Optimal Therapeutic Protocols Research Articles

Photodynamic therapy using m-tetra(hydroxyphenyl) chlorin. An animal model.

To evaluate the potent photosensitizer m-tetra (hydroxyphenyl) chlorin (m-THPC) by using rabbits with cottontail rabbit papillomavirus-induced tumors and the canine larynx as model systems. Nonrandomized control trial. Division of ear, nose, and throat research at a tertiary care teaching hospital. Rabbits were used for relative retention ratio studies and tissue tolerance tests. Studies on the swelling of normal tissues in the larynx after photoactivation were done with canines. Animals were injected with 0.3 mg/kg of m-THPC. At varying intervals, tissues were exposed to 652 nm of light. Outcome measures consisted of four elements: (1) decay of plasma concentration over time, (2) interval to and duration of maximal ratio between drug concentration in normal tissue and tumor, (3) maximal permissible light exposure to normal tissue (skin and laryngeal mucosa) at an optimal interval, and (4) efficacy--number of tumors with partial and complete response. The largest papilloma to skin ratio (10:1) occurred 4 to 8 days after drug injection. The rabbit skin damage threshold was 40 to 60 J/cm2 at 6 days. The canine laryngeal edema and erythema thresholds were 50 to 70 J. A 75% cure rate of papillomas was achieved with tumors that were less than 100 mm2 in area at light doses that ranged from 25 to 75 J/cm2. m-THPC shows efficacy in treating papilloma virus-induced tumors. We present a protocol for rapid optimization of the factors required for tumor destruction with minimal normal tissue damage, thus permitting determination of an optimal therapeutic protocol for any photosensitizer.

Experimental Studies of Cis‐Diamminedichloroplatinum (II) and Cis‐Diammine‐1, 1‐Cyclobutandicarboxylate Platinum (II) Combination Therapy for Malignant Gynecologic Tumors

A comparative exploration of the optimum regimens for CDDP and CBDCA therapy of malignant gynecologic tumors was conducted using both in vitro and in vivo approaches. In vitro, CBDCA exerted less cytotoxicity with short-time exposure, but over a longer time was as effective as CDDP. Pharmacokinetic studies demonstrated rapid binding of all administered CDDP to protein, while free-Pt was seen for many hours after CBDCA treatment. These results suggest that the gradual action of CBDCA leads to the appearance of cytotoxicity, and that in clinical use CBDCA affects the tumor cells for a long time. To increase the active dose of platinum, treatment with high doses of CDDP, or CBDCA, or the two platinum compounds with different pharmacokinetic behavior in combination, was designed for optimal therapeutic protocols. In the CDDP-alone treatment animals, renal toxicity was apparent with the increase in dose level. However, in the combination CDDP-and-CBDCA treatment animals, the total dose level could be elevated without causing toxicity. In the drug-sensitivity test, the combination therapy also exerted strong activity. The fact that the combined CDDP-and-CBDCA therapy appears to exert greater anti-tumor effects without any increment in adverse toxicity of these drugs is clinically promising.

Antitumor response to recombinant murine interferon gamma correlates with enhanced immune function of organ-associated, but not recirculating cytolytic T lymphocytes and macrophages.

The mechanism of therapeutic activity for recombinant murine interferon-gamma (rMu IFN gamma) in the treatment of metastatic disease was investigated by comparing effector cell augmentation with therapeutic activity in mice bearing experimental lung metastases (B16-BL6 melanoma). Effector cell functions in spleen, peripheral blood, and lung (the tumor-bearing organ) were tested after 1 week and 3 weeks of rMu IFN gamma administration (i.v. three times per week). Natural killer (NK), lymphokine-activated killer (LAK), cytolytic T lymphocyte (CTL) activities against specific and nonspecific targets, and macrophage tumoristatic activity were measured. rMu IFN gamma demonstrated immunomodulatory activity in most assays of immune function. The optimal therapeutic protocol of rMu IFN gamma (2.5 x 10(6) U/kg, three times per week) prolonged survival and decreased the number of pulmonary metastatic foci. This therapeutic activity was correlated with specific CTL activity from pulmonary parenchymal mononuclear cells (PPMC), but not from spleen or blood. Macrophage tumoristatic activity in PPMC also correlated with therapeutic activity, but activity in alveolar macrophages did not. However, therapeutic activity did not correlate with NK or LAK activity at any site. These results demonstrate that the optimal therapeutic protocol is the same as the optimal immunomodulatory dose for pulmonary CTL and macrophage activities. Furthermore, while immunological monitoring may help to optimize treatment protocols, current monitoring procedures that use readily accessible sites, particularly peripheral blood, may not accurately predict the therapeutic efficacy of biological response modifiers in clinical trials.

Tumor models and approaches to the development of optimal therapeutic protocols

Tumor models and approaches to the development of optimal therapeutic protocols

Lymphocytes bearing both T and B markers in lymphoproliferative disorders.

The appearance of dual-marked (D) lymphocytes, i.e. lymphocytes having both T and B markers, was investigated in patients with acute (ALL) and chronic lymphocytic leukaemia (CLL) as well as with non-Hodgkin's lymphoma (NHL). E-rosette and immunobead-rosette techniques were combined and simultaneously administered, and the combination was found to be simple, fast and reproducible. D cells could be detected also in normal peripheral blood, however, only in a low percentage. In the blood of 4 patients suffering from ALL, in 2 with CLL and in 1 with NHL the number of D cells were increased significantly. In ALL the relative number of these cells decreased during remission and increased in relapses; thus the determination of the relative frequency of D cells might have prognostic value and could be useful in the choice of an optimal therapeutic protocol.

Cyclophosphamide/X-ray: Combined mode preparation for transplantation therapy

Use of total body irradiation (TBI) and/or chemotherapy as a preparation for marrow transplantation in the treatment of leukemia has been only moderately successful in the clinic. Although cyclophosphamide (CY) has shown promise as a marrow ablative agent, leukemia relapses are often found, and optimal therapeutic protocols have not been established. Our transplantation therapy studies of murine leukemia with parental recipients and hybrid donors provide an excellent model for research aimed at improved survival of human transplant patients. Utilizing a murine leukemia induced by a virus, various doses of CY in combination with sub-lethal irradiation were compared to determine the optimal pretreatment for transplantation therapy. Both normal and leukemic mice were engrafted with virus resistant, histocompatible marrow following these preparations, then monitored for survival and long term effects. Leukemic mice were also evaluated for pluripotent as well as myeloid committed stem cells as a measure of the effectiveness of the treatment in elimination of leukemic cells. Leukemic groups were also compared for the percentage and time of leukemia relapse. All CY/X-ray combinations were more effective in elimination of stem cell populations than supralethal TBI alone. However, the best survival was obtained with lethal TBI alone or low dose CY in combination with 550 R.