isotretinoin and Colonic-Neoplasms

A relatively newer class of chemotherapy agents, known as the epidermal growth factor receptor inhibitors (EGF-RIs), is being used to treat advanced stages of solid tumors. Acneiform eruptions are a frequent adverse effect and one which has been associated with increased survival in some studies. We describe 3 patients who presented shortly after initiation of EGF-RI therapy. Characteristics included an absence of comedones, facial and truncal involvement, and a perifollicular lymphoneutrophilic infiltrate detected on biopsy. Lesion counts were reduced with topical adapalene and oral tetracyclines in two patients. Patient 3 had dramatic clearance with low-dose isotretinoin (20 mg daily) until completion of EGF-RI therapy. Acneiform eruptions are a common adverse reaction to EGF-RI therapy and can be treated with traditional acne therapy. This should not be considered a drug hypersensitivity eruption or allergy, and patients should continue therapy. For patients with severe eruptions, oral isotretinoin is a consideration.

Topics: Acne Vulgaris; Adapalene; Administration, Oral; Administration, Topical; Adult; Anti-Bacterial Agents; Antineoplastic Agents; Colonic Neoplasms; Dermatologic Agents; Dose-Response Relationship, Drug; ErbB Receptors; Humans; Isotretinoin; Lung Neoplasms; Male; Middle Aged; Minocycline; Naphthalenes

Combination of two differentiation agents such as phenylbutyrate (PB) and 13-cis-retinoic acid (CRA) has been shown to have an additive inhibitory effect on tumor growth in preclinical studies. In this report we explored the hypotheses that these "cytostatic" agents may have a greater antitumor activity in combination with "cytotoxic" compounds and their biological effect may be sequence-dependent.. The antitumor activity of combination of PB and CRA with paclitaxel (TX ) and doxorubicin (DOXO) on human prostate and colon carcinoma cell lines was assessed both in vitro and in vivo. The effect on cell cycle, apoptotic rate, cyclin expression and induction of p21 expression was also determined.. Following treatment of tumor cells with PB + CRA + TX or DOXO, inhibition of tumor cell growth was greatly enhanced as compared to PB + CRA, TX or DOXO alone, with >90% growth inhibition. However, when the cells were pretreated with PB + CRA followed by TX or DOXO, the enhanced inhibition was abolished suggesting a protective effect to this sequence. Interestingly treatment with PB + CRA restored sensitivity to DOXO in PC-3 human prostate cancer cell line. PB + CRA induced p21 expression and cell-cycle arrest in G1 phase, while TX and DOXO induced G2/M arrest. p21 and p53-deficient colon carcinoma cell lines were more sensitive to the effect of PB + CRA and TX as single agents and in combination, as compared to the wild type cells. When p21-deficient cells were pretreated with PB + CRA followed by TX the protective effect was still observed. Treatment of tumor cells with combination of these drugs induced cell cycle delay at multiple mitotic checkpoints before undergoing apoptosis. Tumor growth was significantly inhibited and delayed in animals treated with either TX or concomitantly with TX and PB + CRA as compared to control. Animals treated with all three agents demonstrated further growth inhibition or delay than the TX alone or PB + CRA arm.. These results suggest a rational therapeutic approach for combination of differentiation-inducing agents with cytotoxic drugs given concomitantly, but not sequentially.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma; Cell Cycle; Cell Differentiation; Cell Division; Cell Line, Tumor; Colonic Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Flow Cytometry; Humans; Isotretinoin; Male; Phenylbutyrates; Polymerase Chain Reaction; Prostatic Neoplasms

Aberrant crypts are aggregates of single to multiple colonic crypts evidencing hallmarks of dysplasia and may be the earliest detectable pathological lesions for colon cancer. The aberrant crypt assay has been developed in 2 protocols. In one, putative chemoprevention agents are tested for inhibitory effects when administered concomitantly with a carcinogen. In the other, the objective of this study, aberrant crypts were induced in F344 rats by parenteral injection of the colon carcinogen azoxymethane (AOM) and allowed to develop for 4 weeks, when an average of 90-100 aberrant crypt foci per colon were found in the methylene blue-stained colon. Then, during the second 4 weeks of the experiment, aberrant crypts were allowed to further develop to a frequency of > 150 foci per colon, a time when multi-crypt foci were observed. During this time we tested the inhibitory effects of 4 analgesic drugs and 2 differentiation agents for effects of aberrant crypt growth and development. We found the non-steroidal anti-inflammatory drugs piroxicam, aspirin and ibuprofen, but not acetaminophen, to be effective in suppressing aberrant crypt formation or the progression to foci of multiple aberrant crypts. Treatment with chemosuppressing agents 13-cis-retinoic acid (13-cRA) and 4-hydroxyphenretinamide (4-HPR), known differentiating agents, however, did suppress expansion of aberrant crypt foci, with 13-cRA being the much more potent agent.

Topics: Acetaminophen; Adenoma; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aspirin; Azoxymethane; Colonic Neoplasms; Drug Screening Assays, Antitumor; Fenretinide; Ibuprofen; Isotretinoin; Male; Piroxicam; Precancerous Conditions; Rats; Rats, Inbred F344

Topics: Acne Vulgaris; Adenocarcinoma; Colonic Neoplasms; Humans; Hypertrichosis; Isotretinoin; Male; Middle Aged; Paraneoplastic Syndromes; Tretinoin

The effect of 13-cis-retinoic acid (13-cis-RA) on 1,2-dimethylhydrazine (DMH)-induced colon cancer in male, random bred, Sprague-Dawley (S-D) and inbred Wister/Furth (W/Fu) rats and on isograft tumor growth and metastases in a Brown Norwegian (BN) X W/Fu F1 rat was studied. 13-cis-RA (300 mg/kg diet) was administered to S-D rats 1 week before commencing DMH injections and for the duration of the experiment. W/Fu rats received 13-cis-RA (10 mg/kg weight X 5 days) 6 weeks after DMH injection had begun and monthly thereafter. Primary tumors were detected by serial laparotomy under ether anesthesia in both strains. The time to tumor onset was significantly delayed in treated groups, S-D and W/Fu, P = 0.0339 and 0.0322, respectively (Mantel-Haenszel test), compared with placebo-treated controls. 13-cis-RA (15 mg/kg weight) administered 2 days before and for the duration of isograft tumor growth (DMH 2054, a well-differentiated mucin-producing colon adenocarcinoma that spontaneously metastasized to lung) had no effect on tumor growth or metastasis in the BN X W/Fu F1 rat. The findings suggest that the role of 13-cis-RA is in colon cancer prevention and not in its treatment either in an adjuvant or established setting.

Topics: Animals; Colonic Neoplasms; Dimethylhydrazines; Isotretinoin; Lung Neoplasms; Male; Rats; Tretinoin

The possible effect of oral 13 cis retinoic acid (13-cis-RA) on the carcinogenic process induced by 28 weekly s.c. injections of 1,2-dimethylhydrazine (DMH) in 34 Wistar rats was investigated. Using immunohistology, precancerous and cancerous stages were compared with the same stages induced by DMH without additional 13-cis-RA in 33 rats. M1 antigens, which characterize modifications in goblet-cell differentiation occurring early in rat colonic carcinogenesis, were used to investigate the possible effect of retinoids on differentiation during precancerous stages. From 3-20 weeks after the start of the experiment, no significant differences were observed in the timing of M1 antigens in the 2 groups of rats. It was also observed that 13-cis-RA had no effect on histological lesions associated with precancerous mucosa, nor on the occurrence of intestinal adenocarcinomas. Thus, under these conditions, oral administration of 13-cis-RA did not significantly inhibit precancerous or cancerous stages of intestinal carcinoma development.

Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Animals; Carcinogens; Colonic Neoplasms; Dimethylhydrazines; Female; Intestinal Neoplasms; Isotretinoin; Methylhydrazines; Neoplasm Metastasis; Neoplasms, Experimental; Precancerous Conditions; Rats; Rats, Inbred Strains; Tretinoin