Chemosensitizing Agent Research Articles

Rhodamine-123 as a new photochemosensitizing agent with the argon laser: "nonthermal" and thermal effects on human squamous carcinoma cells in vitro.

A human squamous carcinoma cell line (P3) was first exposed to a nontoxic dose of Rhodamine-123 (1 microgram/ml for 1 hour), then subjected to treatment with a single mode argon laser at 514.5 nm. The temperature and energy levels delivered to the target cells were determined by a reproducible method of dosimetry. Cell viability was assessed by the trypan blue exclusion test. Cell duplication and DNA synthesis were measured by the incorporation of 3H-thymidine at 6 and 24 hours post-treatment. The results indicate that Rhodamine-123 at nontoxic doses of 1 microgram/ml enhanced the tumoricidal effects of the argon laser at reduced temperatures as low as 40 degrees C. Furthermore, at physiological temperature ranges as low as 28 to 39 degrees C, an immediate and/or delayed inhibition of cell duplication was demonstrated, while cell viability was not affected. These observations, suggest that Rhodamine-123 can be used effectively as a chemosensitizing agent in the treatment of human tumor cells with the argon laser at 514.5 nm. This new technique of tumor cell targeting by Rhodamine sensitization and specific laser treatment may offer real advantages without the extreme photosensitivity associated with hematoporphyrin derivatives.

N-methylformamide-mediated enhancement of in vitro tumor cell chemosensitivity.

The effects of the differentiation-inducing polar solvent N-methylformamide (NMF) on the in vitro response of murine hepatocarcinoma (HCa-1) cells to 1,3-bis(2-chloroethyl)-1-nitrosourea, cis-diamminedichloroplatinum (II), and melphalan were investigated using the sister chromatid exchange (SCE) and cell survival assays. When cells were exposed to 1.25% NMF, cell culture doubling time increased from 12 to 43 h and cell volume increased from 940 microns 3 to 1440 microns 3. Growth of HCa-1 cells in NMF for 96 h before drug treatment enhanced the SCEs induced by each of the three chemotherapeutic agents. For each drug, maximum enhancement occurred after 72 h of NMF pretreatment, and the enhancement was eliminated 48 h after NMF was removed. Pretreatment with 1.25% NMF for 96 h also enhanced the cell kill induced by each drug. NMF exposure modified primarily the low-dose shoulder region of each drug cell survival curve. The data indicate that NMF is an effective chemosensitizing agent for HCa-1 cells in vitro and suggest that NMF may provide clinical benefits when administered in combination with antineoplastic drugs.

Preliminary evaluation of isocyanate-generating nitroheterocycles as chemosensitizers, radiosensitizers and hypoxic cell cytotoxic agents

Nitro-compounds containing an acetylated acetohydroxamic acid side chain in the N-1 position of a 5-membered ring nitrogen heterocycle have been synthesized. These compounds, which can generate isocyanates via a Lossen rearrangement, were evaluated in order to test the hypothesis that they may be effective radiation and chemo-sensitizing agents by nature of their isocyanate-associated carbamoylating potential. Evaluation of one such compound, DJW-77 (1(O-Acetyl-Acetohydroxamic acid)-3-nitropyrazole) as a radiation sensitizer, chemosensitizer and hypoxic cell toxin is reported. In vitro DJW-77 demonstrates a potent selective cytotoxicity toward hypoxic EMT-6 tumor cells, is an effective potentiator of CCNU toxicity and is comparable to MISO with respect to its radiation-sensitizing potential. The activity of the drug is eliminated under aerobic conditions. To test the hypothesis that the activity of DJW-77 is related to isocyanate generation, the non-acetylated analog of DJW-77 (which does not directly undergo the Lessen rearrangement) and the parent 3-nitropyrazole ring structure were evaluated. Neither compound enhanced CCNU toxicity, and on an equimolar basis were inferior to DJW-77 as radiation sensitizers. While the non-acetylated analog was cytotoxic to hypoxic cells, relative to DJW-77 this activity was substantially reduced. These studies indicate that the addition of a side chain capable of generating an isocyanate can enhance the cytotoxicity and sensitizing activity of nitroheterocycles.