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1.
J Clin Oncol ; 21(4): 652-8, 2003 Feb 15.
Article in English | MEDLINE | ID: mdl-12586802

ABSTRACT

PURPOSE: To study the efficacy and safety of percutaneous cisplatin-epinephrine (CDDP-EPI) injectable gel in patients with localized unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Eligible patients had histologically proven HCC, no prior treatment except for surgery, and no more than three tumors (each measured < or = 7 cm, total tumor volume < or = 200 cm(3)). They were treated percutaneously under ultrasound or computed tomography (CT) guidance, with up to 10 mL of CDDP-EPI gel (1 mL contains 4 mg of CDDP and 0.1 mg of EPI) per treatment and four treatments in 6 weeks to a maximum of eight treatments. The primary end points were tumor response, defined by change of percentage of tumor necrosis according to CT criteria, and safety. Survival parameters were secondary end points. RESULTS: From June 1997 to April 2000, 58 patients (median age, 65 years) entered the study. All patients were assessable for safety, and 51 were assessable for efficacy. The median number of treatments was four (range, one to eight treatments). Objective response rate was 53% (27 of 51 patients), including 16 complete and 11 partial responses. Of the 27 responders, 14 (52%) subsequently developed progressive disease, but in most of them (93%), a new tumor arose at untreated liver sites. Median survival was 27 months (range, 18.4 to 35.7 months). The 1-, 2-, and 3-year survival rates were 79%, 56%, and 14% respectively. The procedure was well tolerated with only minor side effects. CONCLUSION: Percutaneous local ablation with CDDP-EPI injectable gel can induce significant tumor necrosis and local control for localized unresectable HCC, and the treatment is well tolerated.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Cisplatin/therapeutic use , Epinephrine/therapeutic use , Liver Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Cisplatin/administration & dosage , Cisplatin/adverse effects , Drug Combinations , Epinephrine/administration & dosage , Epinephrine/adverse effects , Female , Gels , Humans , Injections, Intralesional , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Middle Aged , Survival Rate
2.
Br J Cancer ; 87(9): 938-44, 2002 Oct 21.
Article in English | MEDLINE | ID: mdl-12434280

ABSTRACT

Patients with recurrent or refractory head and neck squamous cell carcinoma received cisplatin/epinephrine injectable gel or placebo gel injected directly into the clinically dominant tumour. The double-blind phase III trial comprised of up to 6 weekly treatments over 8 weeks, 4 weekly evaluation visits, and then monthly follow-up; open-label dosing began as needed after three blinded treatments. Tumour response was defined as complete (100% regression) or partial (50-99% regression) sustained for > or =28 day, and patient benefit as attainment of palliative or preventive goals prospectively selected by investigators and patients. With cisplatin/epinephrine gel, 25% (14 out of 57) of tumours responded (16% complete regression, 9% partial regression), vs 3% (one out of 35, complete regression) with placebo (P=0.007). Patient benefit was positively associated with target tumour response in the blinded period among cisplatin/epinephrine gel recipients (P=0.024): 43% (six out of 14) of responders benefited, vs 12% (five out of 43) of non-responders. The most frequent adverse event was pain during injection and the next most frequent was local cytotoxic effects consistent with the gel's mode of action. Systemic adverse events typical of intravenous cisplatin were uncommon. Intratumoural therapy with cisplatin/epinephrine gel provided safe, well-tolerated, effective palliative treatment for patients with locally advanced head and neck squamous cell carcinoma, who lack other satisfactory treatment options.


Subject(s)
Adrenergic Agonists/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Cisplatin/therapeutic use , Epinephrine/therapeutic use , Head and Neck Neoplasms/drug therapy , Adrenergic Agonists/administration & dosage , Adrenergic Agonists/adverse effects , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Carcinoma, Squamous Cell/secondary , Cisplatin/administration & dosage , Cisplatin/adverse effects , Double-Blind Method , Drug Combinations , Epinephrine/administration & dosage , Epinephrine/adverse effects , Female , Gels , Head and Neck Neoplasms/pathology , Humans , Injections, Intralesional , Male , Middle Aged , Prospective Studies , Safety , Treatment Outcome
3.
Cancer Chemother Pharmacol ; 44(4): 267-74, 1999.
Article in English | MEDLINE | ID: mdl-10447573

ABSTRACT

PURPOSE: Pancreatic cancer is widespread, associated with high mortality, and rapidly fatal. Most cases are diagnosed too late for surgical treatment, and the disease responds poorly to systemic chemotherapy. Nevertheless, pancreatic cancer cells are sensitive to fluorouracil (5-FU) in a time- and dose-dependent manner, suggesting that improved retention of drug in the tumor may improve patient prognosis. In this study, we evaluated a novel drug delivery system, 5-FU/epinephrine injectable gel (5-FU/epi gel), designed to improve drug retention in tumors. METHODS: We used a BxPC-3 human pancreatic cancer xenograft model in athymic mice to examine drug levels in tumor, liver, and kidney tissue following administration of: (a) 5-FU/epi gel (30 mg 5-FU/ml) intratumorally (i.t.); (b) 5-FU solution i.t.; and (c) 5-FU solution intraperitoneally (i.p.). [(3)H]5-FU was added as a radiolabeled marker to all test formulations. Animals were sacrificed at designated times, and the tumor, liver, and one kidney from each animal were excised and processed for radioactivity analysis. Drug concentration was quantified by both storage-phosphor autoradiography (SPA) and liquid scintillation counting (LSC). RESULTS: Higher and sustained i.t. drug levels were achieved following i.t. administration of 5-FU/epi gel (SPA AUC 18.4 mM. h, LSC AUC 13.0 mM. h) compared with 5-FU solution i.t. (SPA AUC 2.02 mM. h, LSC AUC 1.92 mM. h) or 5-FU solution i.p. (SPA AUC 0.07 mM. h, LSC AUC 0.04 mM. h). Use of the 5-FU/gel system was associated with lower drug levels in liver and kidney, indicating that it produces far less systemic exposure. CONCLUSION: In the human pancreatic cancer xenografts, i.t. administration of 5-FU/epi injectable gel provided significantly higher drug and/or metabolite concentrations for extended periods than was possible with either i.t. or i.p administration of drug solution. This i.t. drug delivery system could potentially be used to treat patients with pancreatic cancer to increase tumor exposure to drug and improve the therapeutic index in comparison to systemic drug administration.


Subject(s)
Antimetabolites, Antineoplastic/pharmacokinetics , Epinephrine/pharmacokinetics , Fluorouracil/pharmacokinetics , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Animals , Antimetabolites, Antineoplastic/administration & dosage , Autoradiography , Epinephrine/administration & dosage , Fluorouracil/administration & dosage , Gels , Humans , Injections, Intralesional , Male , Mice , Mice, Nude , Neoplasm Transplantation , Pharmaceutical Vehicles , Scintillation Counting , Tissue Distribution , Transplantation, Heterologous , Tumor Cells, Cultured
4.
Otolaryngol Head Neck Surg ; 118(4): 496-503, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9560102

ABSTRACT

Intratumoral injections of cisplatin/epinephrine-injectable gel were administered weekly for 4 weeks in 45 patients with malignant tumors of various histologic types. Tumors were located on the skin and subcutaneous tissue primarily of the head, neck, and trunk, and on the tongue, oral pharynx, and esophagus. Patients were not candidates for surgery, radiation, or systemic chemotherapy. Each of the treated tumors (n = 82) was evaluated 2, 4, 8, and 12 weeks after the final injection. The initial dose of cisplatin was 1 mg/cm3 tumor volume, with escalation to 6 mg/cm3 allowed, depending on observed toxicities. The mean cumulative dose per patient for the four treatments ranged from 0.56 to 380 mg cisplatin. No dose-limiting cisplatin-related toxicities, such as nephrotoxicity, neurotoxicity, or ototoxicity, were observed. The overall objective tumor response rate was 50% (41 of 82), with 40% (33 of 82) complete responses and a median response duration of 160 days. Complete responses for adenocarcinoma and squamous cell carcinoma were 58% (21 of 36) and 38% (12 of 32), respectively. These results justified further clinical trials to evaluate the role of local chemotherapy with intratumoral cisplatin/epinephrine-injectable gel in the palliative treatment of patients with selected accessible solid tumors.


Subject(s)
Cisplatin/administration & dosage , Epinephrine/administration & dosage , Head and Neck Neoplasms/drug therapy , Otorhinolaryngologic Neoplasms/drug therapy , Palliative Care , Skin Neoplasms/drug therapy , Soft Tissue Neoplasms/drug therapy , Adenocarcinoma/drug therapy , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/drug therapy , Cisplatin/adverse effects , Dose-Response Relationship, Drug , Epinephrine/adverse effects , Female , Gels , Humans , Injections, Intralesional , Male , Melanoma/drug therapy , Middle Aged , Pilot Projects , Treatment Outcome
5.
J Am Acad Dermatol ; 38(3): 438-42, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9520026

ABSTRACT

BACKGROUND: We attempted to originate a nonsurgical treatment alternative for cutaneous squamous cell carcinoma (SCC), and we evaluated intratumoral modified-release chemotherapy with fluorouracil/epinephrine injectable gel (5-FU/epi gel). OBJECTIVE: To assess the safety and efficacy, we conducted an open-label pilot study of 5-FU/epi gel in 25 patients with biopsy-proven SCC lesions on the face, head, neck, trunk, arms, and hands. METHODS: Each tumor site was injected intradermally with up to 1.0 ml of 5-FU/epi gel. One SCC per patient was treated weekly for up to 6 weeks, then observed for 4 months at which time the tumor site and margins were excised for histologic examination. RESULTS: Overall, 96% (22 of 23) of evaluable treated tumors had histologically confirmed complete tumor clearing. No clinically significant systemic reactions or unexplained treatment-related adverse medical events occurred. The evaluations of the cosmetic appearance of the treated sites, judged subjectively by clinicians and patients, were mostly good to excellent and generally in close agreement. CONCLUSION: Treatment of superficial SCC with 5-FU/epi injectable gel results in a high rate of histologically confirmed complete tumor responses and may provide a nonsurgical treatment alternative in selected patients.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Carcinoma, Squamous Cell/drug therapy , Epinephrine/administration & dosage , Fluorouracil/administration & dosage , Skin Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/pathology , Delayed-Action Preparations , Drug Therapy, Combination , Female , Gels , Humans , Injections, Intralesional , Male , Middle Aged , Pilot Projects , Safety , Skin Neoplasms/pathology , Treatment Outcome
6.
Int J STD AIDS ; 8(10): 639-42, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9310224

ABSTRACT

The efficacy of a single cycle of a new therapy for genital warts, intradermal fluorouracil/epinephrine (5-FU/epi) injectable gel, has been evaluated in 2 large pivotal trials; the objective of this study was to evaluate a second cycle of treatment. Twenty-two patients with total wart areas of 5-447 mm2 were treated with up to 2 cycles of < or =6 treatments of 5-FU/epi gel. After the first cycle of treatments, patients with warts showing a partial response or no response or new warts were continued into a second cycle. Seventy-three per cent (16/22) of patients had complete responses. Patients with total wart areas < or = 100 mm2 tended to respond completely in the first cycle of treatment (average 4.7 treatments). Patients with numerous warts or large total wart areas (>100 mm2) required an average of 7.5 treatments to achieve a complete response. Thus, a second treatment cycle may be appropriate for difficult-to-treat patients with numerous warts or large total wart areas.


Subject(s)
Body Surface Area , Condylomata Acuminata/drug therapy , Condylomata Acuminata/pathology , Epinephrine/therapeutic use , Fluorouracil/therapeutic use , Immunosuppressive Agents/therapeutic use , Vasoconstrictor Agents/therapeutic use , Drug Therapy, Combination , Female , Follow-Up Studies , Gels , Humans , Injections, Intradermal , Injections, Intralesional , Male , Recurrence , Treatment Outcome
7.
Arch Dermatol ; 133(1): 67-73, 1997 Jan.
Article in English | MEDLINE | ID: mdl-9006374

ABSTRACT

BACKGROUND AND DESIGN: A new intralesional sustained-release chemotherapy is under development as a treatment for condylomata acuminata; it is administered as an injectable gel that consists of fluorouracil and epinephrine with a purified bovine collagen as the gellant (fluorouracil/epinephrine gel). In this randomized, double-blind study, we evaluated the safety and efficacy of this intralesional treatment in 401 patients, using 2 active drug formulations (fluorouracil/epinephrine gel and fluorouracil gel alone) and a placebo. Each lesion was injected once a week for up to 6 weeks, and patients were followed up for 3 months. RESULTS: A total of 359 patients with 1926 condylomata underwent evaluation. For all lesions treated with fluorouracil/epinephrine gel, the complete response (CR) rate was 77%. For all patients treated with fluorouracil/epinephrine gel, the CR rate was 61%. The fluorouracil/epinephrine gel was significantly more effective (P < .002) in treating condylomata than the fluorouracil gel without epinephrine (CR rate, 43%); both were superior to placebo (CR rate, 5%). At 3 months after completion of treatment, recurrence rates in patients with CRs were as follows: fluorouracil/epinephrine gel group, 50%; fluorouracil gel group, 58%. No clinically significant drug-related systemic reactions occurred. Finally, the type and severity of local tissue reactions of patients with a positive pretreatment collagen skin test result (6/401 [1.5%]) were similar to those of patients with a negative collagen skin test result. CONCLUSION: The fluorouracil/epinephrine injectable gel is a safe and effective treatment for condylomata acuminata.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Condylomata Acuminata/drug therapy , Epinephrine/administration & dosage , Fluorouracil/administration & dosage , Genital Diseases, Female/drug therapy , Genital Diseases, Male/drug therapy , Adolescent , Adult , Aged , Double-Blind Method , Female , Follow-Up Studies , Gels , Humans , Injections, Intralesional , Male , Middle Aged , Recurrence
8.
J Am Acad Dermatol ; 36(1): 72-7, 1997 Jan.
Article in English | MEDLINE | ID: mdl-8996264

ABSTRACT

BACKGROUND: To develop a nonsurgical treatment alternative for basal cell carcinomas (BCCs), we evaluated intralesional sustained-release chemotherapy with 5-fluorouracil/epinephrine injectable gel (5-FU/epi gel). OBJECTIVE: To optimize the dose and treatment schedule, we compared the safety, tolerance, and efficacy of six treatment regimens of 5-FU/epi gel in patients with BCCs. METHODS: Two doses and four treatment schedules of 5-FU/epi gel were compared in an open-label, randomized study of 122 patients with biopsy-proven BCCs. One BCC per patient was treated for up to 4 to 6 weeks, then observed for 3 months at which time the tumor site was completely excised for histologic examination. RESULTS: Overall, 91% of evaluable treated tumors (106 of 116) in all regimens had histologically confirmed complete tumor resolution. No clinically significant treatment-related systemic adverse events occurred. The best response rate, tolerance, and patient compliance with assigned dose were in patients receiving 0.5 ml of 5-FU/epi gel three times a week for 2 weeks. The complete response rate based on histologic assessment in this group was 100%. CONCLUSION: Results demonstrate that treatment of BCC with 5-FU/epi gel is both safe and effective, may result in histologically confirmed complete response rates comparable to surgery, and provides a nonsurgical treatment alternative in selected patients.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Carcinoma, Basal Cell/drug therapy , Epinephrine/therapeutic use , Fluorouracil/therapeutic use , Skin Neoplasms/drug therapy , Vasodilator Agents/therapeutic use , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/adverse effects , Biopsy , Carcinoma, Basal Cell/pathology , Carcinoma, Basal Cell/surgery , Clinical Protocols , Delayed-Action Preparations , Drug Administration Schedule , Drug Tolerance , Epinephrine/administration & dosage , Epinephrine/adverse effects , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Follow-Up Studies , Gels , Humans , Injections, Intralesional , Male , Middle Aged , Patient Compliance , Remission Induction , Safety , Skin Neoplasms/pathology , Skin Neoplasms/surgery , Vasodilator Agents/administration & dosage , Vasodilator Agents/adverse effects
9.
Genitourin Med ; 73(6): 481-7, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9582466

ABSTRACT

OBJECTIVES: To evaluate a sustained release chemotherapy for treating condylomata acuminata with an injectable gel containing fluorouracil and adrenaline (5-FU/adrenaline gel). Study 1-- To assess contributions of the components of 5-FU/adrenaline gel to efficacy. Study 2--To assess therapeutic contribution of adrenaline and safety and efficacy of the formulations. DESIGN: Randomised, double blind, placebo controlled studies. SETTING: Private practices and university clinics in the United States. PATIENTS: Men and women with new, recurrent, or refractory external condylomata acuminata. INTERVENTION: Six injections over 8 weeks; follow up visits at weeks 1, 4, 8, and 12. EFFICACY: patient/wart response, times to complete response, recurrence rates. SAFETY: injection reactions, tissue conditions, other adverse events, laboratory studies. RESULTS: Study 1: 132 evaluable patients. Complete response (CR) rate was highest for the 5-FU/adrenaline gel group, followed by the 5-FU/adrenaline solution group, then the 5-FU gel group. 5-FU, adrenaline, and the collagen gel vehicle (in the presence of 5-FU) significantly affected CR and strongly influenced time to CR. The effects of 5-FU and adrenaline were statistically significant. Cutaneous reactions were mild to moderate. Study 2: 187 evaluable patients. Patients treated with 5-FU/adrenaline gel had a significantly higher CR rate and lower cumulative 90 day recurrence rate than those treated with 5-FU gel without adrenaline. Treatments were generally well tolerated, with only three treatment related, serious adverse events. CONCLUSION: 5-FU/adrenaline gel is safe and efficacious for treatment of condylomata acuminata, and when compared with individual or various combinations of components, this formulation provided the greatest therapeutic advantage.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Condylomata Acuminata/drug therapy , Epinephrine/administration & dosage , Fluorouracil/administration & dosage , Adolescent , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/adverse effects , Delayed-Action Preparations , Double-Blind Method , Drug Combinations , Epinephrine/adverse effects , Female , Fluorouracil/adverse effects , Gels , Humans , Injections, Intralesional , Male , Middle Aged , Recurrence , Treatment Outcome
10.
Anticancer Drugs ; 6(6): 717-26, 1995 Dec.
Article in English | MEDLINE | ID: mdl-8845483

ABSTRACT

This study provides the first evidence that treatment of human pancreatic adenocarcinoma is markedly improved by the intratumoral administration of chemotherapeutic agents in a novel drug delivery system. The effect of chemotherapeutic agents delivered in a sustained-release, protein-based, injectable gel was evaluated on the growth of human pancreatic adenocarcinoma cell line, BxPC-3. In vitro chemosensitivity of BxPC-3 cells exposed for 24 or 72 h to fluorouracil (0.01-5 mM), cisplatin or doxorubicin (0.1-50 microM) and floxuridine, vinblastine, mitomycin or paclitaxel (1.0-100 microM) was compared with that of untreated cells. In vitro chemosensitivity was also studied with fluorouracil and mitomycin in the poorly differentiated PANC-1, human pancreatic cancer cell line. Survival was determined after 7-10 days. All drugs decreased cell growth in a dose-dependent fashion. The efficacy of fluorouracil, cisplatin and doxorubicin increased with prolonged exposure, rendering these drugs most appropriate for a sustained-release preparation. For in vivo studies, athymic nude mice bearing BxPC-3 xenografts were treated either with fluorouracil, cisplatin or doxorubicin in the therapeutic injectable gel containing epinephrine or with vehicle alone administered intratumorally on days 1 and 4. After 28 days, the mice were sacrificed and tumors dissected and weighed. Tumors in mice treated with the injectable gel decreased in size by 72-79% compared with tumors in untreated controls and tumors treated with vehicle alone. Intratumoral injection of drug solution and intraperitoneal injection of drug in the injectable gel did not change tumor size compared with controls. In a drug-retention study, mice were injected intratumorally with [3H]fluorouracil either in the injectable gel or in solution. Sustained radioactivity was observed in tumors injected with the gel, and, conversely, greater radioactivity was detected in the liver and kidneys in mice receiving the radiolabeled solution. These results suggest that the therapeutic injectable gel chemotherapy, when given intratumorally, may improve tumor response with less systemic toxicity in comparison with conventional systemic chemotherapy.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pancreatic Neoplasms/drug therapy , Adenocarcinoma/metabolism , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Delayed-Action Preparations , Drug Screening Assays, Antitumor , Fluorouracil/pharmacokinetics , Gels , Humans , Injections, Intraperitoneal , Male , Mice , Mice, Nude , Neoplasm Transplantation , Pancreatic Neoplasms/metabolism , Rats , Transplantation, Heterologous , Tumor Cells, Cultured
12.
Eur J Cancer ; 31A(12): 2093-8, 1995 Nov.
Article in English | MEDLINE | ID: mdl-8562171

ABSTRACT

Squamous cell carcinoma (SCC) is the most frequently reported malignant epithelial tumour in dogs. Canine sun-induced SCC represents a useful animal model to evaluate new therapeutic modalities for possible human applications. We evaluated the safety and efficacy of treating sun-induced SCC in dogs with intralesional sustained-released chemotherapeutic gel implants that contained collagen, epinephrine (epi), and either 5-fluorouracil (5-FU) or cisplatin (CDDP). Dogs with large, single SCC or fields of multiple SCC were treated with 5-FU/epi gel for a minimum of three weekly injections. Dogs without a complete response were then treated with CDDP/epi gel for a minimum of three weekly treatments. We treated from one to 11 primary, recurrent, or refractory SCC per dog (tumour size 0.2-92.4 cm2; mean cumulative tumour area of 40.7 cm2 per dog). All dogs had at least 50% reduction in cumulative tumour area after treatment with 5-FU/epi gel. More than half (seven of 13) had complete resolution of SCC after treatment with 5-FU/epi gel or CDDP/epi gel. Minimal local tissue reactions were noted; no systemic toxicity occurred. Sustained-release chemotherapy using intralesional 5-FU/epi gel and CDDP/epi gel therapeutic implants is effective in treating canine sun-induced SCC of the skin.


Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Squamous Cell/veterinary , Dog Diseases/drug therapy , Skin Neoplasms/veterinary , Animals , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/etiology , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Delayed-Action Preparations , Disease-Free Survival , Dog Diseases/etiology , Dog Diseases/pathology , Dogs , Drug Implants , Fluorouracil/administration & dosage , Fluorouracil/therapeutic use , Skin Neoplasms/drug therapy , Skin Neoplasms/etiology , Sunlight/adverse effects , Treatment Outcome
13.
Cancer J Sci Am ; 1(3): 215-21, 1995.
Article in English | MEDLINE | ID: mdl-9166479

ABSTRACT

PURPOSE: The influence of treatment sequence in combination chemotherapy using fluorouracil (5-FU) and cisplatin (CDDP) was investigated in a mouse tumor model. Both drugs were formulated as therapeutic injectable gels, 5-FU/epinephrine gel and CDDP/epinephrine gel, and used intratumorally in a multiple-treatment regimen. By testing various multiple-treatment regimens, we determined optimal treatment sequences for these two injectable gels. Then we compared the antitumor responses achieved using the optimal treatment sequences for the intratumorally administered gels with the responses obtained using 5-FU and CDDP solutions administered intratumorally or systemically in the same treatment sequence. MATERIALS AND METHODS: Tumor-bearing C3H mice received a total of four injections (every 2 to 3 days from day 0 through day 7) of 5-FU solution, CDDP solution, 5-FU/epinephrine gel, or CDDP/epinephrine gel either as single agents or in various combinations and alternate sequences of solutions or gels. The delay in tumor growth was used as a study end-point. RESULTS: The results showed that local treatment (i.e., intratumoral administration) was more efficacious than systemic treatment (i.e., intraperitoneal administration) when both 5-FU solution and CDDP solution were used either alone or in combination. Further, using two drugs in combination was superior to using either drug alone. When both drugs were delivered intratumorally in the injectable gel formulations, the combination treatment sequences initiated with 5-FU/epinephrine gel were superior to sequences initiated with CDDP/epinephrine gel in delaying the tumor growth. The two sequences initiated with 5-FU/epinephrine gel (i.e., two treatments with 5-FU/epinephrine gel followed by two treatments with CDDP/epinephrine gel and the sequence of alternating 5-FU/epinephrine gel and CDDP/epinephrine gel) showed no significant difference in antitumor efficacy. Both these sequences (initiated with 5-FU/epinephrine gel) produced the longest delays in tumor growth, and > or = 50% (7 of 12) animals remained disease free at the end of the 60-day study. CONCLUSION: These studies demonstrate that significant improvement in local tumor control in mice can be achieved with a simple treatment sequence alteration of two established drugs.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Squamous Cell/drug therapy , Fibrosarcoma/drug therapy , Animals , Cisplatin/administration & dosage , Drug Administration Schedule , Epinephrine/administration & dosage , Female , Fluorouracil/administration & dosage , Gels/administration & dosage , Injections, Intralesional , Mice , Mice, Inbred C3H
14.
Cancer Chemother Pharmacol ; 36(1): 27-34, 1995.
Article in English | MEDLINE | ID: mdl-7720172

ABSTRACT

Fluorouracil/epinephrine injectable gel (5-FU/epi gel) was evaluated in vitro for its drug-release profile characteristics and in a mouse tumor model for its antitumor effectiveness. In vitro chemosensitivity studies with 5-FU in RIF-1 fibrosarcoma cells showed less than 1 log of cell kill at 1 mM after 2 h of exposure. Increasing the exposure time to 24 h resulted in greater cell killing (approximately 2.5 log cell kill at 0.5 mM), suggesting that sustained drug levels in tumors would result in an increased efficacy outcome in vivo. A 5-FU/epi injectable gel was designed, providing drug release in vitro of 50% by approximately 4 h and of 80% by 24 h. The retention of 5-FU in RIF-1 mouse tumors was determined after intratumoral administration of 5-FU/epi gel or various combinations of the formulation components. Area-under-the-curve (AUC0-24 h) calculations resulted in an AUC value of 146.4% h for the 5-FU/epi gel formulation as compared with 45.7% h for 5-FU solution. Tumor growth was significantly delayed (P < 0.05) with the 5-FU/epi gel (60 mg/kg) as compared with 5-FU solution given intratumorally or systemically. A fluorouracil dose of 150 mg/kg in the 5-FU/epi gel given weekly for 13 weeks was not lethally toxic, whereas the same dose given as drug solution was 100% lethal, suggesting that the therapeutic index for 5-FU in the gel formulation may be much greater than that for aqueous drug solution delivered intratumorally.


Subject(s)
Epinephrine/administration & dosage , Fibrosarcoma/drug therapy , Fluorouracil/administration & dosage , Animals , Cell Survival/drug effects , Delayed-Action Preparations , Drug Carriers , Female , Fluorouracil/pharmacokinetics , Fluorouracil/toxicity , Gels , Injections, Intradermal , Mice , Mice, Inbred C3H , Tumor Stem Cell Assay
15.
J Am Vet Med Assoc ; 204(2): 229-36, 1994 Jan 15.
Article in English | MEDLINE | ID: mdl-8144382

ABSTRACT

The feasibility, safety, and efficacy of a new method of local, sustained-release chemotherapy by use of intralesional cisplatin implants were evaluated in the treatment of oral malignant melanoma. The implant is an injectable viscous gel composed of a protein carrier matrix, a vasoactive modifier, and a chemotherapeutic drug. Twenty dogs with biopsy-proven melanomas were treated at 1- to 2-week intervals by injection with cisplatin implant. Tumors were treated until they resolved or were judged to be unresponsive. In 3 dogs with tumors unresponsive to cisplatin implants, methotrexate implants were used, and in 2 of these dogs, carmustine implants followed the methotrexate. Tumor responses were evaluated by sequential measurements. Melanomas in 14 (70%) of 20 dogs had a > 50% decrease in volume, and in 11 (55%) of these dogs, had a complete response. Tumors with complete responses received a mean cisplatin dose of 11.7 +/- 1.8 mg, delivered in a mean of 2.6 treatments. Two of the dogs with complete response also were treated with methotrexate and carmustine. Implants were well tolerated. Local necrosis, limited to the treatment site, developed in most tumors (17/20) and was associated with tumor response. Systemic toxicosis was minimal; renal insufficiency after cisplatin implants was not evident. Median survival times of dogs with complete tumor response (51 weeks) was substantially greater than that of dogs without local tumor control (10.5 weeks). Recursive partitioning analysis of variables indicated that mandibular tumors of short duration were associated with a positive outcome.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Cisplatin/therapeutic use , Dog Diseases/drug therapy , Melanoma/veterinary , Mouth Neoplasms/veterinary , Oropharyngeal Neoplasms/veterinary , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carmustine/administration & dosage , Cisplatin/administration & dosage , Delayed-Action Preparations , Dogs , Drug Implants , Female , Gels , Injections, Intralesional/veterinary , Linear Models , Male , Melanoma/drug therapy , Melanoma/mortality , Methotrexate/administration & dosage , Mouth Neoplasms/drug therapy , Mouth Neoplasms/mortality , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/veterinary , Oropharyngeal Neoplasms/drug therapy , Oropharyngeal Neoplasms/mortality , Survival Rate , Treatment Outcome
16.
J Am Acad Dermatol ; 27(5 Pt 1): 723-8, 1992 Nov.
Article in English | MEDLINE | ID: mdl-1430394

ABSTRACT

BACKGROUND: Basal cell carcinomas (BCCs) are usually treated with ablative procedures. A nonsurgical treatment alternative would be of value in selected patients. OBJECTIVE: We evaluated the safety and efficacy of a new preparation for intralesional sustained-release chemotherapy with MPI 5003, 5-Fluorouracil Therapeutic Implant, for treatment of BCCs. METHODS: Two doses of intralesional MPI 5003 (0.25 and 0.5 ml) were compared in a double-blind study of 20 patients with biopsy-proven BCC. One BCC per patient was treated weekly for up to 6 weeks and followed up monthly for 3 months until excisional biopsy for histologic examination. Before excision the cosmetic appearance of the test site was graded. RESULTS: Eighty percent of 10 BCCs treated with 0.5 ml of MPI 5003 had histologically confirmed cures as compared with 60% of 10 tumors treated with the lower dose (0.25 ml). Cosmetic assessments before excision were typically good to excellent. No systemic side effects occurred. CONCLUSION: Results indicate the potential of MPI 5003 for targeted local chemotherapy for BCC.


Subject(s)
Carcinoma, Basal Cell/drug therapy , Fluorouracil/administration & dosage , Skin Neoplasms/drug therapy , Adult , Aged , Carcinoma, Basal Cell/pathology , Double-Blind Method , Drug Carriers , Drug Implants , Female , Fluorouracil/adverse effects , Follow-Up Studies , Humans , Injections, Intralesional , Male , Middle Aged , Pilot Projects , Skin Neoplasms/pathology
18.
J Invest Dermatol ; 92(2): 210-6, 1989 Feb.
Article in English | MEDLINE | ID: mdl-2537364

ABSTRACT

1H nuclear magnetic resonance (NMR) spectroscopy was tested for its applicability in evaluating diseased skin. In order to explore potential spectral markers characteristic of diseased tissue, perchloric acid (PCA) extracts of psoriasis and malignant melanoma tissues were compared with normal skin, and changes in melanoma after heat treatment were monitored. In psoriatic plaque extract, the spectral peak intensity ratios of Glu: Ser, creatine: Gly, and taurine: Ala were approximately three-fold compared with symptom-free or normal skin, whereas Val: Leu/Ile was one-half the normal skin ratio. In melanoma extracts, the phosphorylcholine (PC)/glycerophosphorylcholine (GPC): Ala, Glu: Ser, and lactate: Ala ratios were five-, three-, and two-fold higher, respectively, than normal skin and the Val: Leu/Ile ratio was two-thirds of normal skin. With heat treatment, PC/GPC: Ala and Glu: Ser ratios decreased, whereas lactate: Ala and Val: Leu/Ile ratios increased three-fold and one-third, respectively. Results indicate that 1H NMR spectroscopy is a sufficiently sensitive technique to distinguish normal from diseased skin. The main attraction of this technique lies in the possibility of non-invasive study of various skin diseases, malignant transformation of benign tumors, and responses to treatment. Several methodologic problems remain to be resolved before a meaningful interpretation of in vivo observations becomes feasible. Correlation of in vivo and in vitro findings is an essential step toward this goal.


Subject(s)
Magnetic Resonance Spectroscopy , Skin Diseases/diagnosis , Adult , Animals , Chromatography, Gas , Female , Humans , Male , Melanoma/diagnosis , Mice , Mice, Nude , Protons , Skin Neoplasms/diagnosis , Spectrum Analysis
19.
Int J Dermatol ; 26(10): 660-6, 1987 Dec.
Article in English | MEDLINE | ID: mdl-2828256

ABSTRACT

Compounds related to the flavonoid group of natural products may have potential as antipsoriatic drugs. The dihydrochalcone phloretin, its glycoside derivative phloridzin, and the structurally related compound nordihydroguaiaretic acid (NDGA) were selected for study. Phloretin and NDGA strongly inhibited keratinocyte growth but had no effect on isoproterenol-stimulated adenylate cyclase; phloridzin had no effect on growth but potentiated the response of the enzyme. None had any effect on phosphodiesterase. Neither phloretin or phoridzin inhibited lipoxygenase or, surprisingly, decreased deoxyglucose transport. Phloretin and NDGA should be considered antipsoriatic agents.


Subject(s)
Adenylyl Cyclases/metabolism , Arachidonate 5-Lipoxygenase/metabolism , Arachidonate Lipoxygenases/metabolism , Catechols/pharmacology , Cell Division/drug effects , Hexoses/metabolism , Masoprocol/pharmacology , Phlorhizin/pharmacology , Skin/cytology , Cells, Cultured , Cyclic AMP/metabolism , DNA Replication/drug effects , Deoxyglucose/metabolism , Humans , Lipoxygenase Inhibitors , Phloretin/pharmacology
20.
Arch Dermatol ; 123(11): 1483-7, 1987 Nov.
Article in English | MEDLINE | ID: mdl-3314717

ABSTRACT

Seventy-two adult male patients were entered into a double-blind, placebo-controlled investigation using 2% to 3% topical minoxidil solution for androgenetic alopecia. Fifty-nine patients completed the initial 12 months, and continued to use 3% topical minoxidil solution in an open study design. Hair regrowth (as measured by hair counts and bald-area diameters) was noted in all treatment groups at four months, and appeared to peak at approximately 12 months. At 30 months, mean hair counts had decreased from the 12-months level, but remained elevated over baseline counts, while mean bald-area diameters returned to baseline. However, 70% of the patients who did continue to use the drug for 30 months had 50% or more hairs than when they originally started the drug therapy. A subset of patients appeared to sustain a continued increase in hair counts after 12 months. No systemic side effects were noted.


Subject(s)
Alopecia/drug therapy , Hair/growth & development , Minoxidil/administration & dosage , Administration, Topical , Adult , Clinical Trials as Topic , Double-Blind Method , Humans , Male , Minoxidil/therapeutic use , Random Allocation , Time Factors
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