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Biomedical subjects

R L Comis

Publications and source records attributed to R L Comis.

At least 73 records · Page 4Linked to original sources
PubMed1989

Phase I evaluation of an anti-breast carcinoma monoclonal antibody 260F9-recombinant ricin A chain immunoconjugate.

Four women with metastatic breast cancer were treated with monoclonal antibody 260F9-recombinant ricin A chain, a ricin A chain immunoconjugate (IC) which targets a Mr 55,000 antigen expressed by human mammary carcinomas. Patients were treated by daily, 1-h i.v. injections for 6 to 8 consecutive days. Two patients were treated with 10 micrograms/kg daily and the two others were treated with 50 micrograms/kg daily. The trial was suspended after four patients had been treated because patients treated with a continuous infusion schedule with this IC had developed significant neurological toxicity at doses similar to those used in this study. The half-life of the IC showed a t 1/2 alpha of approximately 1.8 h, a t 1/2 beta of approximately 8.3 h, and a peak concentration of about 200 ng/ml, at the lower dose level, and showed a t 1/2 alpha of approximately 2.5 h, t 1/2 beta of about 10.4 h, and a peak concentration of 500 and 850 ng/ml for the two patients at the higher dose level. All four patients developed evidence of a human anticonjugate antibody response within 16 days of the onset of therapy. The treatment was associated with significant toxicity, manifested by a syndrome consisting of weight gain, edema, hypoalbuminemia, and dyspnea. Similar symptoms were observed in patients treated by continuous infusions of the IC. This clinical syndrome, seen at doses of IC which were insufficient to saturate antigen-expressing malignant tumor deposits in this trial, has been seen in other IC therapy trials and in clinical trials using the cytokine interleukin 2. To investigate a possible mechanism responsible for this toxicity, human monocytes were incubated with varying concentrations of IC. There was detectable binding of IC to human monocytes at IC concentrations which were achieved clinically in this trial. Furthermore, the binding appeared to be abrogated by preincubation of the monocytes with pooled human immunoglobulin, thus suggesting that binding occurs via Fc gamma receptor-mediated mechanisms. Binding was not affected if different linkers between recombinant ricin A chain and the antibody were used or if a different antibody moiety was used in the IC preparation. Chemically linked dimers of MOPC-21 bound to human monocytes at least as well as the ICs; this binding was not abrogated by preincubation with pooled human immunoglobulin. Since the IC preparations used in this clinical trial contained small percentages of dimers and/or multimers, the clinical toxicity syndromes which we observed may be related to this series of observations.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1989

Phase I clinical and pharmacologic trial of trimetrexate in combination with 5-fluorouracil.

Based on the synergy of sequential methotrexate (MTX) and 5-fluorouracil (5-FU) in vitro and in vivo and the superior antitumor activity of trimetrexate (TMTX) compared with MTX in preclinical models, we carried out a phase I trial of TMTX and 5-FU (fixed dose, 400 mg/m2 per day), both given as 10-min i.v. infusions daily x 5 days, every 28 days. The TMTX dose was escalated from 3.0 to 14.0 mg/m2 per day. In all, 92 evaluable courses were given to 34 patients, half of whom were heavily pretreated with radiation or cytotoxics. Myelosuppression and mucositis were the dose-limiting toxicities but were not different in heavily or minimally pretreated patients; there were five episodes of moderate to severe mucositis. Rash, fatigue, and diarrhea were mild toxicities. Plasma TMTX elimination was biexponential, with a mean t.1/2 alpha of 0.23 h and a t.1/2 beta of 16.7 h. The area under the plasma TMTX concentration versus time curve increased linearly with dose, suggesting first-order elimination. Total plasma TMTX clearance (mean +/- SD) was 14.3 +/- 5.9 ml/min per m2. Renal clearance accounted for approximately 7% of total clearance, indicating biotransformation as the major route of elimination. TMTX was highly protein-bound (97%). Thus, TMTX can be given with 5-FU (400 mg/m2) on a daily x 5-day bolus schedule at the 12 mg/m2 per day dose level, which was the recommended dose of TMTX as a single agent for phase II studies using the 5-day bolus schedule.

Adult↗
PubMed1989

Phase II study of iproplatin (CHIP) in previously treated small-cell lung cancer.

Eighteen patients with previously treated extensive small-cell carcinoma of the lung were entered into a Phase II study employing iproplatin (CHIP), a cis-platin analog. Patients had received a mean of two prior chemotherapeutic regimens. Fifty-five percent had received prior cis-platinum and 33% had received prior radiation therapy. CHIP (225 mg/m2) was administered by intermittent intravenous infusion over 30 min for 5 days of a 28-day cycle without prehydration. Sixteen patients with Zubrod performance scores of less than or equal to 3 received 27 courses of therapy (mean 1.7, range 1-6). One partial response of 167 days duration was observed, with complete regression of involved lymph nodes and stabilization of nonevaluable disease in the chest. Six patients had stable disease following one cycle of CHIP, but all progressed following a second cycle of drug. The main toxicity was myelosuppression with prominent thrombocytopenia. Median survival was 75 days from initiation of therapy. In this group of heavily pretreated patients with advanced disease, iproplatin has only minimal activity as a single agent and does not show non-cross-resistance with cis-platinum.

Aged↗
PubMed1989

A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B.

The Cancer and Leukemia Group B (CALGB) conducted a prospective randomized trial to evaluate the role of warfarin and alternating chemotherapy in extensive small-cell lung cancer (SCCL). After stratification for sex and performance status, patients were randomly assigned to receive chemotherapy with methotrexate, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH), cyclophosphamide, and lomustine (CCNU) (MACC), or MACC plus warfarin (MACC + W), or mitomycin, etoposide, cisplatin, and hexamethylmelamine alternating with MACC (MEPH/MACC). Warfarin was given continuously to maintain a prothrombin time of one and one half to twice the control values. A total of 328 patients were enrolled, and 294 were evaluable. There was a statistically significant advantage in objective response rates (complete [CR] and partial responses [PR], respectively) for MACC + W (17% and 50%) as compared with MACC alone (8% and 43%) or MEPH/MACC (10% and 38%) (P = .012). Both failure-free survival (P = .054 Wilcoxon test) and overall survival (P = .098 Wilcoxon test) were higher on MACC + W (median, 6.6 months and 9.3 months, respectively), as compared with MACC (5.0 months and 7.9 months) and MEPH/MACC (5.0 months and 7.9 months). Toxicity was comparable among the three arms, except for increased hemorrhagic events on MACC + W, which were life-threatening in four patients (4%), and lethal in two others (2%). These data support the role of warfarin in the treatment of SCCL, but do not establish its mechanism of action. Warfarin deserves further studies in SCCL, particularly in patients with limited disease.

Altretamine↗
PubMed1989

Exacerbation of epidemic Kaposi's sarcoma with a combination of interleukin-2 and beta-interferon: results of a phase 2 study.

Epidemic Kaposi's sarcoma (EKS) is the most common neoplastic manifestation of acquired immune deficiency syndrome (AIDS). The underlying immune deficiency can be partially reversed in vitro with interleukin-2 (IL-2). The type 1 interferons (IFN), alpha and beta, inhibit the growth of the etiologic agent of AIDS, the human immunodeficiency virus, have antitumor activity against Kaposi's sarcoma, and are synergistic with IL-2 in stimulating natural killer cell activity. Four patients with EKS were treated three times weekly with simultaneous intravenous injections of recombinant IL-2 (5 X 10(6) Cetus units/m2) and recombinant IFN-beta (6 X 10(6) units/m2). All patients had generalized disease, were without systemic symptoms, had no prior opportunistic infection, and had stable disease at the initiation of therapy. No patient had an objective response. Three patients exhibited rapid disease progression within 2-4 weeks of starting treatment, necessitating discontinuation of therapy and early closure of the study. This adverse result may have resulted from the significant levels of gamma-interferon (IFN-gamma) that can be generated with this dose and schedule of IL-2. Investigators using IL-2 should monitor IFN-gamma levels and avoid intermediate to high-dose bolus IL-2 therapy in patients with EKS.

Acquired Immunodeficiency Syndrome↗
PubMed1988

A phase I study of recombinant interleukin 2 plus recombinant beta-interferon.

Interleukin 2 (IL-2) therapies have antitumor activities against several neoplasms. In vitro these activities are enhanced by beta-interferon (IFN-beta). Therefore, we initiated a Phase I trial with a combination of IL-2 and IFN-beta three times weekly. The IFN-beta was administered i.v. Initially, the IL-2 was administered s.c. However, neutralizing antibody to the IL-2 developed in five patients, and the route of administration of the IL-2 was changed to i.v. Forty-seven patients were entered on the study. The maximum tolerated doses for the combination given i.v. were 5 x 10(6) units/m2 of IL-2 and 10 x 10(6) units/m2 of IFN-beta. Dose-limiting toxicities were profound fatigue/decreased performance status, anorexia/weight loss, depression, and arthralgias. Hypotension, exfoliative skin rash, thrombocytopenia, diarrhea, temperature greater than 40.6 degrees C, and peripheral edema were rarely dose limiting. Thirty-two patients were evaluable for response. After 4 weeks of treatment, 21 patients had stable disease, three patients had a minor response, and one patient had a partial response. Significant lymphokine-activated killer cell (LAK) activity was seen in seven patients (22%) and required 5 x 10(6) units/m2 of IL-2. Those who had progressive disease had significantly less LAK activity than those with either stable disease or a response. This therapy also induced more than 60 units/ml of endogenous gamma-interferon 4 h after the i.v. IL-2 administration. This study demonstrates that (a) intermittent i.v. bolus IL-2 therapy can generate LAK activity, (b) LAK activity may be associated with an antitumor response, (c) significant levels of gamma-interferon are induced by this therapy, and (d) IL-2 and IFN-beta given three times weekly i.v. is both tolerable and biologically active. The recommended Phase II dose is 5 x 10(6) units/m2 of IL-2 plus 6 x 10(6) units/m2 of IFN-beta.

Adult↗
PubMed1988

Antibody delivery and effector cell activation in a phase II trial of recombinant gamma-interferon and the murine monoclonal antibody CO17-1A in advanced colorectal carcinoma.

Murine monoclonal antibodies of the immunoglobulin G2a isotype interact with human effector cells to mediate antibody-dependent cellular cytotoxicity (ADCC) directed against malignant cells which express antigens recognized by these antibodies. gamma-Interferon enhances these effects in vitro. In a Phase I trial of murine monoclonal antibody CO17-1A and recombinant gamma-interferon (rIFN-gamma), we demonstrated that low doses of rIFN-gamma were superior to high doses in augmenting ADCC mediated by treated patients' monocytes. These results formed the basis for a Phase II trial of CO17-1A combined with low dose rIFN-gamma. Nineteen patients with metastatic colorectal carcinoma were treated with four consecutive daily infusions of 1.0 X 10(6) IU/m2 rIFN-gamma, with 150 mg of CO17-1A administered on days 2, 3, and 4. Therapy was tolerated well. Peripheral blood mononuclear cells were purified from patient samples obtained at baseline and at 1, 4, or 24 h following the start of the first rIFN-gamma infusion and were tested for their ability to lyse 111In-labeled cells of the SW1116 colorectal line. Enhancement of monocyte ADCC was seen by 24 h, while lymphocyte ADCC and natural killer activity directed against K562 cells were enhanced to a lesser extent. Nonspecific lysis of SW1116 cells by effectors was not seen at the time points examined. While CO17-1A antigen expression was observed in most biopsies, 131I-labeled CO17-1A imaged positively in less than one-half of the organs known to harbor metastases, and therapeutic antibody delivery was not always demonstrated by immunoperoxidase staining techniques of tissue obtained following therapy. In antigen-positive lesions, tissue pO2 levels appear to identify lesions which would image positively. No objective responses were seen. Our findings suggest that prolonged therapy with low doses of rIFN-gamma potentiates ADCC but that physiological obstacles to therapeutic antibody delivery are significant. In order to evaluate the validity of this therapeutic approach, measures to enhance antibody delivery are needed, starting with systematic evaluations of therapy with escalating doses of CO17-1A combined with low dose rIFN-gamma therapy.

Adult↗
PubMed1988

Noncorrelation of the expression of the c-myc oncogene in colorectal carcinoma with recurrence of disease or patient survival.

Our previous work has shown that 26 of 38 cases (68.4%) of primary adenocarcinoma of the colon exhibited significantly elevated levels of c-myc RNA compared to normal colonic mucosa (M. D. Erisman, P. G. Rothberg, R. E. Diehl, C. C. Morse, J. M. Spandorfer, and S. M. Astrin. Mol. Cell. Biol., 5: 1969-1976, 1985; P. G. Rothberg, J. M. Spandorfer, M. D. Erisman, R. N. Staroscik, H. F. Sears, R. O. Petersen, and S. M. Astrin. Br. J. Cancer, 52: 629-632, 1985). In this study, we have compared those levels of expression to the clinical profiles of the affected individuals in an effort to define useful correlates, especially with regard to recurrence of disease and patient survival. Log-rank comparisons of recurrence curves for the entire patient population, for those patients with low levels of c-myc RNA in resected tumor tissue, and for those patients with significantly elevated levels of RNA show no statistically significant differences. Similarly, no statistically significant difference was observed between the high- and low-myc RNA groups with respect to their survival during the postoperative period of observation (median, 25 months). Consequently, the levels of c-myc gene expression observed in primary tumor tissue did not help to define those individuals at higher or lower risk for recurrence of disease and did not point to the likelihood of increased or decreased survival in individuals undergoing surgery for adenocarcinoma of the colon.

Adenocarcinoma↗
PubMed1988

Divergent dose-related effects of gamma-interferon therapy on in vitro antibody-dependent cellular and nonspecific cytotoxicity by human peripheral blood monocytes.

Twenty-seven patients with advanced gastrointestinal malignancies received recombinant gamma-interferon (rIFN-gamma, Biogen) prior to treatment with the murine monoclonal antibody 17-1A (Centocor), which mediates human monocyte antibody-dependent cellular cytotoxicity (ADCC). rIFN-gamma was used because it enhances human monocyte Fc receptor expression, nonspecific monocyte cytotoxicity (NSMC) and ADCC in vitro. The study was designed to identify a rIFN-gamma dose with acceptable toxicities which enhanced NSMC and ADCC. Patients received one course of therapy consisting of rIFN-gamma by 4-h infusions daily for 4 days at doses ranging from 0.001 to 80.0 X 10(6) units/m2/d, followed by 400 mg of 17-1A on day 5. The maximally tolerated dose of rIFN-gamma in this study was 40 X 10(6) units/d. Significant toxicity was seen at the high (greater than 1 X 10(6) units) but not low (less than or equal to 1 X 10(6) units) dose levels. Monocytes were isolated from patients' peripheral blood at baseline and on Days 3 and 5 for cytotoxicity studies which measured 111-In release from SW1116 cells which bear the target antigen of 17-1A. Low dose rIFN-gamma enhanced NSMC by Day 5 as well as did high dose therapy. ADCC enhancement was seen with low dose therapy (% specific lysis on Day 5 = 23.5 +/- 6.4 SEM versus baseline of 9.6 +/- 3.3, P = 0.03), but not with high dose rIFN-gamma treatment. Total (i.e., NSMC + ADCC) monocyte cytotoxicity was equivalent in the low and high dose treatment groups, although ADCC contributed more to total values in the low dose group. These findings were particularly striking if monocytes were exposed to additional rIFN-gamma in vitro prior to incubation with labeled target cells. We conclude that low dose rIFN-gamma therapy is at least equivalent, and possibly superior to high doses in this setting. Furthermore, low dose therapy, supplemented by ex vivo incubation of purified monocytes with rIFN-gamma, may be an optimal treatment strategy for this cytokine.

Adenocarcinoma↗
PubMed1988

Phase I--preliminary phase II trial of iproplatin, a cisplatin analogue.

Iproplatin was administered intravenously over 30 min daily for 5 consecutive days every 3 weeks to 80 evaluable patients with a variety of refractory solid tumor malignancies. Thrombocytopenia was the dose-limiting toxicity. Reversible drug-induced renal dysfunction was observed in 3 patients. One patient sustained mild ototoxicity but neurotoxicity was not encountered. Transient neutropenia, anemia, nausea, vomiting, diarrhea, elevations of liver enzymes, alopecia, and skin rash also occurred. The spectrum and severity of toxicity of iproplatin were found to differ from those of cisplatin. The maximally tolerated dose (MTD) was 45 mg/m2/day in patients who received prior chemotherapy and 65 mg/m2/day in those who did not. No complete responses occurred. Partial responses were obtained in 2/15 patients with colon cancer, 3/18 with breast cancer, 2/4 with carcinoma of unknown primary site and 1/2 with pancreatic cancer. Thirteen patients with lung (5), breast (4), colon (2), head and neck (1) and cervical (1) cancers had stable disease. Based on the different toxicity profiles between iproplatin and cisplatin and the possible antitumor efficacy of the former, phase II investigation of iproplatin has been initiated.

Adult↗
PubMed1988

Regional mapping of unique DNA sequences from human chromosome 3 derived from a flow-sorted chromosome library.

Eight single-copy DNA probes specific for human chromosome 3 were isolated by screening a human chromosome 3-derived genomic library. Southern blot analyses of DNAs isolated from a panel of somatic cell hybrids allowed us to regionally assign all probes to subregions on chromosome 3. Three clones were localized to the short arm of chromosome 3 (3p21----pter), two to the long arm (3q21----qter), and three to the 3q21----3p21 subregion. Six of these DNA sequences map to regions overlapping a segment of chromosome 3 (3p14----p23) frequently deleted in small cell lung cancer cells. Restriction fragment length polymorphism analyses indicate that at least three of the eight single-copy probes studies show MspI or BglII polymorphisms. This library is a useful source of chromosome 3-specific probes.

Chromosome Mapping↗
PubMed1987

Small cell lung cancer cell line derived from a primary tumor with a characteristic deletion of 3p.

Chemotherapy plus surgery is feasible and potentially effective in selected patients with small cell lung cancer (SCLC) and provides a unique opportunity to study SCLC early in its biological history. The in vitro characteristics of a SCLC cell line derived from a resected lung primary tumor after treatment with 3 courses of chemotherapy is described. The original SCLC cell line UMC-SCLC-1 exhibited features of classic SCLC with typical morphology and growth characteristics, high levels of dopa decarboxylase, bombesin-like peptides, neuron-specific enolase and calcitonin, and the presence of neurosecretory granules and demonstrated the deletion of the short arm of chromosome 3. After multiple passages, UMC-SCLC-1 gradually changed its culture characteristics to a cell line, UMC-SCLC-1A, with morphological features of large cell anaplastic carcinoma, an altered growth pattern, decrease in calcitonin, and increase in radioresistance but retained the other biochemical markers of classic SCLC (bombesin and dopa decarboxylase production). Serial DNA content analyses showed that increased aneuploidy during continuous culture in vitro was associated with the morphological changes. Both UMC-SCLC-1 and UMC-SCLC-1A demonstrated the deletion of chromosome 3p, amplification and abundant expression of N-myc, and increased expression of c-raf. Chemotherapy sensitivities were stable throughout multiple passages and correlated with in vivo response. UMC-SCLC-1A represents a unique SCLC cell line with heterogeneous properties of both classic and morphological variant SCLC cell lines. In addition, the characteristic deletion of 3p, previously described in cultures derived from metastatic lesions and heavily pretreated patients, is seen in a primary lesion early in the natural history of SCLC.

Carcinoma, Small Cell↗
PubMed1987

Mixed germ-cell tumor of the pineal region. Case report.

The case is presented of a 15-year-old boy with a mixed nongerminomatous germ-cell tumor of the pineal region associated with elevated cerebrospinal fluid and serum levels of the beta subunit of human chorionic gonadotropin. Treatment consisted of initial subtotal resection followed by radiotherapy and systemic chemotherapy with cisplatin, vinblastine, and bleomycin. The patient is alive without evidence of tumor 37 months after his initial diagnosis. A literature review of intracranial embryonal carcinoma and choriocarcinoma provided the rationale for a combined-modality approach to this otherwise lethal neoplasm.

Adolescent↗
PubMed1986

Clinical trials of cyclophosphamide, etoposide, and vincristine in the treatment of small-cell lung cancer.

Etoposide is one of the most active drugs used in the treatment of small-cell lung cancer (SCLC). Recently, studies were completed that evaluated the substitution of etoposide for doxorubicin (Adriamycin) used in combination with cyclophosphamide and vincristine. This study has shown that equivalent antitumor activity, as measured by objective response, can be obtained with the combination of cyclophosphamide, etoposide, and vincristine (CEV) as compared with the CAV combination. A longer response duration and median survival are seen in extensive-disease patients treated with the CEV combination. As expected, no cardiotoxicity is associated with CEV therapy, and interestingly, there is no potentiating neurotoxicity with CEV. A study recently completed has shown that CEV can be effectively combined with intensive radiation therapy to the chest administered simultaneously. CEV appears to be an effective alternative to CAV, and it can be readily combined with aggressive radiation therapy.

Antineoplastic Combined Chemotherapy Protocols↗