Use of in vitro dose response effects to select antineoplastics for high-dose or regional administration regimens.

Abstract

Several preclinical and clinical studies have documented that dose or dose intensity of chemotherapeutic agents are important factors for response of patients' tumors. This finding has prompted empiric trials of certain chemotherapeutic agents in high-dose or regional administration treatment regimens. The present study was performed to identify agents that would be particularly good candidates for high-dose or regional administration regimens against particular types of tumors. Using a human tumor cloning technique, we constructed dose in vitro response lines for ten different chemotherapeutic agents against seven different histologic types of malignancies. Slopes of the lines indicated the agents with the greatest increases of in vitro response per increment in dose of the agent. Tumors against which the agents gave the steepest dose response lines included lymphoma, head and neck cancer, ovarian cancer, and small-cell lung cancer, while the dose response lines for non-small-cell lung cancer, breast cancer, and colon cancer were quite flat. Suggestions for clinical trials based on these findings include the use of high-dose melphalan for patients with lymphoma, head and neck, and ovarian cancer; the use of mitoxantrone in high-dose regimens for patients with breast cancer; high-dose cisplatin regimens for patients with small-cell lung cancer; high-dose bleomycin regimens for patients with non-small-cell lung and head and neck cancer; and regional perfusion of liver metastases from colorectal cancer with cisplatin. Prospective testing of high-dose or regional administration regimens suggested by this new model should indicate its use for prediction of the best agent to use in high-dose regimens against a particular tumor type.

“Decadose” Effects of Cisplatin on Squamous Cell Carcinoma of the Upper Aerodigestive Tract. I. Histoculture Experiments

“…In the case of cisplatin, there is evidence to suggest that this in vivo resistance can develop rapidly with as few as 1 or 2 exposures to the drug 3 . Using in vitro models, there is also evidence that for most tumors acquired cisplatin resistance is mild to moderate and can be overcome with drug concentrations 5 to 10 times greater than the therapeutic equivalent 1,4,5 . Teicher, et al 1 demonstrated a linear dose‐response relationship for a head and neck carcinoma cell line, which indicated that an additional cell kill of 10 × 2 logarithmic power occurred as a result of doubling the cisplatin dose 1 …”

A multicenter randomized phase II trial of granulocyte-colony stimulating factor-supported, platinum-based chemotherapy with flexible midcycle cisplatin administration in patients with advanced ovarian carcinoma

“…Although the introduction of cisplatin and the use of combination chemotherapy has improved response rates and survival compared with therapy using alkylating agents, this improvement had been modest 2. Retrospective analysis of published trials as well as in vitro studies had suggested that objective tumor response rates are increased with regimens that deliver greater platinum dose intensity 3, 4. However, the results of randomized trials addressing this question are controversial, with no clear evidence of superior results with the dose‐intense regimens and an increase in treatment‐related toxicity 5‐10…”

Sequential cycles of high-dose chemotherapy with dose escalation of carboplatin with or without paclitaxel supported by G-CSF mobilized peripheral blood progenitor cells: a phase I/II study in advanced ovarian cancer

“…7,8 According to in vitro studies, a minimum four-fold increase in dose intensity is necessary to overcome resistance to chemotherapy. [9][10][11] Single high-dose chemotherapy followed by stem cell rescue results in a four-fold or higher dose intensity compared to standard chemotherapy. This therapy yields remission rates between 50% and 80%, even in relapsed patients.…”