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Biomedical subjects

F M Muggia

Publications and source records attributed to F M Muggia.

At least 73 records · Page 4Linked to original sources
PubMed1994

Intraperitoneal 5-fluoro-2'-deoxyuridine with escalating doses of leucovorin: pharmacology and clinical tolerance.

In a preceding study, we established the tolerance and pharmacokinetic behavior of 5-fluoro-2'-deoxyuridine (FdUrd) given by the intraperitoneal (IP) route. A dose of 3 g daily x 3 days was found satisfactory for Phase II study and exploration of biochemical modulation. Therefore, the current study was conducted to study the tolerance and pharmacokinetics of such a dose-schedule and route of FdUrd combined with escalating doses of leucovorin (LV). Fourteen patients were entered and 13 were evaluable for tolerance determination. Pharmacologic determinations of IP FdUrd and 5-Fluorouracil (FUra) derived from it and LV were obtained by HPLC methods on 11 occasions. Findings were compared with the preceding study of FdUrd alone. LV did not appear to alter the tolerance of IP FdUrd even in the four patients receiving the highest dose of LV (640 mg). Toxicities included nausea, vomiting, and rarely neutropenia and diarrhea. Pharmacokinetic parameters indicate a parallel rate of egress of FdUrd and LV from the peritoneal cavity. The pharmacologic advantage for FdUrd is at least 3 logs as previously reported and one log for LV. Evidence of antitumor effect was noted particularly among untreated patients with gastrointestinal primaries. We conclude that IP FdUrd 3 g and LV in doses of up to 640 mg x 3 days are well tolerated. Since FdUrd is more potent, has an even greater hepatic clearance and shows greater potential for modulation with LV than FUra, it may be the preferred fluoropyrimidine for subsequent studies via the IP route in the treatment of carcinomas with prominent peritoneal spread. The pharmacologic advantage for leucovorin is limited but it is a good marker for peritoneal clearance since it parallels FdUrd clearance.

Abdominal Neoplasms↗
PubMed1994

Platinum resistance. Experimental and clinical status.

It has become clear that multiple mechanisms of cellular resistance to platinum compounds exist; however, the knowledge that platinum resistance can not only be explained by processes such as reduced drug accumulation, and increased detoxification, has shifted the attention of researchers to more molecular mechanisms. The introduction of new techniques, such as the PCR technique for example, has opened the possibility to monitor genes involved in antitumor responses and may provide molecular information on the emergency of resistance.

Biological Transport↗
PubMed1994

Platinum compounds in cervical and endometrial cancers: focus on carboplatin.

Drug therapy for cervical cancer is slowly undergoing evaluation in early disease stages, in which it is more likely to make an impact. Cisplatin has been the principal drug used in systemic therapy for all stages, with the possible exception of the radiosensitizer hydroxyurea. Nevertheless, current studies use cisplatin in this role as well. To a limited extent, substitution of carboplatin for cisplatin also has been explored. Conflicting interpretations of carboplatin trials nonetheless support continued study of this drug; its activity is reproducible and it can be combined with radiation therapy in practical dose schedules. The major question in the systemic nonendocrine treatment of endometrial cancer revolves around whether cisplatin adds to results achievable with doxorubicin. Carboplatin, documented as active against this neoplasm, represents a potentially advantageous cisplatin substitute for elderly patients. Moreover, if combination chemotherapy should prove disappointing, single-agent carboplatin may provide the best strategy for palliative therapy.

Carboplatin↗
PubMed1993

Drug-induced DNA modification in buccal cells of cancer patients receiving carboplatin and cisplatin combination chemotherapy, as determined by an immunocytochemical method: interindividual variation and correlation with disease response.

Twenty-six patients with a variety of tumor types were treated according to a phase 1 experimental treatment protocol consisting of repetitive cycles of cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (carboplatin, 200-480 mg/m2) at day 1 and cis-diamminedichloroplatinum(II) (cisplatin, 50-100 mg/m2) at day 3. Buccal cells were collected in one or two treatment cycles prior to carboplatin, 24 h after carboplatin, just prior to cisplatin, and approximately 24 h after cisplatin administration. Drug-induced DNA modification was visualized at the single cell level by anti-serum NKI-A59 and quantitated by microdensitometry. All (39 of 39) treatments with carboplatin, and almost all (33 of 35) treatments with cisplatin resulted in an increase in nuclear stain. Interindividual variation in drug-induced, adduct-specific nuclear stain amounted to a factor of 5-8 for carboplatin and 5-12 for cisplatin. This drug-induced increase was, however, not related to the dose of either carboplatin or cisplatin, suggesting that large interindividual differences in DNA adduct formation and/or repair obscured the effects of dose variation within the relatively small range used for the drugs (2.4 for carboplatin and 2.0 for cisplatin). This explanation was strengthened by the good reproducibility of the immunocytochemical assay and by the reasonable correlation between carboplatin-induced nuclear stain in cycles 1 and 2 (correlation coefficient, 0.69; P = 0.009). Mean carboplatin-induced nuclear stain was significantly higher in the first cycle than in the second cycle (P = 0.0001) but this difference was no longer significant when drug-induced nuclear stain was corrected for carboplatin dose. Differences in cisplatin-induced nuclear stain between cycle 1 and cycle 2 were small and not significant. Carboplatin-induced nuclear stain was significantly higher in the partial responders than in the nonresponders (P < 0.0001, two cycles combined); the level of statistical significance remained the same after dose correction. Cisplatin-induced nuclear stain did not differ significantly between partial responders and nonresponders; this result might, however, be confounded to some extent by remaining carboplatin-induced nuclear stain at the moment of cisplatin administration. It is concluded that determination of the extent of platinum-induced DNA modification might be helpful in predicting the tumor response in cancer patients.

Adult↗
PubMed1993

Platinum-DNA adduct in leukocyte DNA of a cohort of 49 patients with 24 different types of malignancies.

Using atomic absorbance spectrometry with Zeeman background correction, we measured platinum-DNA adduct levels in leukocyte DNA of 49 patients receiving therapy consisting of only carboplatin and cisplatin. Twenty-four histological types of malignancy were included in the cohort. Peripheral blood leukocytes were collected at defined times during the first two cycles of treatment. The relationship between adduct level and disease response was highly statistically significant during cycle 1 of therapy (two-sided P = 0.007 at day 2), but statistical significance was lost during cycle 2. On all days studied, median and mean adduct levels were consistently higher in responders as compared to nonresponders (summary two-sided P = 0.0004). These data suggest that the processes which protect cellular DNA may be common to malignant and nonmalignant rapidly dividing tissues of the same individual, regardless of the type of tumor that individual may harbor.

Carboplatin↗
PubMed1993

Phase I study of (6R)-5,10-dideazatetrahydrofolate: a folate antimetabolite inhibitory to de novo purine synthesis.

BACKGROUND: Cancer chemotherapy with folate antimetabolites has been traditionally targeted at the enzyme dihydrofolate reductase and is based on the requirement of dividing tumor cells for a supply of thymidylate and purines. However, a new compound, 5,10-dideazatetrahydrofolate (DDATHF, whose 6R diastereomer is also known as Lometrexol), has become available that prevents tumor cell growth by inhibiting the first of the folate-dependent enzymes involved in de novo purine synthesis, glycinamide ribonucleotide formyltransferase. PURPOSE: We investigated the toxicity and therapeutic activity of DDATHF in a phase I clinical trial. METHODS: DDATHF was given at one of the following dose levels to 33 patients (16 females and 17 males) with malignant solid tumors: 3.0 mg/m2 per week (level A) to 10 patients, 4.5 mg/m2 per week (level B) to 13 patients, or 6.0 mg/m2 per week (level C) to 10 patients. Each drug cycle consisted of three weekly injections of DDATHF followed by a 2-week rest prior to redosing in the next cycle. RESULTS: Of 33 patients, 27 received at least one full cycle of DDATHF. Thrombocytopenia was the major dose-limiting toxicity, and it was severe in one of 10 patients during the first cycle and in two of four patients during the second cycle. Because of cumulative toxicity at 6.0 mg/m2, second or later cycles were abbreviated to two weekly doses. Stomatitis was generally mild, but it was dose-limiting in one patient. Neutropenia was infrequent and mild, and normocytic anemia requiring blood transfusion was common with repeat dosing. Leucovorin was given for grade 2 or greater thrombocytopenia and resulted in hematologic recovery within 1 week in all eight patients so treated. Without leucovorin, the thrombocytopenia lasted from 7 to 49 days in three patients. A partial response was noted in one patient with non-small-cell lung cancer and a minor response in one patient with breast cancer. Three patients with colorectal cancer achieved stable disease for greater than 3 months with improvement in carcinoembryonic antigen levels in one patient. CONCLUSIONS: DDATHF has an unusual pattern of toxicity with repetitive dosing, and humans with advanced cancer are considerably more sensitive than would be predicted from previous animal studies. Although doses of 6.0 mg/m2 per week on our schedule have been determined to be safe, repeated cycles require careful monitoring because of cumulative toxic effects. IMPLICATIONS: Additional phase I studies of DDATHF that relate toxicity to folate intake and tissue folate pools appear warranted.

Adult↗
PubMed1993

Platinum resistance: laboratory findings and clinical implications.

Platinum compounds are universally recognized as one of the most important classes of chemotherapeutic agents for the treatment of cancer. Emergence of resistance to cisplatin has appeared, however, to be a major prognostic factor of adverse outcome in the otherwise most sensitive of malignancies: testicular and ovarian cancers. After a decade of testing both systemic and regional dose-intensification of cisplatin and its analog carboplatin--which is more amenable to dose escalation with cytokines and bone marrow progenitor cell support--a plateau is apparent even in sensitive tumor types beyond which additional dose escalations do not appreciably increase response. Laboratory work searching for causes of intrinsic and acquired resistance, providing early indication of drug sensitivity, and developing strategies for restoring or overcoming resistance is ongoing and is guiding clinical studies and drug development. Causes of cellular resistance to platinums are complex and include decreased drug accumulation, increased detoxification, increased repair of DNA-platinum adducts, and increased tolerance of DNA lesions. Clinical trials are already ongoing regarding strategies involving protection of specific toxicities, decreasing intracellular glutathione (by buthionine sulfoximine), decreasing DNA repair, and introducing new analogs that are able to overcome certain forms of platinum resistance.

Animals↗
PubMed1993

Intraperitoneal carboplatin and etoposide for persistent epithelial ovarian cancer: analysis of results by prior sensitivity to platinum-based regimens.

Eighteen women with epithelial ovarian cancer and small-volume disease within the peritoneal cavity at reassessment laparotomy after initial treatment with platinum-based regimens received treatment with a combination of intraperitoneal (ip) carboplatin and etoposide administration. The dose of carboplatin was fixed at 200 mg/m2 whereas the dose of etoposide was escalated in cohorts of 4 patients from 50 to 75 and eventually to 100 mg/m2. Hematologic toxicities appeared to be related to decreased renal function, and, in the last cohort of 10 patients, with prior treatment with systemic carboplatin. Because of this shift in patient population, escalations ceased and ip cisplatin was partly substituted for ip carboplatin in 5 patients. The study opened July 1988 and closed on July 1991: 8 patients are alive, with 4 enjoying progression-free survival and no clinical evidence of disease 1 to 4 years after onset of treatment. One patient is alive with no clinical evidence of disease 3+ years after a late relapse was treated with systemic carboplatin. Three other patients are alive with evidence of disease, having experienced improvements with taxol and ip floxuridine. Analysis of this small experience by pretreatment characteristics suggests that patients who are platinum sensitive and not allowed to relapse, have normal baseline CA-125s, and undergo successful secondary cytoreductive surgery may benefit from platinum-based ip therapy.

Adult↗
PubMed1993

Protracted drug infusions in cancer treatment: an appraisal of 5-fluorouracil, doxorubicin, and platinums.

The feasibility to deliver chemotherapeutic agents by protracted i.v. infusion has greatly increased in the recent past. Indwelling ports, longer lasting central venous catheters requiring less than daily maintenance 'flushing', surgical expertise in placement, use in analgesia and nutrition, and 'smart' pump technology have all contributed to their increasing popularity. Justification for use of infusions in cancer chemotherapy has been slow in appearing with few studies proceeding to the comparative stage. This review will focus on three drugs in common use in cancer treatment, with the purpose of appraising the role of such infusions in cancer therapeutics and of deriving some lessons that might be applicable to other drugs or to drug development in general. For fluorouracil and doxorubicin the rationale and clinical findings favoring further development of infusion regimens is particularly strong. In the case of platinum compounds, some toxicologic advantages have emerged, but other measures designed to protect against the toxicities of cisplatin compete with infusion regimens in this regard. The therapeutic potential for this form of drug delivery, therefore, appears still confined to a subset of patients. Stronger rationales for the use of protracted infusions may be forthcoming from pharmacodynamic findings as in the case of etoposide, combined modality therapy with radiation for FU and cisplatin, biochemical modulation for FU, and reversal of multidrug resistance and its modulation for doxorubicin. While awaiting research into these areas of clinical and pre-clinical investigations, the role of infusion appears most evident in the cardiotoxicity protection of anthracyclines, and in further efficacy exploration (through dose or modulation) of FU. Both mechanistic and pharmacologic considerations could also provide additional stimulus for development of new formulations such as long circulating liposomes, and drugs more suitable for oral administration.

Animals↗
PubMed1992

Managing breast cancer in an outpatient setting.

The treatment of advanced breast cancer has undergone relatively little change in the past decade. Reasons for such a static situation are the sobering realization that even effective chemotherapeutic regimens have had a minor impact on survival, and the paucity of new effective agents that have been introduced since initial combination treatments. Based in part on this lack of progress, in recent years dose-intensification in search of a curative strategy has been widely adopted. Its role remains to be defined, but ultimately it is likely to be relegated to situations where tumor burdens have been effectively reduced. This reduction in burden may not currently be feasible in many advanced presentations. Outpatient efforts will therefore focus on the following: 1) employing single agents optimally (e.g. infusion 5-fluorouracil), 2) using regimens which integrate new drugs with activity (e.g. taxol), and 3) testing measures which may improve the quality of life (e.g. bisphosphonates in the presence of bone metastases). Although one cannot approach the treatment of advanced breast cancer with the (misplaced) optimism of two decades ago, the expanded armamentarium currently available should lead to a more rational application of chemotherapy. Treatments will increasingly be based on the biology of the cancer, and on the therapeutic index and action of the drugs.

Algorithms↗
PubMed1992

Intraperitoneal therapy for ovarian cancer: analysis of fluid distribution by computerized tomography.

Nineteen patients with ovarian cancer and minimal residual or persistent disease who were treated with cisplatin or carboplatin-based intraperitoneal (IP) regimens had distribution studies of IP contrast and computerized tomography prior to and during treatment. The distribution pattern was assessed retrospectively and scored for the presence of contrast in each of eight regions: the under surface of right and left diaphragms, the right and left paracolic gutters, the lesser omental sac, the intramesenteric region and the true and false pelvis. Assigning a point to each region with adequate distribution, we classified 10 patients to an excellent pattern (greater than or equal to 7 of 8 regions), 6 to a good pattern (5 to less than 7 regions), and 3 to an inadequate distribution pattern (less than 5 regions). Serial studies were performed in 8 patients after more than 4 cycles of IP therapy. In these patients, all of whom were tolerating treatment without progression, the distribution remained virtually unchanged for those with excellent distribution. One of three with good distribution manifested inadequate distribution on repeat study, and one of two with inadequate distribution improved to show a good pattern. In this small study there was no correlation of distribution patterns with plasma CA-125 at onset of IP treatment and prior surgical procedures or placement of the catheter tip. However, three patients with unsatisfactory patterns had procedures consisting of catheter placement only rather than formal reassessment laparotomies for ovarian cancer. Since satisfactory IP distribution may be required for obtaining a therapeutic advantage from IP therapy, methods for its assessment must be developed.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗