tumour, a 1.5-fold increase in the AUC for skin and little change in the AUC for muscle with hyperthermia. When the tumour DNA cross-linking factor (CLF) was determined, it was found that local hyperthermia treatment (43 degrees C, 30 min) increased the CLF of CDDP from 1.7 to 2.7 and hyperthermia (43 degrees C, 1 h) further increased the CLF to 6.1. Misonidazole (MISO) (1 g/kg) increased the CDDP CLF to 2.0, 6.3 and 15.1 in conjunction with 37, 43 (30 min) and 43 degrees C (1 h), respectively. ETA (1 g/kg) was more effective than MISO at increasing the CDDP CLF, producing CLFs of 2.8, 9.1 and 21.5 at 37, 43 (30 min) and 43 degrees C (1 h), respectively. These changes in CLF were reflected in an increased tumour growth delay in the FSaIIC murine fibrosarcoma with CDDP (5 mg/kg) alone from 4.4 to 5.9 days with 43 degrees C (30 min) and then to 11.9 days with ETA (1 g/kg) and 20.9 days with both ETA and local hyperthermia (43 degrees C, 30 min). When CDDP, ETA and hyperthermia were added to a radiation schedule of 300 cGy daily for five days, it was found that giving ETA (1 g/kg), CDDP (5 mg/kg) and hyperthermia (43 degrees C, 30 min) together on day 1 produced the largest tumour growth delay (43 days) and that other schedules which divided the dose of ETA over the other days of the radiation treatment (including one schedule with a second heat treatment on day 4) were significantly inferior.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Continuous course of megavoltage radiotherapy for carcinoma of the prostate.

Between 1978 and 1983, 55 patients with advanced carcinoma of the prostate (38 with Stage C and 17 with Stage D) were treated with external beam MeV radiotherapy. In 29 patients radiotherapy was the first treatment modality, and 26 patients had previously received hormonal therapy. Both treatment modalities were continued simultaneously for Stage D and bulky Stage C of the disease. Severe urodynamic problems were the main treatment indications for patients with Stage D carcinoma. The treatment consisted of two courses each of 25 gray (Gy) whole pelvic irradiation, interrupted for 2 weeks to deliver a rotation field to the prostate at a dose of 20 Gy. Patients have been followed for a minimum of 36 months. For patients with Stage C disease the overall 3-year survival was 80%, with 55% disease-free survival. Palliative irradiation for Stage D prostatic carcinoma improves the quality of life and probably the survival rate. Acute minor complications were observed in 49% of the patients, and chronic complications occurred in 14% of the patients. The described MeV technique is well tolerated and effective for Stage C as well as for Stage D prostatic cancer patients.

Adenocarcinoma↗
PubMedDate not supplied

Leptomeningeal metastases--treatment results in 98 consecutive patients.

We report 98 consecutive patients with leptomeningeal metastases from lymphoma and other solid tumors. Of 90 who had non-CNS primary tumors, 71 had a life expectancy of at least 2 months from their systemic disease and were treated according to a protocol including radiotherapy to the symptomatic areas of the CNS and chemotherapeutic agents (usually MTX) administered into the CSF. Eight patients with meningeal spread from CNS tumors received craniospinal irradiation and/or systemic or intra-CSF chemotherapy. Of those treated according to the protocol, 30 had lymphoma, 25 of whom achieved a CR and 4 a PR; 27 had breast carcinoma, 9 of whom achieved a CR and 6 a PR; 14 had other solid tumors, 7 of whom achieved a CR and 2 a PR. Median survival was 8 months (range 1 to 87+) in patients with lymphoma and 3 months (range 1 to 40) in breast carcinoma patients. Long-term survivors were seen in these groups. Treatment complications occurred in 30% of patients, resulting in 4 deaths. The indications for aggressive therapy of leptomeningeal metastases and means to reduce its toxicity are discussed.

Adult↗
PubMedDate not supplied

Cyclophosphamide, adriamycin, DTIC and vincristine with methotrexate in the treatment of advanced soft tissue sarcomas.

Twenty-eight consecutive adult patients with locally advanced (inoperable) or metastatic soft tissue sarcomas were treated with a chemotherapy regimen (CADOM) including cyclophosphamide, ADR, and DTIC on Day 1 of each course, and vincristine with intermediate-dose methotrexate (200 mg/m2) on Day 15 followed by leucovorin rescue. Twenty-four of the patients were evaluable for response and toxicity. Three (13%) achieved a CR after chemotherapy and 6 (25%) a PR. Two of the PRs were converted to CR after surgical removal of residual tumor. All five patients achieving a CR are alive 12 to 30 months after beginning chemotherapy. Median survival of patients achieving a PR was 18 months and of patients achieving an MR was 7 months. Three of five patients with sarcomas arising from the female genitalia achieved a CR. No treatment-related deaths occurred. There were five instances of leukopenia and fever. Nausea and vomiting, and alopecia were common. Stomatitis, muscle cramps, paralytic ileus, and peripheral neuropathy were occasionally observed. The addition of methotrexate did not improve the response rate when compared with our previous CYV ADIC protocol.

Adult↗
PubMedDate not supplied

Sub-additive effect of the combination of radiation and cisplatin in cultured murine and human cell lines.

The use of cisplatin (CDDP) as a potential radiosensitizer in tumors is controversial. Reports about CDDP interaction with radiation range from high radiosensitization to a clear sub-additive effect. We examined the effect of the combination of different concentrations of CDDP with radiation in murine mammary adenocarcinoma (EMT-6) and human ovarian carcinoma (OV-1063) cell lines. CDDP was given in the dose range of 0.01-3.0 micrograms/ml and radiation in the dose range of 1-6 Gy. A methylene blue assay of cell density was used for the evaluation of cell survival and rate of proliferation in 96-microwell plates. The validity of this assay for evaluation of cell survival was verified by colony-forming assay and radiolabeled thymidine uptake. The dose response to CDDP for both OV-1063 and EMT-6 cells lines was examined; the ID50 was 0.06 and 0.9 micrograms/ml respectively. A sub-additive effect of the combination of radiation with CDDP was clearly observed in the two cell lines tested; the increase in dose of each modality resulted in a decrease of the relative contribution on the effect of the other. These findings question the rationale of combining CDDP with radiation for the enhancement of tumor response, since with the increase in the dose of either modality the additional effect of the other decreases.

Adenocarcinoma↗